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During the transition&#44; polarized immotile epithelial cells change their morphology to motile mesenchymal cells&#44; assuming increased motility and invasion abilities&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> This transition is also characterized by a reduction in epithelial markers that enhance cell-cell contact&#44; such as E-cadherin&#44; and an increase in mesenchymal markers&#44; such as vimentin and N-cadherin&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Various signaling pathways have been reported to trigger EMT&#46; Forkhead transcription factor FOXQ1 was found to induce EMT in breast cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">6</span></a> It was also reported to mediate the crosstalk between TGF-&#946; and Wnt signaling pathways in colorectal cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a> In lung cancer particularly&#44; FOXQ1 expression contributes to poor prognosis&#44; promotes EMT&#44; and increases chemo-sensitivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">MicroRNAs &#40;miRNAs or miRs&#41; are small non-coding RNA molecules&#44; usually 20&#8211;25 nucleotides long&#46; They recognize specific complementary sequences commonly found in the 3&#8242;-untranslated region &#40;UTR&#41; of target mRNAs&#44; either repressing translation or degrading the target mRNAs&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">10&#44;11</span></a> MiRNAs are involved in the EMT of many types of cancers&#44; including lung cancer&#44; altering the expression of oncogenes or tumor suppressor genes&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> For example&#44; miR-19 was found to trigger EMT and promote migration and invasion of lung cancer cell lines A549 and HCC827&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> In contrast&#44; other miRNAs inhibit this process&#46; One such miRNA is miR-129&#44; which was reported to antagonize EMT and metastasis in non-small cell lung cancer by down-regulating MCRS1&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a> Similarly&#44; low expression of miR-30c was also found to negatively affect the EMT of lung cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a> However&#44; the exact role of miR-133 in regulating EMT in lung cancer remains unclear&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In our current study&#44; we aimed to investigate whether miR-133 is involved in the regulation of EMT in lung cancer cells&#44; and the possible underlying mechanisms of this phenomenon&#46; We found that miR-133 was down-regulated in both A549 and HCC827 human lung cancer cell lines&#44; and miR-133 directly targeted and down-regulated FOXQ1 expression&#46; More importantly&#44; miR-133 expression reversed EMT features&#44; inhibiting the migratory and invasive abilities of lung cancer cells&#46; MiR-133 could serve as a novel molecular therapeutic tool for reversing EMT in lung cancer&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Cell lines&#44; Antibodies and MicroRNAs</span><p id="par0025" class="elsevierStylePara elsevierViewall">The human normal lung cell lines CCD-19Lu and MRC-9&#44; and human lung cancer cell lines A549 and HCC827 were obtained from the American Type Culture Collection &#40;ATCC&#41;&#46; Cells were maintained in complete medium with high-glucose RPMI-DMEM &#40;Hyclone&#59; GE Healthcare&#41; and 10&#37; fetal bovine serum &#40;FBS&#59; Gibco&#41;&#44; at 37&#176;<span class="elsevierStyleHsp" style=""></span>C in a humidified atmosphere containing 5&#37; CO<span class="elsevierStyleInf">2</span>&#46; Antibodies against FOXQ1 &#40;ab194564&#41;&#44; TGF-&#946; &#40;ab9758&#41;&#44; total Smad2&#47;3 &#40;ab63672&#41;&#44; phospho-Smad2&#47;3 &#40;ab63399&#41;&#44; E-cadherin &#40;ab76055&#41;&#44; N-cadherin &#40;ab18203&#41;&#44; vimentin &#40;ab92547&#41;&#44; and GAPDH &#40;ab181602&#41; were all purchased from Abcam&#46; Hsa-miR-133 mirVana miRNA mimic &#40;MC10029&#41; and mirVana miRNA negative control &#40;4464061&#41; were both purchased from Life Technologies&#46; Transfection into cell lines was performed following manufacturer&#39;s instructions&#46; After transfection&#44; cells were incubated for another 48<span class="elsevierStyleHsp" style=""></span>h before being subjected to other experimental assays&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Western Blot</span><p id="par0030" class="elsevierStylePara elsevierViewall">Cells were seeded in 6-well plates at a density of 1&#215;10<span class="elsevierStyleSup">6</span> cells&#47;well with 2<span class="elsevierStyleHsp" style=""></span>ml complete DMEM medium&#46; Twenty-four hours after transfection of either hsa-miR-133 or negative control&#44; total protein was extracted using RIPA buffer &#40;50<span class="elsevierStyleHsp" style=""></span>mM Tris&#8211;HCl&#44; pH 7&#46;4&#44; 150<span class="elsevierStyleHsp" style=""></span>mM NaCl&#44; 1<span class="elsevierStyleHsp" style=""></span>mM EDTA&#44; 1&#37; Triton X-100&#44; 1&#37; sodium deoxycholate&#44; 0&#46;1&#37; SDS&#44; and protease inhibitors&#41;&#46; The protein concentration was determined using the BCA assay&#46; Equal quantities of proteins were separated by SDS-PAGE and transferred to nitrocellulose membrane using a semi-dry transfer unit &#40;Bio-Rad Laboratories&#41;&#46; The membrane was then immersed in blocking buffer &#40;PBS&#44; 0&#46;1&#37; Tween-20&#41; with 5&#37; nonfat milk for 20<span class="elsevierStyleHsp" style=""></span>min and then incubated with appropriate primary antibodies overnight at 4<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; After washing with blocking buffer&#44; blots were incubated with HRP-conjugated secondary antibody &#40;Life Technologies&#41; at room temperature for 1<span class="elsevierStyleHsp" style=""></span>h&#44; washed again with blocking buffer&#44; and visualized using Luminata Forte Western HRP Substrate &#40;EMD Millipore&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Wound-Healing Assay</span><p id="par0035" class="elsevierStylePara elsevierViewall">A total of 1&#215;10<span class="elsevierStyleSup">5</span> cells transfected with miRNA negative control or hsa-miR-133 were seeded into a 6-well plate after transfection&#46; A linear wound was carefully made with a 100<span class="elsevierStyleHsp" style=""></span>&#956;l sterile pipette tip across the confluent cell monolayer&#44; and the cell debris was removed by washing with PBS&#46; The migrated distance of the growing edge on wounded monolayers was measured at 24<span class="elsevierStyleHsp" style=""></span>h after being wounded&#44; and migration rate was expressed as a percentage relative to respective controls&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Cell invasion Assay</span><p id="par0040" class="elsevierStylePara elsevierViewall">Cell invasion assay was performed in a 24-well plate with 8<span class="elsevierStyleHsp" style=""></span>&#956;m pore size chamber inserts &#40;BD Biosciences&#41;&#46; A total of 1&#215;10<span class="elsevierStyleSup">5</span> cells transfected with miRNA negative control or hsa-miR-133 were placed into the upper chamber per well with the Matrigel-coated membrane&#44; diluted with serum-free culture medium&#46; The lower compartment was filled with 500<span class="elsevierStyleHsp" style=""></span>&#956;l of medium containing 10&#37; FBS to attract cells&#46; The cells were incubated at 37<span class="elsevierStyleHsp" style=""></span>&#176;C in a 5&#37; CO<span class="elsevierStyleInf">2</span> humidified incubator for 24<span class="elsevierStyleHsp" style=""></span>h&#44; followed by exposure to 20<span class="elsevierStyleHsp" style=""></span>&#956;M 5-ethynyl-2&#8242;-deoxyuridine &#40;EdU&#41; for an additional 4<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; Membrane inserts were removed from the plate and stained using the ENU kit &#40;Invitrogen&#41;&#46; The cells were counted under six random microscopic fields for each well&#44; and invasion rate was expressed as a percentage relative to respective controls&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Cell Attachment and Detachment Assay</span><p id="par0045" class="elsevierStylePara elsevierViewall">The cells were seeded in a 24-well plate &#40;1&#215;10<span class="elsevierStyleSup">5</span> cells&#47;well&#41;&#46; Briefly&#44; for attachment assay&#44; after 1<span class="elsevierStyleHsp" style=""></span>h incubation&#44; non-attached cells were washed twice with PBS&#44; and the attached cells were counted after trypsinization&#46; The attachment rate was expressed as percentage of cell numbers of the attached cells to total cells&#44; and normalized to respective control&#46; For the detachment assay&#44; the cells were detached with 0&#46;05&#37; trypsin for 3<span class="elsevierStyleHsp" style=""></span>min and counted after the seeded cells were incubated 24<span class="elsevierStyleHsp" style=""></span>h&#46; The remaining attached cells were further trypsinized with 0&#46;25&#37; trypsin and counted&#46; Cells detachment rate was expressed as a percentage of the detached cells to total cells&#44; and normalized to respective control&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical Analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">All values were presented as mean&#177;standard error mean &#40;SEM&#41;&#46; A 2-tailed Student&#39;s <span class="elsevierStyleItalic">t</span>-test was used to establish significant differences between groups&#46; Data were determined to be statistically different when <span class="elsevierStyleItalic">P</span> was &#60;&#46;05&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">MiR-133 is Down-regulated in Lung Cancer Cell Lines</span><p id="par0055" class="elsevierStylePara elsevierViewall">We found that the miR-133 sequence has a putative binding site on the 3&#8242;-UTR of FOXQ1 mRNA&#44; using the microRNA&#46;org resource&#46; Moreover using RT-PCR&#44; upon examination of its expression in two human lung cancer cell lines A549 and HCC827&#44; we found miR-133 levels were significantly lower than in two normal lung cell lines CCD-19Lu and MRC-9&#46; MiR-133 levels in CCD-19Lu and MRC-9 were similar&#44; whereas in A549 it was down-regulated to approximately 30&#37; of the normal cell lines&#44; and in HCC827 to about 40&#37; of the normal cell lines&#46; These results suggested that&#44; compared with normal human lung cells&#44; miR-133 was significantly down-regulated in lung cancer cell lines&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">MiR-133 Directly Targets 3&#8242;-UTR of FOXQ1</span><p id="par0060" class="elsevierStylePara elsevierViewall">We next validated the putative binding site of miR-133 on the 3&#8242;-UTR of FOXQ1&#44; using a luciferase reporter assay&#46; The sequences from wild type &#40;WT-Luc&#41; 3&#8242;-UTR of FOXQ1 mRNA and its mutated version &#40;mut-Luc&#41; were fused to the downstream of luciferase ORF&#44; respectively&#46; The two luciferase constructs were then separately transfected into both A549 and HCC827 cells&#44; together with either miRNA negative control or miR-133 mimic&#46; The luciferase reporter activity was then assessed&#46; As a result&#44; miR-133 dramatically reduced WT-Luc activity to approximately 30&#37; of the control transfected experiments&#44; consistently in both A549 and HCC827 cell lines&#46; On the other hand&#44; activity of mut-Luc was largely unaffected in either miR-133 or control miRNA transfected cells&#46; The complementary sequences on FOXQ1 3&#8242;-UTR were then a direct target of miR-133&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">MiR-133 Down-regulates Expressions of FOXQ1 and TGF-&#946; in Lung Cancer Cell Lines</span><p id="par0065" class="elsevierStylePara elsevierViewall">We continued to determine whether FOXQ1 was indeed an <span class="elsevierStyleItalic">in vivo</span> target of miR-133&#46; MiR-133 and a negative miRNA control were transfected into both A549 and HCC827 cells&#44; which were then subjected to RT-PCR to examine FOXQ1 levels in mRNA&#46; Levels of miR-133 in both A549 and HCC827 cells were indeed greatly increased upon transfection&#46; Compared with control miRNA transfections&#44; miR-133 significantly reduced FOXQ1 messenger levels in both lung cancer cell lines examined &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#44; clearly indicating that FOXQ1 mRNA is a <span class="elsevierStyleItalic">bona fide</span> target of miR-133&#46; Using anti-FOXQ1antibody&#44; we confirmed that its protein level was also markedly reduced in miR-133&#44; but not in control transfected cells &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Other authors have reported that FOXQ1 could promote the expression of TGF-&#946;&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> and was involved in the crosstalk between TGF-&#946; and Wnt signaling pathways in the progression of colorectal cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a> We were curious to investigate whether a similar correlation also existed between these two genes in lung cancer&#46; Interestingly&#44; down-regulation of FOXQ1 by miR-133 transfection also greatly reduced TGF-&#946; expressions in both lung cancer cell lines &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B and D&#41;&#44; suggesting that FOXQ1 and TGF-&#946; are both likely to be involved in tumorigenesis of lung cancer&#46; More importantly&#44; we found that in both lung cancer cell lines A549 and HCC827&#44; miR-133 expression resulted in a significant inhibition of TGF-&#946; pathway&#44; as indicated by reduced phosphorylation of Smad2&#47;3 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#44; both of which are downstream effectors of the TGF-&#946; pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> Of note&#44; we further confirmed that the regulation of TGF-&#946; pathway by miR-133 was indeed mediated through FOXQ1&#44; since in a co-transfection experiment using both miR-133 and a plasmid expressing FOXQ1 without its 3&#8242;-UTR&#44; TGF-&#946; level was also upregulated upon FOXQ1 expression&#44; even in the presence of miR-133 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#8211;D&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">MiR-133 Inhibits Migration and Invasion of Lung Cancer Cells</span><p id="par0075" class="elsevierStylePara elsevierViewall">FOXQ1 is a marker for metastasis and poor prognosis of lung cancer&#44;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">8&#44;9</span></a> so introducing miR-133 to down-regulate FOXQ1 should inhibit the migration and invasion of lung cancer cells&#46; To test this hypothesis&#44; we performed wound-healing and cell invasion assays in both miR-133 and control miRNA-transfected A549 and HCC827 cells&#46; As expected&#44; both cell lines exhibited significantly reduced migration rate after transfection of miR-133&#44; compared with control experiments &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A and B&#41;&#46; Moreover&#44; in a cell invasion assay&#44; miR-133 also consistently reduced the invasion rates of both A549 and HCC827 cells&#44; compared with control transfected experiments &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>C and D&#41;&#46; Taken together&#44; the above results strongly demonstrated the role of miR-133 in inhibiting lung cancer tumorigenesis&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">MiR-133 Inhibits Epithelial&#8211;Mesenchymal Transition &#40;EMT&#41; of Lung Cancer Cells</span><p id="par0080" class="elsevierStylePara elsevierViewall">During the wound-healing and cell invasion assays&#44; we often saw a morphological change in cells after transfection with miR-133&#46; Both A549 and HCC827 cells initially displayed elongated and fibroblastoid morphology&#44; whereas upon miR133 transfection both cell lines assumed rounded cell shapes &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#41;&#44; suggesting a loss of EMT phenotype&#46; During transition&#44; epithelial cells at the primary tumor site acquire the mesenchymal phenotype&#44; resulting in enhanced invasion and metastasis&#44; spreading through the blood stream to reach secondary tissues&#46; To confirm this observation&#44; we performed cell attachment and detachment assays in the two lung cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B and C&#44; miR-133 significantly reduced attachment and detachment rates of both A549 and HCC827 cells&#44; compared with control transfected cells&#46; These results confirmed the loss of EMT features at the cell morphological level&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">At the molecular level&#44; EMT is characterized by reduced epithelial marker E-cadherin and increased mesenchymal marker vimentin&#46; Accordingly&#44; we went on to assess if the same shift in EMT phenomena could also be observed at the molecular level&#46; As expected&#44; miR-133 increased E-cadherin expression&#44; but reduced vimentin and N-cadherin expressions&#44; compared with control transfected cells &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>D&#41;&#44; which clearly demonstrated a reverse of EMT phenotype at the protein level&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Increasing numbers of studies have demonstrated the essential roles of different miRNAs in the tumorigenesis of lung cancer&#46; An understanding of the abnormal expression patterns of miRNAs in lung cancer cells&#44; as well as the underlying molecular programs&#44; could contribute to the development of new clinical therapies in the treatment of lung cancer&#46; In this study&#44; we have demonstrated that miR-133 was down-regulated in two human lung cancer cell lines A549 and HCC827&#44; compared to normal lung cell lines CCD-19Lu and MRC-9&#46; Interestingly&#44; <span class="elsevierStyleItalic">in silico</span> analysis showed that miR-133 has a putative binding site on the 3&#8242;-UTR of FOXQ1 mRNA&#46; Using a luciferase reporter assay&#44; we confirmed that the 3&#8242;-UTR sequence was a direct target of miR-133&#46; Furthermore&#44; by reintroducing miR-133 expression into the A549 and HCC827 lung cancer cell lines&#44; we found both mRNA and protein levels of FOXQ1 were consistently reduced&#44; suggesting that FOXQ1 expression was indeed repressed by miR-133 <span class="elsevierStyleItalic">in vivo</span>&#46; On the other hand&#44; expression of TGF-&#946; was also down-regulated by miR-133 transfection&#46; This finding was consistent with a previous report which suggests that it is a downstream effector of FOXQ1&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> Moreover&#44; miR-133 expression significantly reduced the migration and invasion of lung cancer cells&#44; probably through EMT inhibition&#44; as evidenced by a prominent elevation of epithelial marker E-cadherin and reduction of mesenchymal markers N-cadherin and vimentin&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Recent studies have highlighted the important roles of miRNAs in the EMT of cancer cells&#46; For example&#44; the miR-134&#47;487b&#47;665 cluster regulates TGF-&#946; mediated EMT by targeting membrane-associated guanylate kinase inverted 2 in lung cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a> Additionally&#44; miR-125b&#47;489 was found to regulate EMT pathway in breast cancer&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">19&#44;20</span></a> Down-regulation of miR-200c was found to be responsible for acquired resistance to EGFR inhibitors by manifesting EMT features&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> Moreover&#44; miR-216a&#47;217 was found to induce EMT by targeting PTEN and Smad7 in liver cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Emerging studies have highlighted the role of miR-133 in several types of human cancers&#46; It functions as a tumor suppressor by targeting IGF-1R in hepatocellular carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a> In colorectal cancer&#44; ectopic expression of miR-133 significantly suppressed cancer growth both <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#44; by targeting E3-ubiquitin protein ligase&#44; thereby increasing p53 expression&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">24</span></a> Moreover&#44; miR-133 was also widely down-regulated in several gastric cancer cell lines&#44; where its re-expression was found to repress CDC42-PAK signaling pathway and lead to inhibited cancer cell migration and invasion&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">25</span></a> Quite a few recent studies have consistently reported that miR-133 was also able to directly target epidermal growth factor receptor &#40;EGFR&#41; in prostate cancer&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a> bladder cancer&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a> gastric cancer&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">28</span></a> and glioblastoma multiforme&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">29</span></a> inhibiting proliferation&#44; migration&#44; and invasion of these cancer cells&#46; Together&#44; all the above studies suggest that miR-133 plays a critical and complex role in regulating progression of different human cancers by targeting different signaling pathways&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In conclusion&#44; our study is the first report implicating miR-133 in the EMT of lung cancer&#46; As EMT is commonly associated with aggressiveness of cancer cells&#44; including migration and invasion&#44; inhibiting or reversing this transition could lead to new therapeutic approaches in the treatment of cancer&#46; In this context&#44; we found that miR-133 could reverse the EMT of lung cancer cell lines A549 and HCC827&#44; which may explain why miR-133 could significantly inhibit the migration and invasion of the lung cancer cells&#46; Our results suggest that miR-133&#44; by inhibiting the epithelial&#8211;mesenchymal transition&#44; may have a role as a potential molecular therapeutic tool in the treatment of lung cancer&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Author Contributions</span><p id="par0110" class="elsevierStylePara elsevierViewall">All authors participated in the design and interpretation of the studies&#44; analysis of the data and review of the manuscript&#46; Bo Xiao&#44; Huazhen Liu&#44; and Zeyun Gu conducted the experiments and Bo Xiao and Cheng Ji wrote the manuscript&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Funding</span><p id="par0115" class="elsevierStylePara elsevierViewall">This work was supported by <span class="elsevierStyleGrantSponsor" id="gs1">National Natural Science Foundation of China</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs1">31300969</span>&#41;&#44; <span class="elsevierStyleGrantSponsor" id="gs2">Natural Science Foundation of Jiangsu Province</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs2">BK20130302</span>&#41; and <span class="elsevierStyleGrantSponsor" id="gs3">China Postdoctoral Science Foundation</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs3">2013M540461</span> and <span class="elsevierStyleGrantNumber" refid="gs3">2013M541717</span>&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conflict of Interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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              "titulo" => "Introducci&#243;n"
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              "titulo" => "Cell lines&#44; Antibodies and MicroRNAs"
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              "titulo" => "Western Blot"
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              "titulo" => "MiR-133 is Down-regulated in Lung Cancer Cell Lines"
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              "titulo" => "MiR-133 Directly Targets 3&#8242;-UTR of FOXQ1"
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              "titulo" => "MiR-133 Down-regulates Expressions of FOXQ1 and TGF-&#946; in Lung Cancer Cell Lines"
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              "titulo" => "MiR-133 Inhibits Migration and Invasion of Lung Cancer Cells"
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              "titulo" => "MiR-133 Inhibits Epithelial&#8211;Mesenchymal Transition &#40;EMT&#41; of Lung Cancer Cells"
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          "titulo" => "Discussion"
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          "titulo" => "Author Contributions"
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          "titulo" => "References"
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    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2015-09-16"
    "fechaAceptado" => "2015-10-28"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec739876"
          "palabras" => array:5 [
            0 => "Lung cancer"
            1 => "MicroRNA-133"
            2 => "FOXQ1"
            3 => "TGF-&#946;"
            4 => "Epithelial&#8211;mesenchymal transition"
          ]
        ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec739875"
          "palabras" => array:5 [
            0 => "C&#225;ncer de pulm&#243;n"
            1 => "MicroARN-133"
            2 => "FOXQ1"
            3 => "TGF-&#946;"
            4 => "Transici&#243;n epitelio-mesenquimatosa"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">MicroRNA &#40;miR&#41; was implicated in the tumorigenesis of many types of cancer&#44; but no study was conducted on the exact role of miR-133 in lung cancer&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We have identified miR-133 as a putative regulator of FOXQ1 expression&#44; and investigated the potential involvement of miR-133 in the migration and invasion of lung cancer cells&#44; as well as the underlying molecular mechanism&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">MiR-133 directly targeted and down-regulated FOXQ1 expression&#44; which in turn reduced TGF-&#946; level&#46; MiR-133 was down-regulated in lung cancer cell lines A549 and HCC827&#44; and its re-expression significantly inhibited the migration and invasion of the lung cancer cells&#46; Further investigation revealed that this inhibition was caused by reversing the epithelial&#8211;mesenchymal transition&#44; evidenced by miR-133 induced elevation of epithelial marker E-cadherin&#44; and reduction of mesenchymal marker Vimentin&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Our study is the first to identify miR-133 as a biomarker for lung cancer&#46; It functions to down-regulate FOXQ1&#44; and inhibit epithelial&#8211;mesenchymal transition&#44; which antagonizes lung cancer tumorigenesis&#46; Therefore our data support the role of miR-133 as a potential molecular therapeutic tool in treating lung cancer&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El microARN &#40;miR&#41; se ha relacionado con la g&#233;nesis tumoral en muchos tipos de c&#225;ncer&#44; pero ning&#250;n estudio ha examinado el rol exacto del miR-133 en el c&#225;ncer de pulm&#243;n&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Identificamos el miR-133 como posible regulador de la expresi&#243;n de la FOXQ1 e investigamos la posible implicaci&#243;n del miR-133 en la migraci&#243;n y la invasi&#243;n de c&#233;lulas de c&#225;ncer de pulm&#243;n&#44; y el mecanismo molecular subyacente&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El miR-133 se dirigi&#243; directamente y redujo la expresi&#243;n de la FOXQ1&#44; que a su vez redujo la concentraci&#243;n de TGF-&#946;&#46; El miR-133 disminuy&#243; en l&#237;neas celulares de c&#225;ncer de pulm&#243;n A549 y HCC827&#44; y su reexpresi&#243;n inhibi&#243; significativamente la migraci&#243;n y la invasi&#243;n de c&#233;lulas de c&#225;ncer de pulm&#243;n&#46; Investigaciones subsiguientes revelaron que dicha inhibici&#243;n estaba provocada por una inversi&#243;n de la transici&#243;n epitelio-mesenquimatosa&#44; constatada por una elevaci&#243;n del marcador epitelial E-cadherina inducida por el miR-133 y una reducci&#243;n del marcador vimentina&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Nuestro estudio es el primero que ha identificado el miR-133 como biomarcador del c&#225;ncer de pulm&#243;n&#46; Su funci&#243;n es reducir la FOXQ1 e inhibir la transici&#243;n epitelio-mesenquimatosa&#44; la cual antagoniza la g&#233;nesis tumoral en el c&#225;ncer de pulm&#243;n&#46; Por consiguiente&#44; nuestros datos respaldan el papel del miR-133 como posible instrumento terap&#233;utico molecular en el tratamiento del c&#225;ncer de pulm&#243;n&#46;</p></span>"
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            "titulo" => "M&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0040"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Xiao B&#44; Liu H&#44; Gu Z&#44; Ji C&#46; La expresi&#243;n de microARN-133 inhibe la transici&#243;n epitelio-mesenquimatosa en las c&#233;lulas del c&#225;ncer de pulm&#243;n apuntando directamente al FOXQ1&#46; Arch Bronconeumol&#46; 2016&#59;52&#58;505&#8211;511&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">FOXQ1 is down-regulated by transfection of miR-133 into lung cancer cell lines&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">&#40;A and B&#41; Relative <span class="elsevierStyleItalic">FOXQ1</span> &#40;A&#41; and TGF-&#946; &#40;B&#41; mRNA levels in A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; &#40;C and D&#41; FOXQ1 &#40;C&#41; and TGF-&#946; &#40;D&#41; protein levels in A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; GAPDH was used as a loading control&#46; Quantification of FOXQ1 and TGF-&#946; protein expressions normalized to GAPDH was also shown in the lower panels&#46; Values were mean&#177;standard error mean &#40;SEM&#41; of three independent experiments&#46; &#42;&#42;<span class="elsevierStyleItalic">P</span>&#60;&#46;01 to respective control&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">MiR-133 expression inhibits migration and invasion of lung cancer cells&#46;</p> <p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Wound-healing assay for A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; &#40;B&#41; The migration distances relative to control in wound-healing assay were measured at 24<span class="elsevierStyleHsp" style=""></span>h after being wounded&#46; &#40;C&#41; Cell invasion assay for A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; &#40;D&#41; The invaded cell numbers relative to control were quantified 24<span class="elsevierStyleHsp" style=""></span>h after cells were seeded&#46; Values were mean&#177;SEM of three independent experiments&#46; &#42;<span class="elsevierStyleItalic">P</span>&#60;&#46;05 to respective control&#46;</p>"
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">MiR-133 expression inhibits epithelial&#8211;mesenchymal transition &#40;EMT&#41; of lung cancer cells&#46;</p> <p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Cell morphology was observed for A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; &#40;B and C&#41; Cell attachment &#40;B&#41; and detachment &#40;C&#41; assays were assessed in A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; &#40;D&#41; Expression of EMT phenotypic protein markers were analyzed in A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; Quantification of protein expressions normalized to GAPDH was also shown in the right panels&#46; Values were mean&#177;SEM of three independent experiments&#46; &#42;<span class="elsevierStyleItalic">P</span>&#60;&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">P</span>&#60;&#46;01 to respective control&#46;</p>"
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Original Article
Expression of MicroRNA-133 Inhibits Epithelial–Mesenchymal Transition in Lung Cancer Cells by Directly Targeting FOXQ1
La expresión de microARN-133 inhibe la transición epitelio-mesenquimatosa en las células del cáncer de pulmón apuntando directamente al FOXQ1
Bo Xiaoa,b, Huazhen Liua, Zeyun Gua, Cheng Jia,
Corresponding author
a School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu, China
b Key Laboratory for Ecology and Pollution Control of Coastal Wetlands, School of Environmental Science and Engineering, Yancheng Institute of Technology, Yancheng, China
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        "titulo" => "La expresi&#243;n de microARN-133 inhibe la transici&#243;n epitelio-mesenquimatosa en las c&#233;lulas del c&#225;ncer de pulm&#243;n apuntando directamente al FOXQ1"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">MiR-133 expression inhibits migration and invasion of lung cancer cells&#46;</p> <p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Wound-healing assay for A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; &#40;B&#41; The migration distances relative to control in wound-healing assay were measured at 24<span class="elsevierStyleHsp" style=""></span>h after being wounded&#46; &#40;C&#41; Cell invasion assay for A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; &#40;D&#41; The invaded cell numbers relative to control were quantified 24<span class="elsevierStyleHsp" style=""></span>h after cells were seeded&#46; Values were mean&#177;SEM of three independent experiments&#46; &#42;<span class="elsevierStyleItalic">P</span>&#60;&#46;05 to respective control&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Lung cancer is the leading worldwide cause of cancer-related death&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> Epithelial&#8211;mesenchymal transition &#40;EMT&#41; plays an essential role in the metastasis of human cancers&#44; including lung cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> During EMT&#44; epithelial cells acquire the mesenchymal phenotype and detach from the primary tumor&#44; spreading through the bloodstream to invade a secondary tissue&#44; causing metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">3</span></a> EMT involves both phenotypic changes and molecular reprogramming&#46; During the transition&#44; polarized immotile epithelial cells change their morphology to motile mesenchymal cells&#44; assuming increased motility and invasion abilities&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> This transition is also characterized by a reduction in epithelial markers that enhance cell-cell contact&#44; such as E-cadherin&#44; and an increase in mesenchymal markers&#44; such as vimentin and N-cadherin&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Various signaling pathways have been reported to trigger EMT&#46; Forkhead transcription factor FOXQ1 was found to induce EMT in breast cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">6</span></a> It was also reported to mediate the crosstalk between TGF-&#946; and Wnt signaling pathways in colorectal cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a> In lung cancer particularly&#44; FOXQ1 expression contributes to poor prognosis&#44; promotes EMT&#44; and increases chemo-sensitivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">MicroRNAs &#40;miRNAs or miRs&#41; are small non-coding RNA molecules&#44; usually 20&#8211;25 nucleotides long&#46; They recognize specific complementary sequences commonly found in the 3&#8242;-untranslated region &#40;UTR&#41; of target mRNAs&#44; either repressing translation or degrading the target mRNAs&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">10&#44;11</span></a> MiRNAs are involved in the EMT of many types of cancers&#44; including lung cancer&#44; altering the expression of oncogenes or tumor suppressor genes&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> For example&#44; miR-19 was found to trigger EMT and promote migration and invasion of lung cancer cell lines A549 and HCC827&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> In contrast&#44; other miRNAs inhibit this process&#46; One such miRNA is miR-129&#44; which was reported to antagonize EMT and metastasis in non-small cell lung cancer by down-regulating MCRS1&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a> Similarly&#44; low expression of miR-30c was also found to negatively affect the EMT of lung cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a> However&#44; the exact role of miR-133 in regulating EMT in lung cancer remains unclear&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In our current study&#44; we aimed to investigate whether miR-133 is involved in the regulation of EMT in lung cancer cells&#44; and the possible underlying mechanisms of this phenomenon&#46; We found that miR-133 was down-regulated in both A549 and HCC827 human lung cancer cell lines&#44; and miR-133 directly targeted and down-regulated FOXQ1 expression&#46; More importantly&#44; miR-133 expression reversed EMT features&#44; inhibiting the migratory and invasive abilities of lung cancer cells&#46; MiR-133 could serve as a novel molecular therapeutic tool for reversing EMT in lung cancer&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Cell lines&#44; Antibodies and MicroRNAs</span><p id="par0025" class="elsevierStylePara elsevierViewall">The human normal lung cell lines CCD-19Lu and MRC-9&#44; and human lung cancer cell lines A549 and HCC827 were obtained from the American Type Culture Collection &#40;ATCC&#41;&#46; Cells were maintained in complete medium with high-glucose RPMI-DMEM &#40;Hyclone&#59; GE Healthcare&#41; and 10&#37; fetal bovine serum &#40;FBS&#59; Gibco&#41;&#44; at 37&#176;<span class="elsevierStyleHsp" style=""></span>C in a humidified atmosphere containing 5&#37; CO<span class="elsevierStyleInf">2</span>&#46; Antibodies against FOXQ1 &#40;ab194564&#41;&#44; TGF-&#946; &#40;ab9758&#41;&#44; total Smad2&#47;3 &#40;ab63672&#41;&#44; phospho-Smad2&#47;3 &#40;ab63399&#41;&#44; E-cadherin &#40;ab76055&#41;&#44; N-cadherin &#40;ab18203&#41;&#44; vimentin &#40;ab92547&#41;&#44; and GAPDH &#40;ab181602&#41; were all purchased from Abcam&#46; Hsa-miR-133 mirVana miRNA mimic &#40;MC10029&#41; and mirVana miRNA negative control &#40;4464061&#41; were both purchased from Life Technologies&#46; Transfection into cell lines was performed following manufacturer&#39;s instructions&#46; After transfection&#44; cells were incubated for another 48<span class="elsevierStyleHsp" style=""></span>h before being subjected to other experimental assays&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Western Blot</span><p id="par0030" class="elsevierStylePara elsevierViewall">Cells were seeded in 6-well plates at a density of 1&#215;10<span class="elsevierStyleSup">6</span> cells&#47;well with 2<span class="elsevierStyleHsp" style=""></span>ml complete DMEM medium&#46; Twenty-four hours after transfection of either hsa-miR-133 or negative control&#44; total protein was extracted using RIPA buffer &#40;50<span class="elsevierStyleHsp" style=""></span>mM Tris&#8211;HCl&#44; pH 7&#46;4&#44; 150<span class="elsevierStyleHsp" style=""></span>mM NaCl&#44; 1<span class="elsevierStyleHsp" style=""></span>mM EDTA&#44; 1&#37; Triton X-100&#44; 1&#37; sodium deoxycholate&#44; 0&#46;1&#37; SDS&#44; and protease inhibitors&#41;&#46; The protein concentration was determined using the BCA assay&#46; Equal quantities of proteins were separated by SDS-PAGE and transferred to nitrocellulose membrane using a semi-dry transfer unit &#40;Bio-Rad Laboratories&#41;&#46; The membrane was then immersed in blocking buffer &#40;PBS&#44; 0&#46;1&#37; Tween-20&#41; with 5&#37; nonfat milk for 20<span class="elsevierStyleHsp" style=""></span>min and then incubated with appropriate primary antibodies overnight at 4<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; After washing with blocking buffer&#44; blots were incubated with HRP-conjugated secondary antibody &#40;Life Technologies&#41; at room temperature for 1<span class="elsevierStyleHsp" style=""></span>h&#44; washed again with blocking buffer&#44; and visualized using Luminata Forte Western HRP Substrate &#40;EMD Millipore&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Wound-Healing Assay</span><p id="par0035" class="elsevierStylePara elsevierViewall">A total of 1&#215;10<span class="elsevierStyleSup">5</span> cells transfected with miRNA negative control or hsa-miR-133 were seeded into a 6-well plate after transfection&#46; A linear wound was carefully made with a 100<span class="elsevierStyleHsp" style=""></span>&#956;l sterile pipette tip across the confluent cell monolayer&#44; and the cell debris was removed by washing with PBS&#46; The migrated distance of the growing edge on wounded monolayers was measured at 24<span class="elsevierStyleHsp" style=""></span>h after being wounded&#44; and migration rate was expressed as a percentage relative to respective controls&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Cell invasion Assay</span><p id="par0040" class="elsevierStylePara elsevierViewall">Cell invasion assay was performed in a 24-well plate with 8<span class="elsevierStyleHsp" style=""></span>&#956;m pore size chamber inserts &#40;BD Biosciences&#41;&#46; A total of 1&#215;10<span class="elsevierStyleSup">5</span> cells transfected with miRNA negative control or hsa-miR-133 were placed into the upper chamber per well with the Matrigel-coated membrane&#44; diluted with serum-free culture medium&#46; The lower compartment was filled with 500<span class="elsevierStyleHsp" style=""></span>&#956;l of medium containing 10&#37; FBS to attract cells&#46; The cells were incubated at 37<span class="elsevierStyleHsp" style=""></span>&#176;C in a 5&#37; CO<span class="elsevierStyleInf">2</span> humidified incubator for 24<span class="elsevierStyleHsp" style=""></span>h&#44; followed by exposure to 20<span class="elsevierStyleHsp" style=""></span>&#956;M 5-ethynyl-2&#8242;-deoxyuridine &#40;EdU&#41; for an additional 4<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; Membrane inserts were removed from the plate and stained using the ENU kit &#40;Invitrogen&#41;&#46; The cells were counted under six random microscopic fields for each well&#44; and invasion rate was expressed as a percentage relative to respective controls&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Cell Attachment and Detachment Assay</span><p id="par0045" class="elsevierStylePara elsevierViewall">The cells were seeded in a 24-well plate &#40;1&#215;10<span class="elsevierStyleSup">5</span> cells&#47;well&#41;&#46; Briefly&#44; for attachment assay&#44; after 1<span class="elsevierStyleHsp" style=""></span>h incubation&#44; non-attached cells were washed twice with PBS&#44; and the attached cells were counted after trypsinization&#46; The attachment rate was expressed as percentage of cell numbers of the attached cells to total cells&#44; and normalized to respective control&#46; For the detachment assay&#44; the cells were detached with 0&#46;05&#37; trypsin for 3<span class="elsevierStyleHsp" style=""></span>min and counted after the seeded cells were incubated 24<span class="elsevierStyleHsp" style=""></span>h&#46; The remaining attached cells were further trypsinized with 0&#46;25&#37; trypsin and counted&#46; Cells detachment rate was expressed as a percentage of the detached cells to total cells&#44; and normalized to respective control&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical Analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">All values were presented as mean&#177;standard error mean &#40;SEM&#41;&#46; A 2-tailed Student&#39;s <span class="elsevierStyleItalic">t</span>-test was used to establish significant differences between groups&#46; Data were determined to be statistically different when <span class="elsevierStyleItalic">P</span> was &#60;&#46;05&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">MiR-133 is Down-regulated in Lung Cancer Cell Lines</span><p id="par0055" class="elsevierStylePara elsevierViewall">We found that the miR-133 sequence has a putative binding site on the 3&#8242;-UTR of FOXQ1 mRNA&#44; using the microRNA&#46;org resource&#46; Moreover using RT-PCR&#44; upon examination of its expression in two human lung cancer cell lines A549 and HCC827&#44; we found miR-133 levels were significantly lower than in two normal lung cell lines CCD-19Lu and MRC-9&#46; MiR-133 levels in CCD-19Lu and MRC-9 were similar&#44; whereas in A549 it was down-regulated to approximately 30&#37; of the normal cell lines&#44; and in HCC827 to about 40&#37; of the normal cell lines&#46; These results suggested that&#44; compared with normal human lung cells&#44; miR-133 was significantly down-regulated in lung cancer cell lines&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">MiR-133 Directly Targets 3&#8242;-UTR of FOXQ1</span><p id="par0060" class="elsevierStylePara elsevierViewall">We next validated the putative binding site of miR-133 on the 3&#8242;-UTR of FOXQ1&#44; using a luciferase reporter assay&#46; The sequences from wild type &#40;WT-Luc&#41; 3&#8242;-UTR of FOXQ1 mRNA and its mutated version &#40;mut-Luc&#41; were fused to the downstream of luciferase ORF&#44; respectively&#46; The two luciferase constructs were then separately transfected into both A549 and HCC827 cells&#44; together with either miRNA negative control or miR-133 mimic&#46; The luciferase reporter activity was then assessed&#46; As a result&#44; miR-133 dramatically reduced WT-Luc activity to approximately 30&#37; of the control transfected experiments&#44; consistently in both A549 and HCC827 cell lines&#46; On the other hand&#44; activity of mut-Luc was largely unaffected in either miR-133 or control miRNA transfected cells&#46; The complementary sequences on FOXQ1 3&#8242;-UTR were then a direct target of miR-133&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">MiR-133 Down-regulates Expressions of FOXQ1 and TGF-&#946; in Lung Cancer Cell Lines</span><p id="par0065" class="elsevierStylePara elsevierViewall">We continued to determine whether FOXQ1 was indeed an <span class="elsevierStyleItalic">in vivo</span> target of miR-133&#46; MiR-133 and a negative miRNA control were transfected into both A549 and HCC827 cells&#44; which were then subjected to RT-PCR to examine FOXQ1 levels in mRNA&#46; Levels of miR-133 in both A549 and HCC827 cells were indeed greatly increased upon transfection&#46; Compared with control miRNA transfections&#44; miR-133 significantly reduced FOXQ1 messenger levels in both lung cancer cell lines examined &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#44; clearly indicating that FOXQ1 mRNA is a <span class="elsevierStyleItalic">bona fide</span> target of miR-133&#46; Using anti-FOXQ1antibody&#44; we confirmed that its protein level was also markedly reduced in miR-133&#44; but not in control transfected cells &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Other authors have reported that FOXQ1 could promote the expression of TGF-&#946;&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> and was involved in the crosstalk between TGF-&#946; and Wnt signaling pathways in the progression of colorectal cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a> We were curious to investigate whether a similar correlation also existed between these two genes in lung cancer&#46; Interestingly&#44; down-regulation of FOXQ1 by miR-133 transfection also greatly reduced TGF-&#946; expressions in both lung cancer cell lines &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B and D&#41;&#44; suggesting that FOXQ1 and TGF-&#946; are both likely to be involved in tumorigenesis of lung cancer&#46; More importantly&#44; we found that in both lung cancer cell lines A549 and HCC827&#44; miR-133 expression resulted in a significant inhibition of TGF-&#946; pathway&#44; as indicated by reduced phosphorylation of Smad2&#47;3 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#44; both of which are downstream effectors of the TGF-&#946; pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> Of note&#44; we further confirmed that the regulation of TGF-&#946; pathway by miR-133 was indeed mediated through FOXQ1&#44; since in a co-transfection experiment using both miR-133 and a plasmid expressing FOXQ1 without its 3&#8242;-UTR&#44; TGF-&#946; level was also upregulated upon FOXQ1 expression&#44; even in the presence of miR-133 &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#8211;D&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">MiR-133 Inhibits Migration and Invasion of Lung Cancer Cells</span><p id="par0075" class="elsevierStylePara elsevierViewall">FOXQ1 is a marker for metastasis and poor prognosis of lung cancer&#44;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">8&#44;9</span></a> so introducing miR-133 to down-regulate FOXQ1 should inhibit the migration and invasion of lung cancer cells&#46; To test this hypothesis&#44; we performed wound-healing and cell invasion assays in both miR-133 and control miRNA-transfected A549 and HCC827 cells&#46; As expected&#44; both cell lines exhibited significantly reduced migration rate after transfection of miR-133&#44; compared with control experiments &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A and B&#41;&#46; Moreover&#44; in a cell invasion assay&#44; miR-133 also consistently reduced the invasion rates of both A549 and HCC827 cells&#44; compared with control transfected experiments &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>C and D&#41;&#46; Taken together&#44; the above results strongly demonstrated the role of miR-133 in inhibiting lung cancer tumorigenesis&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">MiR-133 Inhibits Epithelial&#8211;Mesenchymal Transition &#40;EMT&#41; of Lung Cancer Cells</span><p id="par0080" class="elsevierStylePara elsevierViewall">During the wound-healing and cell invasion assays&#44; we often saw a morphological change in cells after transfection with miR-133&#46; Both A549 and HCC827 cells initially displayed elongated and fibroblastoid morphology&#44; whereas upon miR133 transfection both cell lines assumed rounded cell shapes &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#41;&#44; suggesting a loss of EMT phenotype&#46; During transition&#44; epithelial cells at the primary tumor site acquire the mesenchymal phenotype&#44; resulting in enhanced invasion and metastasis&#44; spreading through the blood stream to reach secondary tissues&#46; To confirm this observation&#44; we performed cell attachment and detachment assays in the two lung cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B and C&#44; miR-133 significantly reduced attachment and detachment rates of both A549 and HCC827 cells&#44; compared with control transfected cells&#46; These results confirmed the loss of EMT features at the cell morphological level&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">At the molecular level&#44; EMT is characterized by reduced epithelial marker E-cadherin and increased mesenchymal marker vimentin&#46; Accordingly&#44; we went on to assess if the same shift in EMT phenomena could also be observed at the molecular level&#46; As expected&#44; miR-133 increased E-cadherin expression&#44; but reduced vimentin and N-cadherin expressions&#44; compared with control transfected cells &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>D&#41;&#44; which clearly demonstrated a reverse of EMT phenotype at the protein level&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Increasing numbers of studies have demonstrated the essential roles of different miRNAs in the tumorigenesis of lung cancer&#46; An understanding of the abnormal expression patterns of miRNAs in lung cancer cells&#44; as well as the underlying molecular programs&#44; could contribute to the development of new clinical therapies in the treatment of lung cancer&#46; In this study&#44; we have demonstrated that miR-133 was down-regulated in two human lung cancer cell lines A549 and HCC827&#44; compared to normal lung cell lines CCD-19Lu and MRC-9&#46; Interestingly&#44; <span class="elsevierStyleItalic">in silico</span> analysis showed that miR-133 has a putative binding site on the 3&#8242;-UTR of FOXQ1 mRNA&#46; Using a luciferase reporter assay&#44; we confirmed that the 3&#8242;-UTR sequence was a direct target of miR-133&#46; Furthermore&#44; by reintroducing miR-133 expression into the A549 and HCC827 lung cancer cell lines&#44; we found both mRNA and protein levels of FOXQ1 were consistently reduced&#44; suggesting that FOXQ1 expression was indeed repressed by miR-133 <span class="elsevierStyleItalic">in vivo</span>&#46; On the other hand&#44; expression of TGF-&#946; was also down-regulated by miR-133 transfection&#46; This finding was consistent with a previous report which suggests that it is a downstream effector of FOXQ1&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> Moreover&#44; miR-133 expression significantly reduced the migration and invasion of lung cancer cells&#44; probably through EMT inhibition&#44; as evidenced by a prominent elevation of epithelial marker E-cadherin and reduction of mesenchymal markers N-cadherin and vimentin&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Recent studies have highlighted the important roles of miRNAs in the EMT of cancer cells&#46; For example&#44; the miR-134&#47;487b&#47;665 cluster regulates TGF-&#946; mediated EMT by targeting membrane-associated guanylate kinase inverted 2 in lung cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a> Additionally&#44; miR-125b&#47;489 was found to regulate EMT pathway in breast cancer&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">19&#44;20</span></a> Down-regulation of miR-200c was found to be responsible for acquired resistance to EGFR inhibitors by manifesting EMT features&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> Moreover&#44; miR-216a&#47;217 was found to induce EMT by targeting PTEN and Smad7 in liver cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Emerging studies have highlighted the role of miR-133 in several types of human cancers&#46; It functions as a tumor suppressor by targeting IGF-1R in hepatocellular carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a> In colorectal cancer&#44; ectopic expression of miR-133 significantly suppressed cancer growth both <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#44; by targeting E3-ubiquitin protein ligase&#44; thereby increasing p53 expression&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">24</span></a> Moreover&#44; miR-133 was also widely down-regulated in several gastric cancer cell lines&#44; where its re-expression was found to repress CDC42-PAK signaling pathway and lead to inhibited cancer cell migration and invasion&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">25</span></a> Quite a few recent studies have consistently reported that miR-133 was also able to directly target epidermal growth factor receptor &#40;EGFR&#41; in prostate cancer&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a> bladder cancer&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a> gastric cancer&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">28</span></a> and glioblastoma multiforme&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">29</span></a> inhibiting proliferation&#44; migration&#44; and invasion of these cancer cells&#46; Together&#44; all the above studies suggest that miR-133 plays a critical and complex role in regulating progression of different human cancers by targeting different signaling pathways&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In conclusion&#44; our study is the first report implicating miR-133 in the EMT of lung cancer&#46; As EMT is commonly associated with aggressiveness of cancer cells&#44; including migration and invasion&#44; inhibiting or reversing this transition could lead to new therapeutic approaches in the treatment of cancer&#46; In this context&#44; we found that miR-133 could reverse the EMT of lung cancer cell lines A549 and HCC827&#44; which may explain why miR-133 could significantly inhibit the migration and invasion of the lung cancer cells&#46; Our results suggest that miR-133&#44; by inhibiting the epithelial&#8211;mesenchymal transition&#44; may have a role as a potential molecular therapeutic tool in the treatment of lung cancer&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Author Contributions</span><p id="par0110" class="elsevierStylePara elsevierViewall">All authors participated in the design and interpretation of the studies&#44; analysis of the data and review of the manuscript&#46; Bo Xiao&#44; Huazhen Liu&#44; and Zeyun Gu conducted the experiments and Bo Xiao and Cheng Ji wrote the manuscript&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Funding</span><p id="par0115" class="elsevierStylePara elsevierViewall">This work was supported by <span class="elsevierStyleGrantSponsor" id="gs1">National Natural Science Foundation of China</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs1">31300969</span>&#41;&#44; <span class="elsevierStyleGrantSponsor" id="gs2">Natural Science Foundation of Jiangsu Province</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs2">BK20130302</span>&#41; and <span class="elsevierStyleGrantSponsor" id="gs3">China Postdoctoral Science Foundation</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs3">2013M540461</span> and <span class="elsevierStyleGrantNumber" refid="gs3">2013M541717</span>&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conflict of Interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Materials and Methods"
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              "titulo" => "Cell lines&#44; Antibodies and MicroRNAs"
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              "titulo" => "Western Blot"
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              "titulo" => "Wound-Healing Assay"
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              "titulo" => "Cell invasion Assay"
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              "titulo" => "Statistical Analysis"
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          "titulo" => "Results"
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              "titulo" => "MiR-133 is Down-regulated in Lung Cancer Cell Lines"
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              "titulo" => "MiR-133 Directly Targets 3&#8242;-UTR of FOXQ1"
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              "identificador" => "sec0060"
              "titulo" => "MiR-133 Down-regulates Expressions of FOXQ1 and TGF-&#946; in Lung Cancer Cell Lines"
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              "identificador" => "sec0065"
              "titulo" => "MiR-133 Inhibits Migration and Invasion of Lung Cancer Cells"
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              "identificador" => "sec0070"
              "titulo" => "MiR-133 Inhibits Epithelial&#8211;Mesenchymal Transition &#40;EMT&#41; of Lung Cancer Cells"
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    "fechaRecibido" => "2015-09-16"
    "fechaAceptado" => "2015-10-28"
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          "clase" => "keyword"
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            0 => "Lung cancer"
            1 => "MicroRNA-133"
            2 => "FOXQ1"
            3 => "TGF-&#946;"
            4 => "Epithelial&#8211;mesenchymal transition"
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            0 => "C&#225;ncer de pulm&#243;n"
            1 => "MicroARN-133"
            2 => "FOXQ1"
            3 => "TGF-&#946;"
            4 => "Transici&#243;n epitelio-mesenquimatosa"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">MicroRNA &#40;miR&#41; was implicated in the tumorigenesis of many types of cancer&#44; but no study was conducted on the exact role of miR-133 in lung cancer&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We have identified miR-133 as a putative regulator of FOXQ1 expression&#44; and investigated the potential involvement of miR-133 in the migration and invasion of lung cancer cells&#44; as well as the underlying molecular mechanism&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">MiR-133 directly targeted and down-regulated FOXQ1 expression&#44; which in turn reduced TGF-&#946; level&#46; MiR-133 was down-regulated in lung cancer cell lines A549 and HCC827&#44; and its re-expression significantly inhibited the migration and invasion of the lung cancer cells&#46; Further investigation revealed that this inhibition was caused by reversing the epithelial&#8211;mesenchymal transition&#44; evidenced by miR-133 induced elevation of epithelial marker E-cadherin&#44; and reduction of mesenchymal marker Vimentin&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Our study is the first to identify miR-133 as a biomarker for lung cancer&#46; It functions to down-regulate FOXQ1&#44; and inhibit epithelial&#8211;mesenchymal transition&#44; which antagonizes lung cancer tumorigenesis&#46; Therefore our data support the role of miR-133 as a potential molecular therapeutic tool in treating lung cancer&#46;</p></span>"
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            "titulo" => "Introduction"
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            "titulo" => "Methods"
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          2 => array:2 [
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El microARN &#40;miR&#41; se ha relacionado con la g&#233;nesis tumoral en muchos tipos de c&#225;ncer&#44; pero ning&#250;n estudio ha examinado el rol exacto del miR-133 en el c&#225;ncer de pulm&#243;n&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Identificamos el miR-133 como posible regulador de la expresi&#243;n de la FOXQ1 e investigamos la posible implicaci&#243;n del miR-133 en la migraci&#243;n y la invasi&#243;n de c&#233;lulas de c&#225;ncer de pulm&#243;n&#44; y el mecanismo molecular subyacente&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El miR-133 se dirigi&#243; directamente y redujo la expresi&#243;n de la FOXQ1&#44; que a su vez redujo la concentraci&#243;n de TGF-&#946;&#46; El miR-133 disminuy&#243; en l&#237;neas celulares de c&#225;ncer de pulm&#243;n A549 y HCC827&#44; y su reexpresi&#243;n inhibi&#243; significativamente la migraci&#243;n y la invasi&#243;n de c&#233;lulas de c&#225;ncer de pulm&#243;n&#46; Investigaciones subsiguientes revelaron que dicha inhibici&#243;n estaba provocada por una inversi&#243;n de la transici&#243;n epitelio-mesenquimatosa&#44; constatada por una elevaci&#243;n del marcador epitelial E-cadherina inducida por el miR-133 y una reducci&#243;n del marcador vimentina&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Nuestro estudio es el primero que ha identificado el miR-133 como biomarcador del c&#225;ncer de pulm&#243;n&#46; Su funci&#243;n es reducir la FOXQ1 e inhibir la transici&#243;n epitelio-mesenquimatosa&#44; la cual antagoniza la g&#233;nesis tumoral en el c&#225;ncer de pulm&#243;n&#46; Por consiguiente&#44; nuestros datos respaldan el papel del miR-133 como posible instrumento terap&#233;utico molecular en el tratamiento del c&#225;ncer de pulm&#243;n&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Xiao B&#44; Liu H&#44; Gu Z&#44; Ji C&#46; La expresi&#243;n de microARN-133 inhibe la transici&#243;n epitelio-mesenquimatosa en las c&#233;lulas del c&#225;ncer de pulm&#243;n apuntando directamente al FOXQ1&#46; Arch Bronconeumol&#46; 2016&#59;52&#58;505&#8211;511&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">FOXQ1 is down-regulated by transfection of miR-133 into lung cancer cell lines&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">&#40;A and B&#41; Relative <span class="elsevierStyleItalic">FOXQ1</span> &#40;A&#41; and TGF-&#946; &#40;B&#41; mRNA levels in A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; &#40;C and D&#41; FOXQ1 &#40;C&#41; and TGF-&#946; &#40;D&#41; protein levels in A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; GAPDH was used as a loading control&#46; Quantification of FOXQ1 and TGF-&#946; protein expressions normalized to GAPDH was also shown in the lower panels&#46; Values were mean&#177;standard error mean &#40;SEM&#41; of three independent experiments&#46; &#42;&#42;<span class="elsevierStyleItalic">P</span>&#60;&#46;01 to respective control&#46;</p>"
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">MiR-133 expression inhibits epithelial&#8211;mesenchymal transition &#40;EMT&#41; of lung cancer cells&#46;</p> <p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Cell morphology was observed for A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; &#40;B and C&#41; Cell attachment &#40;B&#41; and detachment &#40;C&#41; assays were assessed in A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; &#40;D&#41; Expression of EMT phenotypic protein markers were analyzed in A549 and HCC827 cell lines&#44; after transfection with either miRNA negative control or miR-133&#46; Quantification of protein expressions normalized to GAPDH was also shown in the right panels&#46; Values were mean&#177;SEM of three independent experiments&#46; &#42;<span class="elsevierStyleItalic">P</span>&#60;&#46;05&#44; &#42;&#42;<span class="elsevierStyleItalic">P</span>&#60;&#46;01 to respective control&#46;</p>"
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ISSN: 15792129
Original language: English
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