Mini-reviewMiR-200, a new star miRNA in human cancer
Introduction
MicroRNAs (miRNAs) are a class of short non-coding RNA molecules with a significant regulatory capacity on gene expression [1], [2]. Similar to protein-coding genes, the primary transcripts of miRNA (pri-miRNA) are derived from genomic DNA and synthesized by RNA polymerase II or III into a hairpin structure [3], [4]. After being further processed by the RNase III family enzymes, Drosha and DiGeorge syndrome critical region gene 8 (DGCR8), the excess nucleotides at both the 3′ and 5′ regions of pri-miRNA are cropped off to form precursor miRNA (pre-miRNA) that is ∼70 nt in length [5], [6], [7], [8]. Then, pre-miRNA will be exported out of the nucleus by the double-stranded RNA binding protein Exportin-5, and this intermediate product is subsequently cleaved by the RNase III family enzyme, Dicer, into imperfect mature miRNA:miRNA∗duplexes in the cytoplasm [9], [10], [11], [12], [13]. The miRNA strand of approximately 18–22 nucleotides is incorporated into the RNA-induced silencing complex (RISC), which guides mature miRNA to trigger the target mRNA for subsequent silencing [14], [15]. Although the extent to which miRNAs regulate the human transcriptome is still under investigation, more and more evidence supports the fact that miRNA plays a crucial regulatory role in the control of gene expression.
To date, a total of 2578 mature miRNA sequences have been identified in humans in accordance to the latest release of the miRBase database (http://www.mirbase.org/). The miRNA-200 family consisting of five members (miR-200a, miR-200b, miR-200c, miR-429, and miR-141), is of particular interest for human health and disease. Based on the chromosomal locations, the miR-200 family can be divided into two clusters: the miR-200ba/429 cluster containing miR-200a, miR-200b, and miR-429, which is located on chromosome 1p36, and the miR-200c/141 cluster, which contains miR-200c and miR-141 and is located on chromosome 12p13. As known, in miRNA biology, seed sequences, in terms of the complementary sequences to binding sites of miRNA within the 3′ untranslated regions (UTRs) of the target genes, play a crucial role in regulatory effects of miRNA on gene expression [16]. Theoretically speaking, the members of a miRNA family contain highly conservative seed sequences; and miRNAs with the identical seed sequences may share the same putative target gene profiles. For the miR-200 family, two types of seed sequences are identified, which only have a nucleotide difference. MiR-200b, miR-200c, and miR-429 contain AAUACUG, whereas miR-200a and miR-141 possess AACACUG as their seed sequences. For the convenience of functional analysis, some studies named the miR-200bc/429 and miR-200a/141 clusters based on the seed sequences and potential similar target gene profiles [17], which are distinct from miR-200ba/429 and miR-200c/141 that are defined based on the chromosomal locations.
The first correlative report showing a relationship between the miR-200 family and human health demonstrated its high olfactory enrichment and neural expression patterns, consistent with a role in olfactory neurogenesis [18]. Soon afterwards, its involvement in human disease was confirmed when new studies demonstrated that miR-200 appeared to be downregulated during tumor progression and acted as a key inhibitor for epithelial-to-mesenchymal transition (EMT), tumor cell invasion, and metastasis. These benchmark results have been summarized in several high quality reviews [19], [20], [21], [22], [23], [24]. To be complementary to these articles, we focus on presentation of the latest findings on studies of miR-200 tumor suppressive roles in human cancer, which include inhibition of EMT, repression of cancer stem cell (CSC) self-renewal and differentiation, modulation of cell division and apoptosis, and involvement in chemoresistance. Moreover, after sorting out many related publications, we summarize the mechanisms accounting for the regulation of miR-200 expression in various cancer cells. These results have not yet been collated to date but will be of importance to understand the tumor suppressor role of miR-200 in human cancer. We hope that this review article can provide useful insights into translation of the achievements gained from miRNA research into the future clinical applications.
Section snippets
Inhibition of epithelial mesenchymal transition (EMT) and tumor metastasis
The involvement of miR-200 in cancer originates from several studies demonstrating a significant role for miR-200 in EMT, which is an important process in tumor progression as well as embryonic development. The expression of miR-200 family members was found to be highly associated with the epithelial phenotype of cancer cells, serving as a class of key markers for E-cadherin-positive and vimentin-negative cancer cell lines [25], [26], [27]. ZEB1 and ZEB2 are two members of the zinc-finger E-box
Regulation of miR-200 expression
Given that miRNA is a class of non-coding small RNA molecules, the transcription factor involved regulation and epigenetic modulation are two major mechanisms that control miRNA expression. Due to the increased interest in miR-200 as well as its tumor suppressor role in a variety of human tumors, better understanding of miR-200 regulatory mechanisms can provide insights into the future translation of miR-200’s tumor suppressive signatures into development of novel strategies for treating human
Conclusion and perspective
The inhibitory effect of miR-200 on EMT by targeting ZEBs is the benchmark achievement to understand the tumor suppressor roles of miR-200 in human cancer. As discussed earlier, the promoter regions of both miR-200 clusters have binding sites for ZEB1 and ZEB2 transcription factors. Interestingly, both ZEBs can be targeted by miR-200, reciprocally, hinting at a possible unknown mechanism by which a feedback inhibition loop can be broken and cells can be switched between an epithelial and
Conflict of Interest
We disclose that we do not have any conflicts of interest.
Acknowledgements
This study is supported by the American Cancer Society Research Scholar Grant (RSG-13-265-01-RMC, to Xi) and the NIH/NCI R21 Grant (5R21CA160280, to Xi). We sincerely apologize to those whose work was not cited due to time and space constraints.
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