Biochemical and Biophysical Research Communications
Malat1 activates autophagy and promotes cell proliferation by sponging miR-101 and upregulating STMN1, RAB5A and ATG4D expression in glioma
Introduction
Glioma is the most frequent primary brain tumor, and associated with fatal clinical results [1]. Despite the diagnosis and treatment developments of glioma, the prognosis of glioma patients is still poor, and there is no successful treatment for highly malignant glioma [2]. Undoubtedly, a deeper understanding of the molecular mechanisms of glioma initiation and progression will contribute to develop more effective therapy for this disease.
As untranslated RNA molecules, long non-coding RNAs (lncRNAs) with more than 200 nucleotides in length have attracted increasing attention in recent years due to their crucial biological effects in tumor initiation and progression. To date, a large number of lncRNAs have been identified and their roles in cancer have been widely studied. Among these lncRNAs, Malat1, one highly conserved lncRNA amongst mammals, has been widely reported to be upregulated in various tumors, and promote tumor progress by different action mechanisms. For example in glioma, Ma et al. [3] demonstrate that Malat1 is upregulated in glioma tissues, and is associated significantly with WHO grade, tumor size, and overall survival of glioma patients. However, the specific role and molecular mechanism of Malat1 in glioma are still unclear.
Autophagy is a highly conserved catabolic process for the degradation of damaged long-lived proteins and organelles, and helps cells to survive under stressful circumstances. In recent years, increasing evidence suggests that autophagy as a self-protective mechanism can be regulated by miRNA and implicated in various physiologic and pathophysiologic processes, including cancer. For example, miR-375 inhibits autophagy and reduces viability in hepatocellular carcinoma cells under hypoxic conditions; miR-205 impairs the autophagic flux and enhances cisplatin cytotoxicity in castration-resistant prostate cancer cells; and miR-22 regulates 5-FU sensitivity by inhibiting autophagy and promoting apoptosis in colorectal cancer cells [4], [5], [6]. miRNA as small ncRNA with 18–25 nucleotides in length has been widely reported to be sponged by lncRNA and make the derepression of miRNA target, thereby playing the role. Thus, we speculate that lncRNA may participate in autophagy as a miRNA sponge. In fact, many lncRNAs have been reported to be able to regulate autophagy as a miRNA sponge. For example, lncRNA APF regulates autophagy and myocardial infarction by targeting miR-188-3p; and lncRNA HNF1A-AS1 functions as an oncogene and autophagy promoter in hepatocellular carcinoma through sponging miR-30b-5p. Malat1 has also been reported to be able to regulate autophagy in several tumors [7], [8]. However, there are few reports about the role and molecular mechanism of Malat1 on autophagy in glioma.
Here, we determined the expression level of Malat1 in glioma tissues and cell lines by quantitative Real-Time PCR (qRT-PCR), and investigated the association between Malat1 expression and glioma cell autophagy and proliferation. Furthermore, we explored the molecular mechanism whereby Malat1 exerted regulatory effects on glioma cell autophagy and proliferation.
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Samples and cell lines
A total 32 glioma tissue and paired adjacent normal tissue specimens were collected from glioma patients receiving no preoperative chemotherapy or radiotherapy in the First Affiliated Hospital of Zhengzhou University. This study was approved by the First Affiliated Hospital ethics committee, and the written informed consent was obtained from all patients. Five human glioma cell lines U87, U118, U251, U373 and D247 were purchased from the Health Science Research Bank (Osaka, Japan). Primary
Upregulated Malat1 is relevant to increased autophagy activation in glioma tissues
Malat1 expression was determined in 32 pairs of glioma tissues and the adjacent normal tissues by using qRT-PCR. The results showed that Malat1 expression was significantly increased in glioma tissues compared with adjacent normal tissues (Fig. 1A). Meanwhile, we also determined autophagy activation in glioma tissues and normal tissues. LC3 is present predominantly in a cytoplasmic form (LC3-I) that, upon autophagy induction, is converted into an active lipidated form (LC3-II) present on
Discussion
The human transcriptome has been found to be not only a collection of protein-coding genes, but also including extensive antisense and non-coding RNA (ncRNA). Although ncRNA is initially considered as the transcriptional noise, it has become increasingly clear that ncRNAs are crucial regulators of cellular activities in various human diseases, including cancer [10], [11].
Malat1 as an oncogenic lncRNA has been reported to promote initiation and progression of many tumors by different action
Disclosure of conflict of interest
None.
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