Upregulation of miR‐153 promotes cell proliferation via downregulation of the PTEN tumor suppressor gene in human prostate cancer

Abstract. Malignant gliomas are the most common and deadly primary brain tumors in adults and the high proliferative ability of these cells is one of the most important causes of the poor prognosis of this cancer. Suppressing the proliferation of malignant gliomas cells by altering effector molecules can significantly improve the prognosis of a patient. microRNAs (miRNAs) are small non-coding RNA molecules ~22 nucleotides in length that are able to function as oncogenes or tumor suppressors in human cancer. In the present study, it was demonstrated that the expression level of miRNA-218 (miR-218) is markedly downregulated in glioma cell lines and human primary glioma tissues. Upregulation of miR-218 in glioma U87 cells dramatically inhibited the proliferation by inducing G 1 -S checkpoint arrest. Furthermore, it was demonstrated that ectopically expressing miR-218 in glioma U87 cells results in the downregulation of the expression of cyclin dependent kinase (CDK)6 and cyclin D1 and upregulation of the expression of p21 Cip1/Waf1 . In addition, it was identified that miR-218 inactivated the CDK6/cyclin D1/p21 Cip1/Waf1 pathway by downregulating CDK6 expression through the direct targeting of the 3'-untranslated region of CDK6. The present results suggest that miR-218 plays an important role in the prevention of the proliferation of glioma cells, and the present study also revealed a novel mechanism for miRNA-mediated direct suppression of the CDK6/cyclin D1/p21Cip1/Waf1 pathway in glioma cells. IntroductionHuman glioma is the most common primary tumor in the central nervous system and is characterized by a high proliferative and invasive ability (1). Standard therapies for glioma, including surgery, radiation and chemotherapy, are only effective in treating patients with a high-grade condition. Numerous glioma patients have already developed metastasis at the onset of clinical symptoms (2). The mechanism of glioma tumorigenesis remains unclear, and the molecular determinants of the aggressiveness of glioma have been the subject of numerous studies, but these investigations have not yet reached full fruition (3-6). Therefore, there is an acknowledged requirement for novel approaches based on increased understanding of the biological and molecular nature of these tumors. microRNAs (miRNAs) are short non-coding, single-stranded RNA molecules that are 22-25 nucleotides in length and negatively regulate gene expression by post-transcriptional silencing of target messenger RNAs (mRNAs) through complementary binding (7,8). An increasing number of studies have indicated that miRNA plays an important role in the development of various cancers, including glioma, and miRNA has been associated with tumor suppressor and oncogenic activities (9,10). Out of these miRNA molecules, miRNA 218 (miR-218) has been revealed to be downregulated in human glioblastoma multiforme (GBM) specimens compared with the adjacent brain tissue that is devoid of tumor cells (11)(12)(13)(14). Accumulated data have demonstrated that the upregulati...

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“…Cip1 (22). However, the underlying mechanism that modulates the abundance of the cyclins and CDKs in glioma has yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

miR-218 inhibits the proliferation of glioma U87 cells through the inactivation of the CDK6/cyclin D1/p21Cip1/Waf1 pathway

2015

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“…Glutathione peroxidase-3 acts as a tumor suppressor, and it is lost during PCa progression (141). miR-153 is another oncogenic miRNA that reportedly contributes to PCa progression through direct regulation of PTEN and FOXO1, and activation of the AKT pathway (142).…”

Section: Other Oncogenic Mirnasmentioning

confidence: 99%

Microdissecting the role of microRNAs in the pathogenesis of prostate cancer

2015

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“…An increasing number of studies have shown that miRNAs may not only play a significant role in PCa progression (6,7) such as proliferation (7), the cell cycle (8), apoptosis (9), invasion and metastasis (10)(11)(12) but also function as tumor suppressors or oncogenes depending on the genes that they regulate (13).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-340 inhibits prostate cancer cell proliferation and metastasis by targeting the MDM2-p53 pathway

Huang

Tang

et al. 2015

Oncology Reports

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Abstract. An increasing number of studies have demonstrated the important role of microRNAs (miRNAs) in modulating cancer progression and metastasis, but the mechanisms by which miRNAs regulate prostate cancer (PCa) tumorigenesis remain poorly understood. In the present study, we found that miR-340 may act as a tumor suppressor based on our finding that it was significantly downregulated in PCa tumor tissues and cell lines. Moreover, the expression of miR-340 was found to be correlated with the inhibition of cell proliferation, migration and invasion in vitro, and had a suppressive effect on tumor growth in a xenograft mouse model as well. The suppressive effect of miR-340 overexpression was observed in cell lines DU145 and BPH-1 which express wild-type (WT) p53. However, in the p53-null PC-3 cell line, the suppressive effect was not found, indicating that miR-340 may play a critical role in the p53 pathway. Further investigation revealed that mouse double minute 2 (MDM2), an important regulator of p53, was targeted by miR-340 through the direct binding to the 3'UTR of MDM2, which inhibited MDM2 translation. In addition, miR-340 expression stabilized p53 protein levels which caused an increase in p21 expression but a decrease in the anti-apoptotic protein, BCL-2, in the p53 WT cell lines. Moreover, the miR-340-mediated inhibition of cell progression was mitigated by re-expressing MDM2 in the stable miR-340-overexpressing PCa cell line, which harbors WT p53. Our findings suggest that miR-340 may function as a novel tumor suppressor in PCa through the MDM2-p53 pathway by directly targeting MDM2, which may be a promising miRNA-targeted therapy for PCa.

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Upregulation of miR‐153 promotes cell proliferation via downregulation of the PTEN tumor suppressor gene in human prostate cancer

Abstract: Taken together, our results suggest that miR-153 play an important role in promoting proliferation of human prostate cancer cells and present a novel mechanism of microRNA-mediated direct suppression of PTEN expression in prostate cancer cells.

Cited by 110 publications

References 39 publications

miR-218 inhibits the proliferation of glioma U87 cells through the inactivation of the CDK6/cyclin D1/p21Cip1/Waf1 pathway

miR-218 inhibits the proliferation of glioma U87 cells through the inactivation of the CDK6/cyclin D1/p21Cip1/Waf1 pathway

Microdissecting the role of microRNAs in the pathogenesis of prostate cancer

MicroRNA-340 inhibits prostate cancer cell proliferation and metastasis by targeting the MDM2-p53 pathway

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