Downregulation of miR-205 and miR-31 confers resistance to chemotherapy-induced apoptosis in prostate cancer cells

Bhatnagar, Namrata; Li, X; Padi, Megha; Zhang, Qi; Tang, M-s; Guo, Bin

doi:10.1038/cddis.2010.85

Cited by 186 publications

(169 citation statements)

References 29 publications

(29 reference statements)

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“…15 We noticed two peaks of p63, at a À 13 Kb and þ 2 Kb from the recently identified 16 miR-205 transcriptional start site (TSS; Figure 2a). Search for p63 motifs in these regions highlighted three highly predicted consensus sequences in the former, and two flanking the þ 2 Kb site (Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

miR-205 regulates basement membrane deposition in human prostate: implications for cancer development

et al. 2012

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The basement membrane (BM) is a layer of specialized extracellular matrix that surrounds normal prostate glands and preserves tissue integrity. Lack or discontinuity of the BM is a prerequisite for tumor cell invasion into interstitial spaces, thus favoring metastasis. Therefore, BM maintenance represents a barrier against cancer development and progression. In the study, we show that miR-205 participates in a network involving DNp63a, which is essential for maintenance of the BM in prostate epithelium. At the molecular level, DNp63a is able to enhance miR-205 transcription by binding to its promoter, whereas the microRNA can post-transcriptionally limit the amount of DNp63a protein, mostly by affecting DNp63a proteasomal degradation rather than through a canonical miRNA/target interaction. Functionally, miR-205 is able to control the deposition of laminin-332 and its receptor integrin-b4. Hence, pathological loss of miR-205, as widely observed in prostate cancer, may favor tumorigenesis by creating discontinuities in the BM. Here we demonstrate that therapeutic replacement of miR-205 in prostate cancer (PCa) cells can restore BM deposition and 3D organization into normal-like acinar structures, thus hampering cancer progression. MicroRNAs (miRNAs) are short, non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. 1 By hybridizing to at least partially complementary regions on target mRNAs, miRNAs can induce mRNA degradation or translation inhibition, thus finely tuning protein expression in a variety of biological processes. 1 Consequently, aberrant miRNA expression and function have been linked to the pathogenesis of human diseases, including cancer, where specific miRNAs have been proven to act as oncogenes or tumor suppressors. 2 We previously showed that miR-205 is downregulated in prostate cancer (PCa) compared with adjacent non-neoplastic tissue. 3 This finding was then confirmed by several independent studies (reviewed in Gandellini et al. 4 ; Schaefer et al. 5 ), and miR-205 recognized as the best single miRNA able to correctly distinguish prostate tumor from normal tissue. 6 We also reported that miR-205 acts as a tumor suppressor in human prostate, as its reintroduction in PCa cells reverts epithelial-to-mesenchymal transition (EMT), 3 thus suggesting that miR-205 reduction may drive the progression toward a cell phenotype with enhanced invasive properties and favor metastasis. Accordingly, tumors from patients with lymph node dissemination show lower miR-205 expression than those from node-negative patients. 3 However, evidence of a downregulation of the miRNA in clinically localized carcinomas 4 suggests that loss of miR-205 in PCa may anticipate disease progression. To gain insight into this early loss of the miRNA and into the mechanisms of PCa development, we investigated the physiological role of miR-205 in normal prostate.Prostatic epithelium is characterized by three different cell layers: (i) an outer, androgen-independent basal layer, lying on a basement m...

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Section: Resultsmentioning

confidence: 99%

miR-205 regulates basement membrane deposition in human prostate: implications for cancer development

et al. 2012

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“…Growing evidence indicates that miRNAs can act as ideal molecular targets for cancer diagnosis, prognosis and therapy in many types of cancers (20)(21)(22). Various miRNAs have been used to detect cancer and to develop miRNA-based therapeutic strategies in PCa (23)(24)(25). To explore different strategies for cancer therapeutics, more studies are needed to identify novel and valuable miRNAs and further, to investigate the role and molecular mechanisms of these miRNAs in PCa tumorigenesis.…”

Section: Discussionmentioning

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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“…To date, considerable evidence has revealed the important roles of miR-31 in cancer, but whether this miRNA functions as a tumor suppressor or an oncogene differs according to cancer type. miR-31 reportedly contributes to apoptosis resistance in PCa cells by targeting the antiapoptotic protein E2F6 29,35 and can antagonize metastasis by suppressing expression levels of ITGA5, RDX and RhoA in breast cancer. 36 Interestingly, our functional analyses showed that restoration of miR-31 in PCa cell lines inhibited cell migration and invasion more significantly than cell proliferation, suggesting that miR-31 may also contribute to cancer invasion and metastasis in PCa.…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressive microRNAs (miR-222 and miR-31) regulate molecular pathways based on microRNA expression signature in prostate cancer

et al. 2012

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microRNAs (miRNAs) have key roles in human tumorigenesis, tumor progression and metastasis. miRNAs are aberrantly expressed in many human cancers and can function as tumor suppressors or oncogenes that target many cancer-related genes. This study seeks to identify novel miRNA-regulated molecular pathways in prostate cancer (PCa). The miRNA expression signature in clinical specimens of PCa showed that 56 miRNAs were significantly downregulated in PCa compared with nonPCa tissues. We focused on the top four downregulated miRNAs (miR-187, miR-205, miR-222 and miR-31) to investigate their functional significance in PCa cells. Expression levels of these four miRNAs were validated in PCa specimens (15 PCa tissues and 17 non-PCa tissues) to confirm that they were significantly reduced in these PCa tissues. Gain-of-function analysis demonstrated that miR-222 and miR-31 inhibited cell proliferation, invasion and migration in PCa cell lines (PC3 and DU145), suggesting that miR-222 and miR-31 may act as tumor suppressors in PCa. Genome-wide gene expression analysis using miR-222 or miR-31 transfectants to identify the pathways they affect showed that many cancer-related genes are regulated by these miRNAs in PC3 cells. Identification and categorization of the molecular pathways regulated by tumor suppressive miRNAs could provide new information about the molecular mechanisms of PCa tumorigenesis.

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Downregulation of miR-205 and miR-31 confers resistance to chemotherapy-induced apoptosis in prostate cancer cells

Cited by 186 publications

References 29 publications

miR-205 regulates basement membrane deposition in human prostate: implications for cancer development

miR-205 regulates basement membrane deposition in human prostate: implications for cancer development

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

Tumor suppressive microRNAs (miR-222 and miR-31) regulate molecular pathways based on microRNA expression signature in prostate cancer

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