MicroRNA-124 regulates TGF-α-induced epithelial-mesenchymal transition in human prostate cancer cells

Qin, Wei; Pan, Yujia; Zheng, Xiaodong; Li, Dong; Bu, Jingyi; Xu, Chunyan; Tang, Jingling; Cui, Rongjun; Lin, Ping; Yu, Xiuchong

doi:10.3892/ijo.2014.2506

Cited by 31 publications

(22 citation statements)

References 37 publications

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“…Slug, a regulator of E-cadherin and epithelial-to-mesenchymal transition (EMT), was demonstrated to be a direct target for miR-124 in breast carcinoma cells (30). Consistent with the finding, an independent group showed that miR-124 inhibits TGF-α-induced EMT by modulating Slug in DU145 prostate carcinoma cells (31). Moreover, miR-124 was shown to negatively regulate signal transducers and activators of transcription 3 (STAT3) to reduce the tumorigenicity of colorectal and hepatocellular carcinoma cells (32, 33).…”

Section: Discussionsupporting

confidence: 75%

miR-124 Regulates the Epithelial-Restricted with Serine Box/Epidermal Growth Factor Receptor Signaling Axis in Head and Neck Squamous Cell Carcinoma

Zhang

Piao

Datta

et al. 2015

Molecular Cancer Therapeutics

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Epithelial-restricted with serine box (ESX), a member of the ETS transcription factor family, is elevated and regulates epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanisms that contribute to ESX dysregulation remains to be elucidated. In this study, in silico analysis of the 3′-untranslated region (UTR) of ESX predicted two miR-124 binding sites. Delivery of miR-124 inhibited the 3′UTR ESX-driven reporter activity by 50% (p<0.05) confirming ESX as a direct target of miR-124. Loss of miR-124 was found to a frequent event in HNSCC. miR-124 expression was significantly depleted in the primary tumor compared to matched normal tissue in 100% (12/12) of HNSCC patients; relative mean miR-124 expression of 0.01197 and 0.00118 (p<0.001, n=12) in matched normal adjacent tissue and primary HNSCC tumor, respectively. Over-expression of miR-124 decreased ESX and EGFR levels in miR-124low/ESXhigh/EGFRhigh SCC15 HNSCC cells and reduced cell invasion, migration, proliferation and colony formation. SCC15 cells with miR-124 restoration were less tumorigenic in vivo than miR-control SCC15 cells (70% inhibition, p<0.01). Restoration of miR-124 in SCC15 cells enhanced the anti-proliferative efficacy of the EGFR/Her2 TKIs. Furthermore, recapitulation of EGFR in miR-124 over-expressing SCC15 cells was sufficient to completely block the anti-proliferative effects of lapatinib and afatinib. Taken together, our work provides intriguing evidence that miR-124 is a novel therapeutic approach to reduce ESX/EGFR and may be a tractable strategy to enhance the response rate of HNSCC patients to current anti-EGFR/Her2 therapies.

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Section: Discussionsupporting

confidence: 75%

miR-124 Regulates the Epithelial-Restricted with Serine Box/Epidermal Growth Factor Receptor Signaling Axis in Head and Neck Squamous Cell Carcinoma

Zhang

Piao

Datta

et al. 2015

Molecular Cancer Therapeutics

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“…Overexpression of miR-124 on the TGF-α treated PCa cells inhibited the EMT inducing effects of TGF-α and reduced cellular invasion. Further, the authors demonstrated that miR-124 directly targets Slug (Figure 1) [70]. …”

Section: Micrornas and Emt In Prostate Cancermentioning

confidence: 99%

MicroRNAs and epithelial-mesenchymal transition in prostate cancer

et al. 2016

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Prostate cancer (PCa) is a leading cause of male cancer-related deaths. A significant fraction of prostate tumors are very aggressive, often metastasizing to bone, causing significant morbidity and mortality. Also, PCa is associated with high rates of recurrence, often attributed to the existence of cancer stem cells. Epithelial-mesenchymal transition (EMT), a process characterized by decreased expression of epithelial genes and increased expression of mesenchymal genes, plays a critical role in tumor invasion, metastasis and recurrence. In PCa, EMT has been implicated particularly in the context of metastatic disease and microRNAs have emerged as critical post-transcriptional regulators of PCa EMT. In this review, we summarize the role of miRNAs in PCa EMT that play a role in progression, metastasis and recurrence. Studies till date suggest that microRNAs mediate efficient and reversible control of PCa EMT via multiple mechanisms including either by (i) directly repressing single or multiple EMT-TFs or regulating cytoskeletal components (epithelial/mesenchymal genes) or (ii) regulating key signaling pathways involved in EMT. Oncogenic microRNAs often act as EMT promoters by repressing epithelial characteristics and tumor suppressive miRNAs act by inhibiting mesenchymal progression. Further, EMT is mechanistically linked to stem cell signatures in PCa and several miRNAs implicated in EMT have been reported to influence PCa stem cells. Loss of EMT-inhibiting miRNAs and/or gain of EMT promoting miRNAs lead to induction of PCa EMT, leading to tumor progression, metastasis and recurrence. Restoring expression of tumor suppressive miRNAs and inhibiting oncogenic miRNAs represent potential therapeutic opportunities to prevent disease metastasis and recurrence.

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“…Capn4 is involved in the EMT of glioma cells. miR-124 has been demonstrated to reverse the EMT (16). We investigated whether Capn4 was involved in this process.…”

Section: Mir-124 Suppresses the Migration And Invasion Of Glioma Cellmentioning

confidence: 99%

miR-124 suppresses the migration and invasion of glioma cells in vitro via Capn4

Cai

Chen

et al. 2015

Oncology Reports

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miR-124 and Capn4 are aberrantly expressed in glioblastoma multiforme (GBM) tissues. In the present study, we investigated miR-124 and Capn4 expression in GBM tissue specimens. The role of miR-124 and Capn4 in the migration and invasion of glioma cells in vitro was also examined. miR-124 and Capn4 expression in 20 GBM and 6 control brain specimens was examined using RT-qPCR and immuno-blotting. Data from The Cancer Genome Atlas were retrieved. Candidate mRNA target sites of miR-124 were predicted using TargetScan/microRNA and binding was examined using dual luciferase reporter assays. The U87 and U251 cells were transfected with scrambled microRNA, miR-124 mimics and/or pLenti-Capn4 prior to wound‑healing and Transwell invasion assays. Proteins involved in the epithelial-mesenchymal transition were examined using immunoblotting. The results showed that miR-124 was significantly downregulated in GBM tissues. Immunoblotting showed a marked upregulation of Capn4 expression in GBM tissues. The Spearman's correlation analysis revealed a negative association between miR-124 expression and Capn4 protein levels. TargetScan/microRNA predicted the miR-124 binding site in the nucleotide 440-446 region within the Capn4 3'-UTR, which was confirmed by luciferase assays. Wound‑healing and Transwell invasion assays demonstrated that Capn4 downregulation or miR-124 mimics suppressed the migration and invasion of glioma cells. Capn4 downregulation or miR-124 mimics reduced the level of phospho-FAK and MMP2, vimentin and N-cadherin in U87 cells. In conclusion, miR-124 was found to suppress the migration and invasion of glioma cells in vitro via Capn4.

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MicroRNA-124 regulates TGF-α-induced epithelial-mesenchymal transition in human prostate cancer cells

Cited by 31 publications

References 37 publications

miR-124 Regulates the Epithelial-Restricted with Serine Box/Epidermal Growth Factor Receptor Signaling Axis in Head and Neck Squamous Cell Carcinoma

miR-124 Regulates the Epithelial-Restricted with Serine Box/Epidermal Growth Factor Receptor Signaling Axis in Head and Neck Squamous Cell Carcinoma

MicroRNAs and epithelial-mesenchymal transition in prostate cancer

miR-124 suppresses the migration and invasion of glioma cells in vitro via Capn4

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