MicroRNA‑1291 mediates cell proliferation and tumorigenesis by downregulating MED1 in prostate cancer

Cai, Qing-Qing; An, Zhen; Ren, Lele; Chen, Jing; Liao, Kaisen; Wang, Zhanshi; Zhang, Wei

doi:10.3892/ol.2019.9980

Cited by 11 publications

(22 citation statements)

References 26 publications

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“…Studies showed that miR-1291 had anti-tumor effects in multiple cancers including renal cancer, esophagus cancer, pancreatic cancer, and prostate cancer [34][35][36][37]. As the target for miR-1291, several molecules have been identi ed.…”

Section: Discussionmentioning

confidence: 99%

“…These include SLC2A1/GLUT1 in A498 and 786-O renal cancer cells [34], MUC1 in human esophagus cancer EC9706 and EC-1 cells [35], the forkhead box protein A2-anterior gradient 2 (FOXA2-AGR2) pathway in PANC-1 pancreatic cancer cells [36]. Furthermore, miR-1291 has been shown to inhibit cell growth and tumorigenesis in prostate cancer by binding to MED1 [37]. However, to the best of our knowledge, there is no previous report of miR-1291 in CRC which is one of the widespread cancers in the world.…”

Section: Discussionmentioning

confidence: 99%

“…Through in silico analysis and in vitro selection, we focused on miR-1291 as a possible upstream modulator for DCLK-1. In recent years, miR-1291 has been demonstrated to have anti-tumor effects in carcinoma of the kidney, esophagus, pancreas, and prostate [34][35][36][37]. However, to the best of our knowledge, miR-1291 in CRC has not been reported.…”

Section: Introductionmentioning

confidence: 90%

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Anti-tumor effect of miR-1291 in colon cancer cells

Wang

Hirose

Yokoyama

et al. 2020

Preprint

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Background: Cancer stem cells (CSCs) are drug-tolerant and cause distant metastasis and recurrence in various cancers, including colorectal cancer (CRC). Thus, CSC-targeted therapy may be an effective curative approach in CRC. MiR-1291 has an anti-tumor effect in carcinoma of kidney, esophagus, pancreas, and prostate. However, there is no report about the effect of miR-1291 on CRC.Methods: In this study, we took CSC marker DCLK-1 as a target gene, and screened promising miRNAs that may suppress DCLK-1 by using TargetScan Human. We performed luciferase reporter assay, quantitative real-time PCR analysis, and Western blot analysis to verify the interaction between DCLK-1 and miR-1291 in CRC cells. We also confirmed the function of miR-1291 on cancer stemness by identifying the expression of Bmi1 and CD133 in CRC cells by quantitative real-time PCR analysis, Western blot analysis, and flow cytometric analysis, as well as performing sphere formation assay. We also explored the effect of miR-1291 on cell proliferation, invasion, and wound-healing, colony formation, and cell cycle regulation. Results: We found a 7-base seed sequence of miR-1291 that matches the 3’ UTR sequence of DCLK-1 using TargetScan Human. A luciferase reporter assay showed that miR-1291 directly bound the 3’ UTR sequence of DCLK-1 and suppressed its expression at both the mRNA and protein levels. In addition, miR-1291 suppressed CSC markers Bmi1 and CD133 as well as sphere formation ability in CRC cells. Moreover, miR-1291 significantly suppressed the proliferation, invasion, wound-healing, and colony formation capability of colon cancer cell lines. MiR-1291 caused altered expression of the cell cycle-regulatory proteins representatively, CDK inhibitors p21WAF1/CIP1 and p27KIP1. Conclusions: Taken together, these findings indicate that miR-1291 has an anti-tumor effect by modulating multiple functions, including, cancer stemness, cell cycle, and invasiveness. Our data suggest that miR-1291 could be a promising nucleic acid medicine against CRC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

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Anti-tumor effect of miR-1291 in colon cancer cells

Wang

Hirose

Yokoyama

et al. 2020

Preprint

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“…These results were consistent with a previous study reporting that MED1 was often either upregulated or downregulated in melanoma 36 , which also showed that low MED1 expression correlated with a highly tumorigenic phenotype. Multiple other studies have also demonstrated that MED1 31,[37][38][39][40][41] and Mediator subunits are deregulated in melanoma and other cancer types 31,[42][43][44][45][46] . The observed differences in expression of different MEDs may translate into diffences in the activity of the Mediator complex to support tumorigenesis and specific phenotypes, such as SSX2 expression.…”

Section: Expression Of Mediator Subunits Is Deregulated In Melanomamentioning

confidence: 90%

A functional genetic screen identifies the Mediator complex as essential for SSX2-induced senescence

et al. 2019

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The senescence response to oncogenes is believed to be a barrier to oncogenic transformation in premalignant lesions, and describing the mechanisms by which tumor cells evade this response is important for early diagnosis and treatment. The male germ cell-associated protein SSX2 is ectopically expressed in many types of cancer and is functionally involved in regulating chromatin structure and supporting cell proliferation. Similar to many wellcharacterized oncogenes, SSX2 has the ability to induce senescence in cells. In this study, we performed a functional genetic screen to identify proteins implicated in SSX2-induced senescence and identified several subunits of the Mediator complex, which is central in regulating RNA polymerase-mediated transcription. Further experiments showed that reduced levels of MED1, MED4, and MED14 perturbed the development of senescence in SSX2expressing cells. In contrast, knockdown of MED1 did not prevent development of B-Raf-and Epirubicin-induced senescence, suggesting that Mediator may be specifically linked to the cellular functions of SSX2 that may lead to development of senescence or be central in a SSX2-specific senescence response. Indeed, immunostaining of melanoma tumors, which often express SSX proteins, exhibited altered levels of MED1 compared to benign nevi. Similarly, RNA-seq analysis suggested that MED1, MED4, and MED14 were downregulated in some tumors, while upregulated in others. In conclusion, our study reveals the Mediator complex as essential for SSX2-induced senescence and suggests that changes in Mediator activity could be instrumental for tumorigenesis.

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“…In recent years, miR-1291 has been demonstrated to have anti-tumor effects in carcinoma of the kidney, esophagus, pancreas, and prostate [31][32][33][34]. However, to the best of our knowledge, miR-1291 in CRC has not been reported.…”

Section: Introductionmentioning

confidence: 90%

Anti-tumor effect of miR-1291 in colorectal cancer

Wang

Hirose

Yokoyama

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: MiR-1291 has an anti-tumor effect in carcinoma of kidney, esophagus, pancreas, and prostate. However, it’s role in colorectal cancer (CRC) has not been elucidated.Methods: In this study, we explored the effect of miR-1291 in CRC cells (HCT116, DLD-1, and HT29) in vitro, and performed a tumor growth inhibitory assay in a mouse therapeutic model using DLD-1 cells. Flow cytometric analysis and Western blotting were performed to examine a role of miR-1291 in cell cycle regulation. We performed luciferase reporter assay to verify the interaction between DCLK1 and miR-1291 in HCT116 cells. Cancer stemness was evaluated by identifying the expression of BMI1 and CD133, as well as performing sphere formation assay. Results: We found that miR-1291 significantly suppressed the proliferation, invasion, cell mobility, and colony formation capability of CRC cell lines. MiR-1291 caused altered expression of the cell cycle-regulatory proteins, representatively CDK inhibitors p21WAF1/CIP1 and p27KIP1 or CDK4. Moreover, intravenous administration of miR-1291 loaded on the super carbonate apatite delivery system significantly inhibited a tumor growth in the DLD-1 xenograft mouse model. A luciferase reporter assay showed that miR-1291 directly bound the 3’ UTR sequence of DCLK1 and suppressed its expression at both the mRNA and protein levels in HCT116 expressing the DCLK1 protein. In addition, miR-1291 suppressed cancer stem cell (CSC) markers BMI1 and CD133 as well as sphere formation ability in HCT116 cells. Conclusions: Taken together, these findings indicate that miR-1291 has an anti-tumor effect by modulating multiple functions, including cell cycle, invasiveness, and cancer stemness. Our data suggest that miR-1291 could be a promising nucleic acid medicine against CRC.

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MicroRNA‑1291 mediates cell proliferation and tumorigenesis by downregulating MED1 in prostate cancer

Cited by 11 publications

References 26 publications

Anti-tumor effect of miR-1291 in colon cancer cells

Anti-tumor effect of miR-1291 in colon cancer cells

A functional genetic screen identifies the Mediator complex as essential for SSX2-induced senescence

Anti-tumor effect of miR-1291 in colorectal cancer

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