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Published on: January 22, 2013
Elevated miR-182-5p Associates with Renal Cancer Cell Mitotic Arrest through Diminished MALAT-1 Expression
Priyanka Kulkarni1,2, Pritha Dasgupta1,2, Nadeem S Bhat3
1Department of Urology, Veterans Affairs Medical Center, San Francisco, California.
Abstract:
The molecular heterogeneity of clear cell renal carcinoma (ccRCC) makes prediction of disease progression and therapeutic response difficult. Thus, this report investigates the functional significance, mechanisms of action, and clinical utility of miR-182-5p and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1/NEAT2), a long noncoding RNA (lncRNA), in the regulation of kidney cancer using human kidney cancer tissues as well as in vitro and in vivo model systems. Profiling of miR-182-5p and MALAT-1 in human renal cancer cells and clinical specimens was done by quantitative real-time PCR (qPCR). The biological significance was determined by series of in vitro and in vivo experiments. The interaction between miR-182-5p and MALAT-1 was investigated using luciferase reporter assays. In addition, the effects of miR-182-5p overexpression and MALAT-1 downregulation on cell-cycle progression were assessed in ccRCC cells. The data indicate that miR-182-5p is downregulated in ccRCC; the mechanism being CpG hypermethylation as observed from 5-Aza CdR treatment that decreased promoter methylation and expression of key methylation regulatory genes like DNMT1, DNMT3a, and DNMT3b Overexpression of miR-182-5p-inhibited cell proliferation, colony formation, apoptosis, and led to G2-M-phase cell-cycle arrest by directly targeting MALAT-1 Downregulation of MALAT-1 led to upregulation of p53, downregulation of CDC20, AURKA, drivers of the cell-cycle mitotic phase. Transient knockdown of MALAT-1 mimicked the effects of miR-182-5p overexpression. Finally, overexpression of miR-182-5p decreased tumor growth in mice, compared with controls; thus, demonstrating its antitumor effect in vivo Implications: This is the first study that offers new insight into role of miR-182-5p/MALAT-1 interaction on inhibition of ccRCC progression. Mol Cancer Res; 16(11); 1750-60. ©2018 AACR.
Insights
This study reveals that restoring miR-182-5p levels inhibits clear cell renal cell carcinoma (ccRCC) progression by targeting MALAT1. Overexpression of miR-182-5p demonstrates significant antitumor effects in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Clear cell renal cell carcinoma (ccRCC) exhibits molecular heterogeneity, complicating disease progression prediction and treatment response.
- Identifying key regulatory molecules is crucial for understanding and targeting ccRCC pathogenesis.
Purpose of the Study:
- To investigate the functional role, mechanism of action, and clinical relevance of miR-182-5p and the long noncoding RNA MALAT1 in ccRCC.
- To elucidate the regulatory interaction between miR-182-5p and MALAT1 in kidney cancer.
Main Methods:
- Quantitative real-time PCR (qPCR) for profiling miR-182-5p and MALAT1 expression in ccRCC tissues and cell lines.
- In vitro and in vivo experiments to assess biological significance, including cell proliferation, apoptosis, and cell-cycle progression assays.
- Luciferase reporter assays to confirm the direct interaction between miR-182-5p and MALAT1.
- In vivo studies involving tumor growth assessment in mice following miR-182-5p overexpression.
Main Results:
- miR-182-5p was found to be downregulated in ccRCC, associated with CpG hypermethylation and increased expression of DNMT1, DNMT3a, and DNMT3b.
- Overexpression of miR-182-5p inhibited ccRCC cell proliferation, colony formation, and induced apoptosis, leading to G2-M cell-cycle arrest by directly targeting MALAT1.
- Downregulation of MALAT1 resulted in p53 upregulation and CDC20/AURKA downregulation, mimicking miR-182-5p overexpression effects.
- Overexpression of miR-182-5p significantly reduced tumor growth in a mouse model, confirming its in vivo antitumor activity.
Conclusions:
- This study establishes miR-182-5p as a tumor suppressor in ccRCC, with its downregulation mediated by epigenetic silencing.
- The miR-182-5p/MALAT1 interaction plays a critical role in inhibiting ccRCC progression.
- These findings offer novel therapeutic strategies targeting the miR-182-5p/MALAT1 axis for ccRCC treatment.
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