Elevated miR-182-5p associates with renal cancer cell mitotic arrest through diminished MALAT-1 expression

Priyanka Kulkarni, Pritha Dasgupta, Nadeem S. Bhat, Varahram Shahryari, Marisa Shiina, Yutaka Hashimoto, Shahana Majid, Guoren Deng, Sharanjot Saini, Z. Laura Tabatabai, Soichiro Yamamura, Yuichiro Tanaka, Rajvir Dahiya

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1750-1760
Number of pages11
JournalMolecular Cancer Research
Volume16
Issue number11
DOIs
StatePublished - Nov 2018
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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  • Cite this

    Kulkarni, P., Dasgupta, P., Bhat, N. S., Shahryari, V., Shiina, M., Hashimoto, Y., Majid, S., Deng, G., Saini, S., Tabatabai, Z. L., Yamamura, S., Tanaka, Y., & Dahiya, R. (2018). Elevated miR-182-5p associates with renal cancer cell mitotic arrest through diminished MALAT-1 expression. Molecular Cancer Research, 16(11), 1750-1760. https://doi.org/10.1158/1541-7786.MCR-17-0762