A novel microRNA regulator of prostate cancer epithelial-mesenchymal transition

Nathan Bucay, Divya Bhagirath, Kirandeep Sekhon, Thao Yang, Shinichiro Fukuhara, Shahana Majid, Varahram Shahryari, Z. Laura Tabatabai, Kirsten L. Greene, Yutaka Hashimoto, Marisa Shiina, Soichiro Yamamura, Yuichiro Tanaka, Guoren Deng, Rajvir Dahiya, Sharanjot Saini

Research output: Contribution to journalArticle

Abstract

The most frequent alteration in the prostate oncogenome is loss of chromosome (chr) 8p21 that has been associated with loss of NKX3.1 homeobox gene. Chr8p21 deletions increase significantly with tumor grade and are associated with poor prognosis in prostate cancer (PCa), suggesting critical involvement of this region in tumor progression. Recent studies suggest that apart from NKX3.1, this region harbors alternative tumor suppressors that are yet undefined. We proposed a novel, paradigm shifting hypothesis that this locus is associated with a miRNA gene cluster-miR-3622a/b-that plays a crucial suppressive role in PCa. Here we demonstrate the crucial role of miR-3622a in prostate cancer epithelial-To-mesenchymal transition (EMT). MicroRNA expression profiling in microdissected human PCa clinical tissues showed that miR-3622a expression is widely downregulated and is significantly correlated with poor survival outcome and tumor progression. To understand the functional significance of miR-3622a, knockdown and overexpression was performed using non-Transformed prostate epithelial and PCa cell lines, respectively, followed by functional assays. Our data demonstrate that endogenous miR-3622a expression is vital to maintain the epithelial state of normal and untransformed prostate cells. miR-3622a expression inhibits EMT, progression and metastasis of PCa in vitro and in vivo. Further, we found that miR-3622a directly targets EMT effectors ZEB1 and SNAI2. In view of these data, we propose that frequent loss of miR-3622a at chr8p21 region leads to induction of EMT states that in turn, promotes PCa progression and metastasis. This study has potentially significant implications in the field of prostate cancer as it identifies an important miRNA component of a frequently lost chromosomal region with critical roles in prostate carcinogenesis which is a highly significant step towards understanding the mechanistic involvement of this locus. Also, our study indicates that miR-3622a is a novel PCa biomarker and potential drug target for developing therapeutic regimens against advanced PCa.

Original languageEnglish (US)
Pages (from-to)1263-1274
Number of pages12
JournalCell Death and Differentiation
Volume24
Issue number7
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

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Epithelial-Mesenchymal Transition
MicroRNAs
Prostatic Neoplasms
Prostate
Neoplasms
Neoplasm Metastasis
Homeobox Genes
Tumor Biomarkers
Multigene Family
Carcinogenesis
Down-Regulation
Chromosomes
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Bucay, N., Bhagirath, D., Sekhon, K., Yang, T., Fukuhara, S., Majid, S., ... Saini, S. (2017). A novel microRNA regulator of prostate cancer epithelial-mesenchymal transition. Cell Death and Differentiation, 24(7), 1263-1274. https://doi.org/10.1038/cdd.2017.69

A novel microRNA regulator of prostate cancer epithelial-mesenchymal transition. / Bucay, Nathan; Bhagirath, Divya; Sekhon, Kirandeep; Yang, Thao; Fukuhara, Shinichiro; Majid, Shahana; Shahryari, Varahram; Laura Tabatabai, Z.; Greene, Kirsten L.; Hashimoto, Yutaka; Shiina, Marisa; Yamamura, Soichiro; Tanaka, Yuichiro; Deng, Guoren; Dahiya, Rajvir; Saini, Sharanjot.

In: Cell Death and Differentiation, Vol. 24, No. 7, 01.07.2017, p. 1263-1274.

Research output: Contribution to journalArticle

Bucay, N, Bhagirath, D, Sekhon, K, Yang, T, Fukuhara, S, Majid, S, Shahryari, V, Laura Tabatabai, Z, Greene, KL, Hashimoto, Y, Shiina, M, Yamamura, S, Tanaka, Y, Deng, G, Dahiya, R & Saini, S 2017, 'A novel microRNA regulator of prostate cancer epithelial-mesenchymal transition', Cell Death and Differentiation, vol. 24, no. 7, pp. 1263-1274. https://doi.org/10.1038/cdd.2017.69
Bucay N, Bhagirath D, Sekhon K, Yang T, Fukuhara S, Majid S et al. A novel microRNA regulator of prostate cancer epithelial-mesenchymal transition. Cell Death and Differentiation. 2017 Jul 1;24(7):1263-1274. https://doi.org/10.1038/cdd.2017.69
Bucay, Nathan ; Bhagirath, Divya ; Sekhon, Kirandeep ; Yang, Thao ; Fukuhara, Shinichiro ; Majid, Shahana ; Shahryari, Varahram ; Laura Tabatabai, Z. ; Greene, Kirsten L. ; Hashimoto, Yutaka ; Shiina, Marisa ; Yamamura, Soichiro ; Tanaka, Yuichiro ; Deng, Guoren ; Dahiya, Rajvir ; Saini, Sharanjot. / A novel microRNA regulator of prostate cancer epithelial-mesenchymal transition. In: Cell Death and Differentiation. 2017 ; Vol. 24, No. 7. pp. 1263-1274.
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abstract = "The most frequent alteration in the prostate oncogenome is loss of chromosome (chr) 8p21 that has been associated with loss of NKX3.1 homeobox gene. Chr8p21 deletions increase significantly with tumor grade and are associated with poor prognosis in prostate cancer (PCa), suggesting critical involvement of this region in tumor progression. Recent studies suggest that apart from NKX3.1, this region harbors alternative tumor suppressors that are yet undefined. We proposed a novel, paradigm shifting hypothesis that this locus is associated with a miRNA gene cluster-miR-3622a/b-that plays a crucial suppressive role in PCa. Here we demonstrate the crucial role of miR-3622a in prostate cancer epithelial-To-mesenchymal transition (EMT). MicroRNA expression profiling in microdissected human PCa clinical tissues showed that miR-3622a expression is widely downregulated and is significantly correlated with poor survival outcome and tumor progression. To understand the functional significance of miR-3622a, knockdown and overexpression was performed using non-Transformed prostate epithelial and PCa cell lines, respectively, followed by functional assays. Our data demonstrate that endogenous miR-3622a expression is vital to maintain the epithelial state of normal and untransformed prostate cells. miR-3622a expression inhibits EMT, progression and metastasis of PCa in vitro and in vivo. Further, we found that miR-3622a directly targets EMT effectors ZEB1 and SNAI2. In view of these data, we propose that frequent loss of miR-3622a at chr8p21 region leads to induction of EMT states that in turn, promotes PCa progression and metastasis. This study has potentially significant implications in the field of prostate cancer as it identifies an important miRNA component of a frequently lost chromosomal region with critical roles in prostate carcinogenesis which is a highly significant step towards understanding the mechanistic involvement of this locus. Also, our study indicates that miR-3622a is a novel PCa biomarker and potential drug target for developing therapeutic regimens against advanced PCa.",
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AU - Majid, Shahana

AU - Shahryari, Varahram

AU - Laura Tabatabai, Z.

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