Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression

DIvya Bhagirath, Thao Ly Yang, Z. Laura Tabatabai, Varahram Shahryari, Shahana Majid, Rajvir Dahiya, Yuichiro Tanaka, Sharanjot Saini

Research output: Contribution to journalArticle

Abstract

The prostate cancer (PCa) genome is characterized by deletions of chromosome 8p21-22 region that increase significantly with tumor grade and are associated with poor prognosis. We proposed and validated a novel, paradigm-shifting hypothesis that this region is associated with a set of microRNA genes - miR-3622, miR-3622b, miR-383 - that are lost in PCa and play important mechanistic roles in PCa progression and metastasis. Extending our hypothesis, in this study, we evaluated the role of a microRNA gene located in chromosome 8p - miR-4288 - by employing clinical samples and cell lines. Our data suggests that (i) miR-4288 is widely downregulated in primary prostate tumors and cell lines; (ii) miR-4288 expression is lost in metastatic castration-resistant PCa; (ii) miR-4288 downregulation is race-related PCa alteration that is prevalent in Caucasian patients and not in African Americans; (iii) in Caucasians, miR-4288 was found to be associated with increasing tumor grade and high serum prostate-specific antigen, suggesting that miR-4288 downregulation/loss may be associated with tumor progression specifically in Caucasians; (iv) miR-4288 possess significant potential as a molecular biomarker to predict aggressiveness/metastasis; and (v) miR-4288 is anti-proliferative, is anti-invasive and inhibits epithelial-to-mesenchymal transition; and (vi) miR-4288 directly represses expression of metastasis/invasion-associated genes MMP16 and ROCK1. Thus, the present study demonstrates a tumor suppressor role for a novel miRNA located with a frequently lost region in PCa, strengthening our hypothesis that this locus is causally related to PCa disease progression via loss of microRNA genes. Our study suggests that miR-4288 may be a novel biomarker and therapeutic target, particularly in Caucasians.

Original languageEnglish (US)
Pages (from-to)633-642
Number of pages10
JournalCarcinogenesis
Volume40
Issue number5
DOIs
StatePublished - Jul 4 2019
Externally publishedYes

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MicroRNAs
Prostatic Neoplasms
Neoplasms
Down-Regulation
Neoplasm Metastasis
Genes
Biomarkers
Chromosomes, Human, Pair 22
Epithelial-Mesenchymal Transition
Castration
Prostate-Specific Antigen
Tumor Cell Line
African Americans
Disease Progression
Prostate
Chromosomes
Genome
Cell Line
Serum

ASJC Scopus subject areas

  • Cancer Research

Cite this

Bhagirath, DI., Yang, T. L., Tabatabai, Z. L., Shahryari, V., Majid, S., Dahiya, R., ... Saini, S. (2019). Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression. Carcinogenesis, 40(5), 633-642. https://doi.org/10.1093/carcin/bgz058

Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression. / Bhagirath, DIvya; Yang, Thao Ly; Tabatabai, Z. Laura; Shahryari, Varahram; Majid, Shahana; Dahiya, Rajvir; Tanaka, Yuichiro; Saini, Sharanjot.

In: Carcinogenesis, Vol. 40, No. 5, 04.07.2019, p. 633-642.

Research output: Contribution to journalArticle

Bhagirath, DI, Yang, TL, Tabatabai, ZL, Shahryari, V, Majid, S, Dahiya, R, Tanaka, Y & Saini, S 2019, 'Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression', Carcinogenesis, vol. 40, no. 5, pp. 633-642. https://doi.org/10.1093/carcin/bgz058
Bhagirath, DIvya ; Yang, Thao Ly ; Tabatabai, Z. Laura ; Shahryari, Varahram ; Majid, Shahana ; Dahiya, Rajvir ; Tanaka, Yuichiro ; Saini, Sharanjot. / Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression. In: Carcinogenesis. 2019 ; Vol. 40, No. 5. pp. 633-642.
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AU - Majid, Shahana

AU - Dahiya, Rajvir

AU - Tanaka, Yuichiro

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AB - The prostate cancer (PCa) genome is characterized by deletions of chromosome 8p21-22 region that increase significantly with tumor grade and are associated with poor prognosis. We proposed and validated a novel, paradigm-shifting hypothesis that this region is associated with a set of microRNA genes - miR-3622, miR-3622b, miR-383 - that are lost in PCa and play important mechanistic roles in PCa progression and metastasis. Extending our hypothesis, in this study, we evaluated the role of a microRNA gene located in chromosome 8p - miR-4288 - by employing clinical samples and cell lines. Our data suggests that (i) miR-4288 is widely downregulated in primary prostate tumors and cell lines; (ii) miR-4288 expression is lost in metastatic castration-resistant PCa; (ii) miR-4288 downregulation is race-related PCa alteration that is prevalent in Caucasian patients and not in African Americans; (iii) in Caucasians, miR-4288 was found to be associated with increasing tumor grade and high serum prostate-specific antigen, suggesting that miR-4288 downregulation/loss may be associated with tumor progression specifically in Caucasians; (iv) miR-4288 possess significant potential as a molecular biomarker to predict aggressiveness/metastasis; and (v) miR-4288 is anti-proliferative, is anti-invasive and inhibits epithelial-to-mesenchymal transition; and (vi) miR-4288 directly represses expression of metastasis/invasion-associated genes MMP16 and ROCK1. Thus, the present study demonstrates a tumor suppressor role for a novel miRNA located with a frequently lost region in PCa, strengthening our hypothesis that this locus is causally related to PCa disease progression via loss of microRNA genes. Our study suggests that miR-4288 may be a novel biomarker and therapeutic target, particularly in Caucasians.

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