Oncotarget

Research Papers:

Oncogenic microRNA-4534 regulates PTEN pathway in prostate cancer

Hannah Nip, Altaf A. Dar, Sharanjot Saini, Melissa Colden, Shahryari Varahram, Harshika Chowdhary, Soichiro Yamamura, Yozo Mitsui, Yuichiro Tanaka, Taku Kato, Yutaka Hashimoto, Marisa Shiina, Priyanka Kulkarni, Pritha Dasgupta, Mitsuho Imai-Sumida, Z. Laura Tabatabai, Kirsten Greene, Guoren Deng, Rajvir Dahiya, Shahana Majid _

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Oncotarget. 2016; 7:68371-68384. https://doi.org/10.18632/oncotarget.12031

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Abstract

Hannah Nip1, Altaf A. Dar2, Sharanjot Saini1, Melissa Colden1, Shahryari Varahram1, Harshika Chowdhary1, Soichiro Yamamura1, Yozo Mitsui 1, Yuichiro Tanaka1, Taku Kato1, Yutaka Hashimoto1, Marisa Shiina1, Priyanka Kulkarni1, Pritha Dasgupta1, Mitsuho Imai-Sumida1, Z. Laura Tabatabai1, Kirsten Greene1, Guoren Deng1, Rajvir Dahiya1, Shahana Majid1

1Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA

2Research Institute, California Pacific Medical Center, San Francisco, California, USA

Correspondence to:

Shahana Majid, email: Shahana.Majid@ucsf.edu

Keywords: microRNA, prostate cancer, oncogene, PTEN, miR-4534

Received: June 07, 2016     Accepted: August 26, 2016     Published: September 15, 2016

ABSTRACT

Prostate carcinogenesis involves alterations in several signaling pathways, the most prominent being the PI3K/AKT pathway. This pathway is constitutively active and drives prostate cancer (PCa) progression to advanced metastatic disease. PTEN, a critical tumor and metastasis suppressor gene negatively regulates cell survival, proliferation, migration and angiogenesis via the PI3K/Akt pathway. PTEN is mutated, downregulated/dysfunctional in many cancers and its dysregulation correlates with poor prognosis in PCa. Here, we demonstrate that microRNA-4534 (miR-4534) is overexpressed in PCa and show that miR-4534 is hypermethylated in normal tissues and cell lines compared to PCa tissues/cells. miR-4534 exerts its oncogenic effects partly by downregulating the tumor suppressor PTEN gene. Knockdown of miR-4534 impaired cell proliferation, migration/invasion and induced G0/G1 cell cycle arrest and apoptosis in PCa. Suppression of miR-4534 and its effects on tumor growth was confirmed in a xenograft mouse model. We performed parallel experiments in non-cancer RWPE1 cells by overexpessing miR-4534 followed by functional assays. Overexpression of miR-4534 induced pro-cancerous characteristics in this non-cancer cell line. Statistical analyses revealed that miR-4534 has potential to independently distinguish malignant from normal tissues and positively correlated with poor overall and PSA recurrence free survival. Taken together, our results show that depletion of miR-4534 in PCa induces a tumor suppressor phenotype partly through induction of PTEN. These results have important implications for identifying and defining the role of new PTEN regulators such as microRNAs in prostate tumorigenesis. Understanding aberrantly overexpressed miR-4534 and its downregulation of PTEN will provide mechanistic insight and therapeutic targets for PCa therapy.


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