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

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)68371-68384
Number of pages14
JournalOncotarget
Volume7
Issue number42
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Keywords

  • MiR-4534
  • MicroRNA
  • Oncogene
  • PTEN
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Nip, H., Dar, A. A., Saini, S., Colden, M., Varahram, S., Chowdhary, H., Yamamura, S., Mitsui, Y., Tanaka, Y., Kato, T., Hashimoto, Y., Shiina, M., Kulkarni, P., Dasgupta, P., Imai-Sumida, M., Laura Tabatabai, Z., Greene, K., Deng, G., Dahiya, R., & Majid, S. (2016). Oncogenic microRNA-4534 regulates PTEN pathway in prostate cancer. Oncotarget, 7(42), 68371-68384. https://doi.org/10.18632/ONCOTARGET.12031