title: Oncogenic microRNA-4534 regulates PTEN pathway in prostate cancer.
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.
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Nip
authors.affiliation: Research Institute, California Pacific Medical Center, San Francisco, California, USA.
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Dar
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Sharanjot
authors.initials: S
authors.lastname: Saini
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Colden
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Shahryari
authors.initials: S
authors.lastname: Varahram
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Harshika
authors.initials: H
authors.lastname: Chowdhary
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Mitsui
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Taku
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Shiina
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Kulkarni
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Pritha
authors.initials: P
authors.lastname: Dasgupta
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Mitsuho
authors.initials: M
authors.lastname: Imai-Sumida
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Z Laura
authors.initials: ZL
authors.lastname: Tabatabai
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Greene
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA.
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019175:DNA Methylation; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D014183:Transplantation, Heterologous
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PTEN; miR-4534; microRNA; oncogene; prostate cancer