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.
Highlights
Prostate cancer is the second most prevalent cause of cancer deaths among males in the United States [1] and the fourth most common tumor type worldwide [2]
A set of miRNAs, miR-205, -203, 23b and -34b were found to be significantly downregulated whereas miR-4534 was significantly upregulated in prostate cancer cells compared to a non-malignant cell line
In this study we report that: (i) miR-4534 is overexpressed in prostate cancer tissues and cell lines compared to matched normal samples and cell lines; (ii) miR-4534 has potential to distinguish malignant from normal tissues; (iii) miR-4534 functions as an oncomiR as its attenuation results in cell cycle arrest, apoptosis, impaired migration/invasion and colony forming capability of prostate cancer cells; (iv) miR-4534 directly targets PTEN and its downstream effectors to exert its functional effects; (v) intra-tumoral delivery of administration of miR-4534 miRVANA miRNA inhibitor (antimiR)-4534 inhibits in-vivo tumor growth in nude mice xenografts
Summary
Prostate cancer is the second most prevalent cause of cancer deaths among males in the United States [1] and the fourth most common tumor type worldwide [2]. The five year relative survival rate of early stage prostate cancer is > 99% while that of advanced metastatic disease is only 28% [1]. The clinical behavior of localized prostate cancer is highly variable, while some men have aggressive cancer leading to metastasis and death from the disease, many others have indolent cancers that are cured with initial therapy or may be safely observed. Multiple risk stratification systems have been developed, combining the best currently www.impactjournals.com/oncotarget available clinical and pathological parameters (such as Gleason score, PSA levels and clinical and pathological staging); several areas of urgent unmet need remain [3,4,5], e.g., a validated biomarker to complement PSA for screening, prognostic biomarkers with clinical utility, further risk stratification using molecular differentiation could potentially help distinguish indolent from aggressive prostate cancer. The PI3K/Akt pathway is frequently activated due to inactivation of PTEN
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
