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MicroRNA-939 Directly Targets HDGF to Inhibit the Aggressiveness of Prostate Cancer via Deactivation of the WNT/β-Catenin Pathway

Authors Situ J, Zhang H, Jin Z, Li K, Mao Y, Huang W

Received 16 February 2020

Accepted for publication 8 April 2020

Published 18 May 2020 Volume 2020:13 Pages 4257—4270


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Yong Teng

Jie Situ,1,* Hao Zhang,1,* Zi Jin,2 Ke Li,1 Yunhua Mao,1 Wentao Huang1

1Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Hepatological Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Wentao Huang
Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510000, People’s Republic of China

Purpose: MicroRNA-939 (miR-939) has crucial roles in several types of human cancer. However, the expression profile and precise functions of miR-939 in prostate cancer (PCa) are still unclear. This study aimed to determine miR-939 expression in PCa and explore its roles in PCa tumorigenesis.
Methods: miR-939 expression was determined in PCa tissues and cell lines using reverse transcription–quantitative polymerase chain reaction. Cell Counting Kit-8, colony formation, and flow cytometric assays were used to determine the role of miR-939 in PCa cell proliferation and apoptosis in vitro, whereas a tumor xenograft model was generated to evaluate the effect of miR-939 on tumor growth in vivo. Transwell assays were performed to investigate whether miR-939 affects the migration and invasiveness of PCa cells.
Results: miR-939 was found to be downregulated in PCa tissues and cell lines, and this downregulation was significantly correlated with tumor stage and lymphatic metastasis. Patients with PCa exhibiting low miR-939 expression had shorter overall survival than those exhibiting high miR-939 expression. Exogenous miR-939 expression suppressed PCa cell proliferation, colony formation, migration, and invasion in vitro; enhanced apoptosis in vitro; and decreased tumor growth in vivo. Investigation of the underlying molecular mechanisms revealed hepatoma-derived growth factor (HDGF) as a direct target gene of miR-939 in PCa. HDGF was found to be significantly upregulated in PCa tissues, and its expression was inversely correlated with miR-939 expression. HDGF silencing and miR-939 upregulation showed similar effects in PCa. Restored HDGF expression counteracted the tumor-suppressive activity of miR-939 overexpression in PCa cells. Furthermore, ectopic miR-939 expression inhibited the WNT/β-catenin pathway activation in PCa both in vitro and in vivo by downregulating HDGF.
Conclusion: miR-939 functions as a tumor suppressor during PCa tumorigenesis by directly targeting HDGF and deactivating the WNT/β-catenin pathway, suggesting the miR-939/HDGF/WNT/β-catenin pathway as an effective target for PCa therapy.

Keywords: microRNA-939, prostate cancer, hepatoma-derived growth factor, WNT/β-catenin signaling

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