Downregulation of miR-133a-3p promotes prostate cancer bone metastasis via activating PI3K/AKT signaling

Journal of Experimental & Clinical Cancer Research

Qingde Wa¹  Xinsheng Peng²  Dong Ren²  Peiheng He²  Shuai Huang³  Xin Zhang⁴  Ronggang Li⁴  Yubo Tang⁵  Jincheng Pan⁶  Yongxiang Luo⁷  Xuenong Zou⁸ 

[1] Department of Orthopaedic Surgery, the Affiliated Hospital of Zunyi Medical college;Department of Orthopaedic Surgery, the First Affiliated Hospital of Sun Yat-sen University;Department of Orthopaedic Surgery, the Second Affiliated Hospital of Guangzhou Medical University;Department of Pathology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University;Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University;Department of Urology Surgery, the First Affiliated Hospital of Sun Yat-sen University;Department of biomedical engineering, health science center, Shenzhen University;Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, the First Affiliated Hospital of Sun Yat-sen University;

关键词: miR-133a-3p;    Cytokine receptor;    Bone metastasis;    PI3K/AKT signaling pathway;    Prostate cancer;   

DOI  :  10.1186/s13046-018-0813-4

来源: DOAJ

【 摘 要 】

Abstract Background Bone metastasis is a leading cause of morbidity and mortality in advanced prostate cancer (PCa). Downexpression of miR-133a-3p has been found to contribute to the progression, recurrence and distant metastasis in PCa. However, clinical significance of miR-133a-3p in bone metastasis of PCa, and the biological role of miR-133a-3p and its molecular mechanisms underlying bone metastasis of PCa remain unclear. Methods miR-133a-3p expression was evaluated in 245 clinical PCa tissues by real-time PCR. Statistical analysis was performed to evaluate the clinical correlation between miR-133a-3p expression and clinicopathological features, and overall and bone metastasis-free survival in PCa patients. The biological roles of miR-133a-3p in the bone metastasis of PCa were investigated both in vitro and in vivo. Bioinformatics analysis, real-time PCR, western blot and luciferase reporter analysis were applied to demonstrate the relationship between miR-133a-3p and its potential targets. Western blotting and luciferase assays were examined to identify the underlying pathway involved in the anti-tumor role of miR-133a-3p. Clinical correlation of miR-133a-3p with its targets was verified in human PCa tissues. Results miR-133a-3p expression is reduced in PCa tissues compared with the adjacent normal tissues and benign prostate lesion tissues, particularly in bone metastatic PCa tissues. Low expression of miR-133a-3p is significantly correlated with advanced clinicopathological characteristics and shorter bone metastasis-free survival in PCa patients by statistical analysis. Moreover, upregulating miR-133a-3p inhibits cancer stem cell-like phenotypes in vitro and in vivo, as well as attenuates anoikis resistance in vitro in PCa cells. Importantly, administration of agomir-133a-3p greatly suppresses the incidence of PCa bone metastasis in vivo. Our results further demonstrate that miR-133a-3p suppresses bone metastasis of PCa via inhibiting PI3K/AKT signaling by directly targeting multiple cytokine receptors, including EGFR, FGFR1, IGF1R and MET. The negative clinical correlation of miR-133a-3p with EGFR, FGFR1, IGF1R, MET and PI3K/AKT signaling activity is determined in clinical PCa tissues. Conclusion Our results unveil a novel mechanism by which miR-133a-3p inhibits bone metastasis of PCa, providing the evidence that miR-133a-3p may serve as a potential bone metastasis marker in PCa, and delivery of agomir-133a-3p may be an effective anti-bone metastasis therapeutic strategy in PCa.

【 授权许可】

Unknown