Abstract
BackgroundBone 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.MethodsmiR-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.ResultsmiR-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.ConclusionOur 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.
Highlights
Bone metastasis is a leading cause of morbidity and mortality in advanced prostate cancer (PCa)
We further examined miR-133a-3p expression levels in our clinical PCa tissues and benign prostate lesions, including benign prostate hyperplasia and prostatitis, and found that miR-133a-3p expression was reduced in primary PCa tissues compared with that in benign prostate lesion tissues (Fig. 1d and e), and in bone metastatic PCa tissues (Fig. 1f )
We further examined the expression levels of miR-133a-3p in normal prostate epithelial cells RWPE-1 and other 6 PCa cells and found that miR-133a-3p expression were differentially downregulated compared with RWPE-1, especially in bone metastatic PCa cell lines (VCaP and PC-3) (Fig. 1g)
Summary
Bone metastasis is a leading cause of morbidity and mortality in advanced prostate cancer (PCa). Prostate cancer (PCa) is the second common diagnosed cancer in men worldwide and the fifth leading cause of cancer-related deaths [1]. The 5-year relative survival rate of primary PCa patients is > 99%, while that of patients with distant metastasis sites is no more than 30% [2]. Once tumor cell metastasis to bone, it will cause several bone- associated complications, including hypercalcemia, intractable pain, fracture, or nerve compression syndrome, contributing to the poor survival in PCa patients [4]. A major challenge for treatment of advanced metastatic disease is due to incomplete understanding of the molecular mechanisms underlying the high avidity of PCa to bone. It’s significantly necessary to unveil the molecular mechanism underlying the high bone metastatic propensity of PCa
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