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

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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0813-4) contains supplementary material, which is available to authorized users.

LncRNA LOXL1‐AS1/miR‐let‐7a‐5p/EGFR‐related pathway regulates the doxorubicin resistance of prostate cancer DU‐145 cells

“…But in the DU‐145/DOX cells, transfection of miR‐let‐7a‐5p mimics decreased the number of migration cells and promoted apoptosis (* p < .05), while the LOXL1‐AS1 group promoted cell migration and inhibited apoptosis (* p < .05), and the LOXL1‐AS1 + miR‐let‐7a‐5p mimics group was consistent with NC group (Figure d,f). In addition, previous reports showed that EGFR/PI3K/Akt signaling pathway was closely related with prostate cancer progression . In DU‐145 cells, downregulation of LOXL1‐AS1 decreased the expression levels of EGFR and genes in PI3K/Akt signaling including p‐PI3K and p‐Akt, which could be retrieved to normal expression level after cotransfection with miR‐let‐7a‐5p inhibitor.…”

“…In addition, previous reports showed that EGFR/PI3K/Akt signaling pathway was closely related with prostate cancer progression. 28,29 In DU-145 cells, downregulation of LOXL1-AS1 decreased the expression levels of EGFR and genes in PI3K/Akt signaling including p-PI3K and p-Akt, which could be retrieved to normal expression level after cotransfection with miR-let-7a-5p inhibitor. In addition, upregulation of LOXL1-AS1 increased the expression levels of EGFR, p-PI3K, and p-Akt, which could be recovered to normal expression level after cotransfection with miR-let-7a-5p mimics in DU-145/DOX cells ( Figure S1).…”

Signatures containing miR-133a identified by large scale miRNA profiling in bladder cancer

“…It has been shown that miR-133a-3p acts as a tumor suppressor in BC.Numerous studies demonstrated that miR-133a inhibits cell proliferation, migration, and invasion in various tumors by targeting to different signaling pathways, such as caspase signaling pathway, insulin/IGF signaling pathway, and EGFR signaling pathway (21)(22)(23)(24)(25)(26)(27)(28). The connecting between the importance of miR-133a in tumorigenesis and significant downregulation of miR-133a in BC has shed light on the molecular mechanism of miRNA-133a in the tumorigenesis of BC.…”

PSMA-Targeting Redox Hyperbranched Poly (Amido Amine)-Mediated miR-133a-3p Delivery to Inhibit Bone Metastasis of Prostate Cancer

“…HUVECs were purchased from Shanghai Chinese Academy of Sciences cell bank (China). LNCaP and HUVECs were cultured as described previously [12].…”

“…Many lines of evidence have demonstrated that miRNA-based therapies hold great prospects in the treatment of PCa [7,11] . In our previous study, miRNA-133a-3p was proven to be a tumor suppressor gene in prostate cancer and downregulates several cytokine receptors associated with PCa growth, including FGFR, EGFR, IGFR and MET, inactivating the PI3K/AKT signaling pathway [12].…”