Downregulation of miR-133a-3p promotes prostate cancer bone metastasis via activating PI3K/AKT signaling.
Downregulation of miR-133a-3p promotes prostate cancer bone metastasis via activating PI3K/AKT signaling.
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miR-133a-3p下调通过激活PI3K/AKT信号促进前列腺癌骨转移
DOI：
10.1186/s13046-018-0813-4
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发表时间：
2018-07-18
期刊：
影响因子：
--
通讯作者：
Wa Q
中科院分区：
文献类型：
--
作者：
Tang Y;Pan J;Huang S;Peng X;Zou X;Luo Y;Ren D;Zhang X;Li R;He P;Wa Q
背景骨转移是晚期前列腺癌（PCa）发病和死亡的主要原因。研究发现miR-133a-3p的下调与前列腺癌的进展、复发和远处转移有关。然而，miR-133a-3p在PCa骨转移中的临床意义，以及miR-133a-3p在PCa骨转移中的生物学作用及其分子机制尚不清楚。方法采用实时荧光定量PCR检测245例临床前列腺癌组织中smir -133a-3p的表达情况。统计学分析miR-133a-3p表达与PCa患者临床病理特征、总体生存率及骨转移生存率的临床相关性。体外和体内研究miR-133a-3p在PCa骨转移中的生物学作用。应用生物信息学分析、实时PCR、western blot和荧光素酶报告基因分析证实miR-133a-3p与其潜在靶点之间的关系。通过Western blotting和荧光素酶检测来确定miR-133a-3p抗肿瘤作用的潜在途径。在人PCa组织中证实了miR-133a-3p与其靶点的临床相关性。结果smir -133a-3p在前列腺癌组织中的表达明显低于癌旁正常组织和前列腺良性病变组织，尤其是骨转移性前列腺癌组织。统计学分析表明，miR-133a-3p低表达与PCa患者的晚期临床病理特征和较短的骨转移生存期显著相关。此外，上调miR-133a-3p在体外和体内抑制癌症干细胞样表型，并减弱体外PCa细胞的anoikis抗性。重要的是，施用agomir-133a-3p可显著抑制体内PCa骨转移的发生率。我们的研究结果进一步证明，miR-133a-3p通过直接靶向多种细胞因子受体，包括EGFR、FGFR1、IGF1R和MET，抑制PI3K/AKT信号通路，从而抑制PCa骨转移。在临床PCa组织中，miR-133a-3p与EGFR、FGFR1、IGF1R、MET和PI3K/AKT信号活性呈负相关。结论本研究揭示了miR-133a-3p抑制前列腺癌骨转移的新机制，证明miR-133a-3p可能是前列腺癌骨转移的潜在标志物，而递送agomir-133a-3p可能是一种有效的抗前列腺癌骨转移治疗策略。
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.
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影响因子：
6.6
作者：
Kodahl AR;Lyng MB;Binder H;Cold S;Gravgaard K;Knoop AS;Ditzel HJ
通讯作者：
Ditzel HJ
影响因子：
8.8
作者：
Kojima, S.;Chiyomaru, T.;Kawakami, K.;Yoshino, H.;Enokida, H.;Nohata, N.;Fuse, M.;Ichikawa, T.;Naya, Y.;Nakagawa, M.;Seki, N.
通讯作者：
Seki, N.
影响因子：
9.9
作者：
Chen, William W.;Schoeberl, Birgit;Jasper, Paul J.;Niepel, Mario;Nielsen, Ulrik B.;Lauffenburger, Douglas A.;Sorger, Peter K.
通讯作者：
Sorger, Peter K.
影响因子：
9
作者：
Kanaan, Ziad;Rai, Shesh N.;Galandiuk, Susan
通讯作者：
Galandiuk, Susan
TGF-β 信号负调节器 PICK1 抑制前列腺癌骨转移
影响因子：
8.8
作者：
Dai, Yuhu;Ren, Dong;Peng, Xinsheng
通讯作者：
Peng, Xinsheng