Department of Pharmacy, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
Department of Pathology, School of Medicine, Shandong University, Jinan 250012, China; Research Center for Medicinal Biotechnology, Shandong Academy of Medicinal Sciences, Jinan 250012, China.
Biochem Biophys Res Commun. 2014 Sep 26;452(3):746-52. doi: 10.1016/j.bbrc.2014.08.154. Epub 2014 Sep 6.
Tumor metastasis is the leading cause of mortality and morbidity of prostate cancer (PCa) patients. Epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression and metastasis. Recent evidence suggested that diabetic patients treated with metformin have lower PCa risk and better prognosis. This study was aimed to investigate the effects of metformin on EMT in PCa cells and the possible microRNA (miRNA)-based mechanisms. MiRNAs have been shown to regulate various processes of cancer metastasis. We herein showed that metformin significantly inhibits proliferation of Vcap and PC-3 cells, induces G0/G1 cell cycle arrest and inhibits invasiveness and motility capacity of Vcap cells. Metformin could inhibit TGF-β-induced EMT in Vcap cells, as manifested by inhibition of the increase of N-cadherin (p=0.013), Vimentin (p=0.002) and the decrease of E-cadherin (p=0.0023) and β-catenin (p=0.034) at mRNA and protein levels. Notably, we demonstrated significant upregulation of miR30a levels by metformin (P<0.05) and further experiments indicated that miR30a significantly inhibits proliferation and EMT process of Vcap cells. Interestingly, we identified that SOX4, a previously reported oncogenic transcriptional factor and modulator of EMT, is a direct target gene of miR30a. Finally, we screened the expression of miR30a and SOX4 in 84 PCa cases with radical prostatectomy. Of note, SOX4 overexpression is significantly associated with decreased levels of miR30a in PCa cases. In all, our study suggested that inhibition of EMT by metformin in PCa cells may involve upregulation of miR30a and downregulation of SOX4.
肿瘤转移是导致前列腺癌（PCa）患者死亡和发病的主要原因。上皮-间充质转化（EMT）在癌症进展和转移中起着关键作用。最近的证据表明，接受二甲双胍治疗的糖尿病患者患 PCa 的风险较低，预后较好。本研究旨在探讨二甲双胍对 PCa 细胞 EMT 的影响及其可能的基于 microRNA（miRNA）的机制。miRNA 已被证明可以调节癌症转移的各种过程。我们在此表明，二甲双胍可显著抑制 Vcap 和 PC-3 细胞的增殖，诱导 G0/G1 细胞周期停滞，并抑制 Vcap 细胞的侵袭和运动能力。二甲双胍可抑制 TGF-β诱导的 Vcap 细胞 EMT，表现在 N-钙粘蛋白（p=0.013）、波形蛋白（p=0.002）增加和 E-钙粘蛋白（p=0.0023）和 β-连环蛋白（p=0.034）mRNA 和蛋白水平降低。值得注意的是，我们证明了二甲双胍显著上调 miR30a 水平（P<0.05），进一步的实验表明 miR30a 显著抑制 Vcap 细胞的增殖和 EMT 过程。有趣的是，我们鉴定出 SOX4，一种先前报道的致癌转录因子和 EMT 调节剂，是 miR30a 的直接靶基因。最后，我们筛选了 84 例接受根治性前列腺切除术的 PCa 病例中 miR30a 和 SOX4 的表达。值得注意的是，SOX4 的过表达与 PCa 病例中 miR30a 水平的降低显著相关。总之，我们的研究表明，二甲双胍抑制 PCa 细胞 EMT 可能涉及 miR30a 的上调和 SOX4 的下调。
