MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer
MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer
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DOI：
10.1002/hep.26369
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发表时间：
2013-08-01
期刊：
影响因子：
13.5
通讯作者：
Hui, Kam M.
中科院分区：
文献类型：
--
作者：
Xia, Hongping;Ooi, London Lucien P. J.;Hui, Kam M.
肿瘤复发和转移是影响肝细胞癌（HCC）患者预后改善的主要障碍。为了确定与HCC复发和转移相关的新危险因素，我们使用微阵列技术，通过比较复发性和非复发性人类HCC组织样本中的miRNA表达，建立了一个复发相关microrna （miRNA）小组（复发定义为在最初治疗后2年内发生的复发性疾病）。在该小组中，miR-216a/217簇的表达在HCC组织样本和细胞系中一致且显著上调，这些细胞系与早期肿瘤复发、无病生存期差和上皮-间质转化（EMT）表型相关。miR-216a/217诱导的EMT的稳定过表达增加了干细胞样细胞的数量、迁移和上皮性HCC细胞的转移能力。磷酸酶和紧张素同源物（PTEN）和母亲抗十足瘫痪同源物7 （SMAD7）随后被确定为miR-216a/217的两个功能靶点，PTEN和SMAD7在HCC中均下调。PTEN或SMAD7的异位表达部分挽救了miR-216a/217介导的肝癌细胞EMT、细胞迁移和干细胞样特性。先前，SMAD7被证明是一种转化生长因子β (TGF-) 1型受体拮抗剂。本研究进一步证明，miR-216a/217过表达在HCC细胞中作为TGF-通路和参与磷酸化肌醇3激酶/蛋白激酶K （PI3K/Akt）信号激活的典型通路的正反馈调节因子。此外，HCC细胞中TGF-和PI3K/ akt信号通路的激活导致对索拉非尼的获得性耐药，而阻断TGF-通路的激活克服了miR-216a/217诱导的索拉非尼耐药，并阻止了HCC中的肿瘤转移。结论：过表达miR-216a/217通过靶向PTEN和SMAD7激活PI3K/Akt和TGF-通路，参与HCC的肝癌发生和肿瘤复发。(肝脏病学58:629 2013;641)
Tumor recurrence and metastases are the major obstacles to improving the prognosis of patients with hepatocellular carcinoma (HCC). To identify novel risk factors associated with HCC recurrence and metastases, we have established a panel of recurrence-associated microRNAs (miRNAs) by comparing miRNA expression in recurrent and nonrecurrent human HCC tissue samples using microarrays (recurrence is defined as recurrent disease occurring within a 2-year time point of the original treatment). Among the panel, expression of the miR-216a/217 cluster was consistently and significantly up-regulated in HCC tissue samples and cell lines associated with early tumor recurrence, poor disease-free survival, and an epithelial-mesenchymal transition (EMT) phenotype. Stable overexpression of miR-216a/217-induced EMT increased the stem-like cell population, migration, and metastatic ability of epithelial HCC cells. Phosphatase and tensin homolog (PTEN) and mothers against decapentaplegic homolog 7 (SMAD7) were subsequently identified as two functional targets of miR-216a/217, and both PTEN and SMAD7 were down-regulated in HCC. Ectopic expression of PTEN or SMAD7 partially rescued miR-216a/217-mediated EMT, cell migration, and stem-like properties of HCC cells. Previously, SMAD7 was shown to be a transforming growth factor beta (TGF-) type 1 receptor antagonist. Here, we further demonstrated that overexpression of miR-216a/217 acted as a positive feedback regulator for the TGF- pathway and the canonical pathway involved in the activation of phosphoinositide 3-kinase/protein kinase K (PI3K/Akt) signaling in HCC cells. Additionally, activation of the TGF-- and PI3K/Akt-signaling pathways in HCC cells resulted in an acquired resistance to sorafenib, whereas blocking activation of the TGF- pathway overcame miR-216a/217-induced sorafenib resistance and prevented tumor metastases in HCC. Conclusion: Overexpression of miR-216a/217 activates the PI3K/Akt and TGF- pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis and tumor recurrence in HCC. (Hepatology 2013;58:629-641)