Supervillin promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma in hypoxia via activation of the RhoA/ROCK-ERK/p38 pathway.
Supervillin promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma in hypoxia via activation of the RhoA/ROCK-ERK/p38 pathway.
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Supervillin通过激活RhoA/ROCK-ERK/p38通路促进缺氧条件下肝细胞癌的上皮间质转化和转移
DOI：
10.1186/s13046-018-0787-2
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发表时间：
2018-06-28
期刊：
影响因子：
--
通讯作者：
Fang Z
中科院分区：
文献类型：
--
作者：
Chen X;Zhang S;Wang Z;Wang F;Cao X;Wu Q;Zhao C;Ma H;Ye F;Wang H;Fang Z
肝细胞癌（Hepatocellular carcinoma，HCC）是世界上最常见的恶性肿瘤之一，转移是HCC死亡的主要原因。缺氧触发癌细胞的上皮-间质转化（EMT），这增强了癌细胞的恶性特征并提高了转移风险。超绒毛蛋白与细胞膜和细胞骨架紧密结合，促进细胞运动、侵袭和细胞存活。然而，超绒毛蛋白在肝癌转移中的作用仍不清楚。MethodsTissue microarray技术被用来在173 HCC组织标本和表达水平与临床病理变量相关的超绒毛蛋白抗体的免疫化学染色。研究了肿瘤细胞的运动性和侵袭性，以及与癌细胞EMT相关的基因的mRNA表达水平的变化。supervillin和Rho GTPases之间的关系进行了检查，使用Co-IP和GST pull-down.ResultsHypoxia-induced上调supervillin促进癌细胞的迁移和侵袭通过激活ERK/p38通路下游的RhoA/ROCK信号。此外，supervillin调节EMT基因的表达，在缺氧和加速转移的HCC in vivo.ConclusionsHypoxia-induced增加supervillin表达是一个显着的和独立的预测癌症转移，这导致在HCC患者的生存差。我们的结果表明，超绒毛可能是肝癌的候选预后因素和有价值的治疗靶点。
BackgroundHepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with HCC. Hypoxia triggers the epithelial-mesenchymal transition (EMT) of cancer cells, which enhances their malignant character and elevates metastatic risk. Supervillin associates tightly with the membrane and cytoskeleton, promoting cell motility, invasiveness, and cell survival. However, the roles of supervillin in HCC metastasis remain unclear.MethodsTissue microarray technology was used to immunohistochemically stain for supervillin antibody in 173 HCC tissue specimens and expression levels correlated with the clinicopathological variables. Tumor cell motility and invasiveness, as well as changes in the mRNA expression levels of genes associated with cancer cell EMT, were investigated. The relationship between supervillin and Rho GTPases was examined using Co-IP and GST pull-down.ResultsHypoxia-induced upregulation of supervillin promoted cancer cell migration and invasion via the activation of the ERK/p38 pathway downstream of RhoA/ROCK signaling. Furthermore, supervillin regulated the expression of EMT genes during hypoxia and accelerated the metastasis of HCC in vivo.ConclusionsHypoxia-induced increase in supervillin expression is a significant and independent predictor of cancer metastasis, which leads to poor survival in HCC patients. Our results suggest that supervillin may be a candidate prognostic factor for HCC and a valuable target for therapy.
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