HSP4 triggers epithelial-mesenchymal transition and promotes motility capacities of hepatocellular carcinoma cells via activating AKT
HSP4 triggers epithelial-mesenchymal transition and promotes motility capacities of hepatocellular carcinoma cells via activating AKT
复制标题
HSP4通过激活AKT触发上皮间质转化并促进肝癌细胞的运动能力
DOI：
10.1111/liv.14410
复制
发表时间：
2020-05-01
影响因子：
6.7
通讯作者：
Yu, Kai-Huan
中科院分区：
文献类型：
--
作者：
Ma, Peng;Tang, Wei-Guo;Yu, Kai-Huan
热休克因子4（Heat shock factor 4，HSF 4）在肿瘤的发生、发展过程中起重要作用。方法采用RT-PCR和western blot方法检测HSF 4在肝癌细胞和组织中的表达水平。对104例肝癌根治性切除患者的组织芯片进行免疫组化染色。通过体外集落形成和transwell实验检测HSF 4对HCCLM 3、Huh 7、MHCC 97 L和SMMC 7721细胞增殖、迁移和侵袭的影响。采用RT-PCR、WB和免疫荧光法检测HCCLM 3和MHCC 97 L细胞的上皮间质转化（EMT）。结果HSF 4在复发患者原发性肝癌组织中表达增高，且表达水平与肝癌细胞株的侵袭能力呈正相关。临床上，HSF 4高表达的患者预后明显较差。体外实验表明，HSF 4沉默抑制HCC细胞增殖、迁移和侵袭，而HSF 4过表达则具有相反的作用。此外，HSF 4的沉默诱导上皮样表型，而HSF 4的过表达通过激活AKT通路导致HCC中的间充质样表型。进一步的实验表明，HSF 4可以通过低氧诱导因子-1 α（HIF-1 alpha）依赖而非转化生长因子-β（TGF-β）依赖的方式激活AKT通路。此外，HSF 4高表达是根治性切除术后预后不良的一个有希望的预测指标。HSF 4可以通过以HIF 1 α依赖性方式激活AKT通路来增强EMT，从而促进肿瘤的侵袭性行为。
Background and Aims Heat shock factor (HSF4) plays a vital role in carcinogenesis and tumour progression. However, its clinical significance implications in hepatocellular carcinoma (HCC) remained elusive.Methods RT-PCR and western blot were used to detect the HSF4 expression levels in HCC cells and tissues. Immunohistochemistry staining was performed on a tissue microarray containing 104 HCC patients received radical resection. In vitro effects of HSF4 on proliferation, migration and invasion were determined by colony formation and transwell assays in HCCLM3, Huh7, MHCC97L and SMMC7721 cells. Epithelial-mesenchymal transition (EMT) was identified by RT-PCR, WB and immunofluorescence in HCCLM3 and MHCC97L cells. AKT pathway activation was detected by WB and dual luciferase report system in HCCLM3 and MHCC97L cells.Results HSF4 expression was higher in primary HCC tissues derived from recurrent patients, and positively correlated with invasiveness potentials of cell lines. Clinically, patients with high HSF4 expression had significant poorer prognosis. In vitro experiments showed HSF4 silencing inhibited HCC cell proliferation, migration and invasion, whereas HSF4 overexpression had inverse effects. Moreover, silence of HSF4 induced an epithelial-like phenotype, whereas the overexpression of HSF4 resulted in a mesenchymal-like phenotype in HCC by activating AKT pathway. Further experiments showed that HSF4 could activate AKT pathway in a hypoxia-inducible factor-1 alpha (HIF-1 alpha) dependent, but transforming growth factor-beta (TGF-beta) independent manner.Conclusions HSF4 is upregulated in HCC, resulting in greater proliferation, migration and invasion capacities. Moreover, high HSF4 expression is a promising predictive indicator of poor outcome after radical resection. HSF4 may promote aggressive tumour behaviour by enhancing EMT through activating AKT pathway in a HIF1 alpha-dependent manner.