Ma Peng, Tang Wei-Guo, Hu Jin-Wu, Hao Ying, Xiong Liang-Kun, Wang Mao-Ming, Liu Hao, Bo Wen-Hui, Yu Kai-Huan
Department of Hepatobiliary Surgery, Renmin Hospital, Wuhan University, Wuhan, P.R. China.
Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, P.R. China.
Liver Int. 2020 May;40(5):1211-1223. doi: 10.1111/liv.14410. Epub 2020 Mar 8.
Heat shock factor (HSF4) plays a vital role in carcinogenesis and tumour progression. However, its clinical significance implications in hepatocellular carcinoma (HCC) remained elusive.
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.
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-1α (HIF-1α) dependent, but transforming growth factor-β (TGF-β) independent manner.
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 HIF1α-dependent manner.
热休克因子（HSF4）在肿瘤发生和肿瘤进展中起着至关重要的作用。然而，其在肝细胞癌（HCC）中的临床意义仍不明确。
采用逆转录-聚合酶链反应（RT-PCR）和蛋白质免疫印迹法检测肝癌细胞和组织中HSF4的表达水平。对104例行根治性切除的肝癌患者的组织芯片进行免疫组化染色。通过集落形成实验和Transwell实验检测HSF4对HCCLM3、Huh7、MHCC97L和SMMC7721细胞增殖、迁移和侵袭的体外影响。通过RT-PCR、蛋白质免疫印迹法和免疫荧光法在HCCLM3和MHCC97L细胞中鉴定上皮-间质转化（EMT）。通过蛋白质免疫印迹法和双荧光素酶报告系统检测HCCLM3和MHCC97L细胞中AKT通路的激活情况。
复发患者的原发性肝癌组织中HSF4表达较高，且与细胞系的侵袭潜能呈正相关。临床上，HSF4高表达的患者预后明显较差。体外实验表明，沉默HSF4可抑制肝癌细胞的增殖、迁移和侵袭，而HSF4过表达则产生相反的效果。此外，沉默HSF4可诱导上皮样表型，而HSF4过表达则通过激活AKT通路在肝癌中导致间质样表型。进一步实验表明，HSF4可通过缺氧诱导因子-1α（HIF-1α）依赖但转化生长因子-β（TGF-β）非依赖的方式激活AKT通路。
HSF4在肝癌中上调，导致更强的增殖、迁移和侵袭能力。此外，HSF4高表达是根治性切除术后预后不良的一个有前景预测指标。HSF4可能通过以HIF1α依赖的方式激活AKT通路增强EMT来促进肿瘤的侵袭性行为。
