背景:Src同源性和胶原蛋白4(SHC4)是一种重要的细胞内衔接蛋白,已显示其在黑素瘤和神经胶质瘤中发挥促癌作用。然而,SHC4在肝细胞癌进展中的生物学功能和详细机制尚不清楚。本研究旨在评估SHC4在HCC患者中的潜在预后和治疗价值。
方法:采用免疫组织化学和免疫印迹法检测肝癌组织中SHC4的表达情况。在大量HCC患者队列中评估了SHC4的临床意义。SHC4抑制或过表达对迁移的影响,入侵,和肿瘤生长通过集落形成试验检测,伤口愈合,transwell分析,和异种移植试验。通过蛋白质印迹和免疫荧光检测细胞周期和EMT相关蛋白。此外,通过蛋白质印迹法发现肝癌中SHC4和STAT3信号之间的分子调控,免疫荧光和异种移植试验。
结果:与癌旁正常肝组织相比,SHC4在HCC中过度表达,并且SHC4表达增加与高AFP水平相关,不完全的肿瘤封装,肿瘤分化差,预后差。SHC4被证明可以增强细胞增殖,菌落形成,细胞在体外迁移和侵袭,并促进肝癌细胞的细胞周期进程和EMT过程。肿瘤异种移植模型测定证实了SHC4在裸鼠致瘤性中的致癌作用。此外,在SHC4过表达的HCC细胞和HCC组织中发现了STAT3信号的激活。STAT3的进一步干预证实STAT3是SHC4在HCC中致癌作用的重要信号通路。
结论:一起,我们的结果表明,SHC4激活STAT3信号促进HCC进展,为肝癌的治疗提供新的临床思路。
BACKGROUND: The Src homology and collagen 4 (
SHC4) is an important intracellular adaptor protein that has been shown to play a pro-cancer role in melanoma and glioma. However, the biological function and detailed mechanisms of
SHC4 in hepatocellular carcinoma progression are unclear. This study aimed to evaluate the potential prognostic and treatment value of
SHC4 in patients with HCC.
METHODS: The expression status of SHC4 in HCC tissues were investigated by immunohistochemistry and western blotting. Clinical significance of
SHC4 was evaluated in a large cohort of HCC patients. The effects of SHC4 repression or overexpression on migration, invasion, and tumor growth were detected by colony formation assay, wound healing, transwell assays, and xenograft assay. Cell cycle and EMT-related proteins were detected by western blotting and immunofluorescence. In addition, the molecular regulation between SHC4 and STAT3 signaling in HCC were discovered by western blotting, immunofluorescence and xenograft assay.
RESULTS: SHC4 was overexpressed in HCC compared to adjacent normal liver tissues and increased SHC4 expression was associated with high AFP level, incomplete tumor encapsulation, poor tumor differentiation and poor prognosis. SHC4 was shown to enhance cell proliferation, colony formation, cells migration and invasion in vitro, and promotes cell cycle progression and EMT process in HCC cells. Tumor xenograft model assay confirmed the oncogenic role of
SHC4 in tumorigenicity in nude mice. Moreover, activation of STAT3 signaling was found in the SHC4 overexpressed HCC cells and HCC tissues. Further intervention of STAT3 confirmed STAT3 as an important signaling pathway for the oncogenic role of SHC4 in HCC.
CONCLUSIONS: Together, our results reveal that SHC4 activates STAT3 signaling to promote HCC progression, which may provide new clinical ideas for the treatment of HCC.