Abstract
BackgroundThe 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.MethodsThe 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.ResultsSHC4 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.ConclusionsTogether, our results reveal that SHC4 activates STAT3 signaling to promote HCC progression, which may provide new clinical ideas for the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common and highly malignant neoplastic diseases, with a global morbidity ranking sixth among all tumors and a mortality rate ranking third among tumor-related deaths [1]
Src homology and collagen 4 (SHC4) is significantly upregulated in HCC and positively associated with aggressive clinicopathological characteristics and poor prognosis in HCC patients To investigate the relevance of SHC4 to HCC, we first examined SHC4 protein expression in a liver tumor tissue microarray containing 105 HCC tissue and adjacent normal liver tissues by IHC staining
We found that SHC4 was significantly overexpressed in HCC compared to adjacent normal liver tissues (Fig. 1A, B)
Summary
Hepatocellular carcinoma (HCC) is one of the most common and highly malignant neoplastic diseases, with a global morbidity ranking sixth among all tumors and a mortality rate ranking third among tumor-related deaths [1]. Since sorafenib been approved as a systemic drug for HCC by FDA, lenvatinib, regorafenib, and cabozantinib have been approved for the treatment of advanced HCC patients [3,4,5]. It still shows unfavorable efficacy [6]. 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
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