SHC4 promotes tumor proliferation and metastasis by activating STAT3 signaling in hepatocellular carcinoma

Abstract

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.

TAP1, a potential immune-related prognosis biomarker with functional significance in uveal melanoma

“…In this network, we found that many genes were directly associated with various cancers. SHC4 promotes tumor proliferation and metastasis in melanoma and hepatocellular carcinoma [ 37 , 38 ], whereas MEGF10 modulates the cellular aggressiveness of UVM [ 39 ]. CHAC1 , a ferroptosis-related gene, is correlated with breast cancer [ 40 ].…”

Identification of the Factor That Leads Human Mesenchymal Stem Cell Lines into Decellularized Bone

“…Melanie et al found that SHC4 promoted the autophosphorylation of EGFR in the absence of external stimuli. The authors used a quantitative PCR (qPCR) analysis of biopsy cores representing Grade I–IV astrocytomas to demonstrate the significantly higher expression of SHC4 in tumor tissue compared to benign tissue [ 24 , 25 ]. Xin Zhang et al showed that SHC4 is expressed in hepatocellular carcinoma tissues and that SHC4 promotes hepatocellular carcinoma progression by activating STAT3 signaling.…”

“…Xin Zhang et al showed that SHC4 is expressed in hepatocellular carcinoma tissues and that SHC4 promotes hepatocellular carcinoma progression by activating STAT3 signaling. They further noted that a high expression of SHC4 is associated with clinicopathological features and poor prognoses in patients with hepatocellular carcinoma [ 24 ]. SHC4 works as an oncogene and causes carcinoma cells to proliferate and become malignant.…”

Deciphering the role of transcription factors in glioblastoma cancer stem cells

“…Similarly, adenovirus infection of glioma cells promotes GSC formation via the TLR9/NEAT1/STAT3 pathway [127]. STAT3 also contributes to tumor cell invasion and cell cycle regulation through mechanisms such as TGFBI secretion by tumor-associated macrophages (TAMs) and ARPC1B activation, which supports mesenchymal phenotype maintenance and radiotherapy resistance in GSCs [128][129][130]. In the context of immune resistance, STAT3 establishes an immunosuppressive tumor microenvironment, with processes such as CXCL8 maintaining the mesenchymal state of GSCs and inducing M2-like TAM polarization and the TFPI2-CD51-STAT6 axis facilitating immunosuppressive microglial polarization [131,132].…”