SURF4 regulates RRM2 to activate the PI3K/AKT pathway and promote malignant progression in hepatocellular carcinoma

Abstract SURF4 , a member of the Surfeit gene cluster, is widely expressed and localizes to the endoplasmic reticulum membrane. As a cargo receptor, it is involved in the transport of various proteins between the endoplasmic reticulum and the Golgi apparatus, and is closely associated with the progression of multiple tumors. However, the role and potential molecular mechanisms of SURF4 in the proliferation, migration, invasion, and apoptosis of hepatocellular carcinoma (HCC) remain unclear. First, the protein expression of SURF4 was evaluated in HCC tissues and their paired adjacent non-tumor counterparts utilizing a tissue microarray platform combined with immunohistochemical (IHC) analysis. SURF4 was knocked down by lentivirus-mediated short hairpin RNA (shRNA) in PLC/PRF/5 and Huh-7 cell lines. The effects of SURF4 knockdown on HCC cell proliferation, migration, and invasion were evaluated through a series of experiments. A subcutaneous xenograft model in nude mice was established to investigate the effect of SURF4 knockdown on in vivo tumor growth. Subsequently, quantitative proteomic analysis was conducted, which identified RRM2 as a key differentially expressed protein. For functional rescue assays, cells were transduced with Lenti‑RRM2 or control vectors. Results showed that RRM2 overexpression reversed the proliferative, migratory, and invasive phenotypes induced by SURF4 knockdown in HCC cells. Finally, we examined the expression changes of key downstream signaling molecules and apoptosis-related proteins, thereby elucidating the role of SURF4 in HCC cell apoptosis. SURF4 protein was highly expressed in HCC tissues, and its expression level was significantly correlated with tumor size, differentiation grade, and microvascular invasion. Cytological experiments confirmed that SURF4 was highly expressed in HCC cell lines, promoting cell proliferation, invasion, and migration. SURF4 knockdown effectively inhibited the growth of HCC cells in nude mouse xenograft experiments. Quantitative proteomics, bioinformatic analyses, and Western blot assays demonstrated that SURF4 promoted proliferation, migration, and invasion while inhibiting apoptosis in HCC cells by upregulating RRM2 expression and activating the PI3K/AKT signaling pathway. SURF4 was highly expressed in HCC tissues and cell lines. Its overexpression promoted HCC cell proliferation, migration, and invasion, while inhibiting apoptosis, by upregulating RRM2 and thereby regulating the PI3K/AKT signaling pathway.