Abstract
PURPOSE: The study aims to further classify hepatocellular carcinoma (HCC) based on proliferative capacity, identify hub genes associated with highly proliferative HCC, and investigate its regulatory roles in HCC. MATERIALS AND METHODS: Bioinformatics analysis was employed to establish classification of HCC and further identify the hub gene. Cell counting kit-8 (CCK-8) assay, colony formation assay, Western Blot assay and tumor xenograft assay were employed to detect the proliferation of HCC cells. Transwell assay and Western blot assay were employed to detect the migration of HCC cells. RNA sequencing analysis was employed to explore the signaling pathways activated by the gene and verify it through rescue experiments. RESULTS: We classified HCC into three more precise subtypes termed Prolifer-low, Prolifer-mid and Prolifer-high, and also found that Cms1 ribosomal small subunit homolog 1 (CMSS1) was a hub gene associated with stronger proliferative capacity subgroup of HCC. Functional studies revealed that CMSS1 overexpression significantly promoted the proliferation of HCC cells in vitro and in vivo. Additionally, CMSS1 could also promote the migration and epithelial-mesenchymal transition of HCC cells. Mechanistically, RNA sequencing analysis revealed that CMSS1 knockdown inhibited the tumor necrosis factor (TNF) and downstream nuclear factor kappa B (NF-κB) signaling pathways. More importantly, TNF or NF-κB suppression could reverse the promoting effects of CMSS1 on HCC cells proliferation and migration. CONCLUSION: The study suggested that CMSS1 could be a critical modulator of HCC tumorigenesis and metastasis through the TNF/NF-κB signaling pathway, thus being considered as a potential therapeutic target for HCC. Targeting CMSS1 may offer a novel strategy to inhibit NF-κB-driven inflammatory signaling and suppress tumor progression in HCC.