PCGF2 and PCGF4 Oppositely Drive Stem-like Properties in Hepatocellular Carcinoma

Abstract Background: PCGF4 as a cancer stem cells (CSC) marker displays stem cell-like properties, and drug resistance in hepatocellular carcinoma (HCC). PCGF2, a homologue of PCGF4, the effect of PCGF2 on liver CSCs (LCSCs) and drug resistance and the molecular mechanism of this effect have not been documented.Methods: To measure the cell viability, CSCs properties of the cells, the Cell Counting Kit-8, spheroid assay, and flow cytometry assays were applied in the HCC cell lines, respectively. The self-renewal was determined by limiting dilution assay. Also, IHC and western blotting were used to detect protein expression of PCGF2 and PCGF4 in human HCC tissues, cell lines and the effects of PCGF2 overexpression on the p38 MAPK genes expression. Kaplan-Meier curves were generated for overall survival (OS) and disease-free survival (DFS). We performed KEGG analysis on target genes through the R language cluster profiler package.Results: IHC showed that expression of PCGF4 and PCGF2 correlate inversely in HCC cell lines and HCC tumors. Overexpression of PCGF2 inhibited the stemness of HCC cells refected by decreasing sphere-forming and self-renewal capacities as well as the expression of CSCs markers. Interestingly, down-regulating PCGF4 led to similar results as up-regulating PCGF2. We also found that PCGF2 and PCGF4 oppositely regulated the stem-like properties driven by the p38 MAPK signalling pathway.Conclusion: Our results suggest that PCGF2 inhibits the stem cell population, reduces the sphere formation ability in HCC cell lines, and increases sensitivity to sorafenib by targeting p38 MAPK signalling.