Prognostic Value of Complement Component 2 and Its Correlation with Immune Infiltrates in Hepatocellular Carcinoma.

BACKGROUND: Single nucleotide polymorphism (SNP) of complement component 2 (C2) has been found to be significantly associated with hepatocellular carcinoma (HCC). However, little is known about the role and mechanism of C2 in HCC. In the present study, we aimed to explore the prognostic value of C2 and its correlation with tumor-infiltrating immune cells in HCC. MATERIALS AND METHODS: mRNA expression was downloaded from TCGA (365 HCC patients and 50 healthy controls), GSE14520 (220 HCC patients and 220 adjacent normal tissues), and ICGC HCC (232 HCC patients) cohorts. Unpaired Student's t-tests or ANOVA tests were used to evaluate differences of C2 expression. Univariate and multivariate analyses were used to analyze the prognostic value of C2. CIBERSORT was used to calculate the proportion of 22 kinds of tumor-infiltrating immune cells. RESULTS: Significantly lower C2 expression was found at HCC compared to healthy controls, and C2 was associated with TNM stages. Higher C2 expression was significantly associated with better prognosis, and multivariate analysis showed that C2 was also an independent factor for the prognosis of HCC. Moreover, elevated CD4 T cells were found at HCC patients with higher C2 expression while the higher proportion of macrophage M0 cells was found in HCC patients with lower C2 expression. KEGG analysis showed that "cell cycle," "AMPK signaling pathway," and "PPAR signaling pathway" were enriched in HCC patients with higher C2 expression. CONCLUSION: C2 is a prognostic factor for HCC and may be used as a therapeutic target for future treatment of HCC.

Suppression of complement component 2 expression by hepatitis B virus contributes to the viral persistence in chronic hepatitis B patients.

Previously, we identified rare missense mutations of complement component 2 (C2) to be associated with chronic hepatitis B (CHB) by exome sequencing. However, up to now, little is known about the role of C2 in CHB. In the present study, we aimed to perform preliminary exploration about the underlying role of C2 in CHB. Serum samples from 113 CHB patients and 30 healthy controls, and liver biopsy samples from 5 CHB patients and 3 healthy controls were obtained from the Third Affiliated Hospital of Sun Yat-sen University between January 2018 and January 2020. HepG2.2.15 and HepG2-NTCP cells infected with HBV were used to examine the influence of HBV infection on C2 expression. IFN-treated HepG2.2.15 cells were used to assess the effect of IFN on C2 expression. C2-overexpressing or C2-silencing HepG2.2.15 cells were constructed to evaluate the effect of C2 on HBV infection. Western blot and RT-qPCR were used to measure C2 expression in biopsy samples. HBeAg and HBsAg in culture medium and C2 of serum samples were measured by ELISA. HBV-DNA was measured by RT-qPCR. GSE84044, GSE54747 and GSE27555 were downloaded from GEO. C2 expression in liver tissue and serum was significantly lower in CHB patients compared to healthy controls, and significantly higher C2 expression was found in CHB patients with lower ALT, AST, Scheuer grade and stages compared to CHB patients with higher ALT, AST, Scheuer grades and Scheuer stage. Besides, HBV infection could decrease C2 expression by increasing expression of Sp1 and reducing expression of HDAC4. Moreover, C2 could enhance the anti-virus effect of IFN on HepG2.2.15 cells and also inhibit HBV replication in HepG2.2.15 cells by inhibition of p38-MAPK signalling pathway. In conclusion, HBV may promote viral persistence in CHB patients by inhibiting C2 expression.

Transcriptional expressions of Chromobox 1/2/3/6/8 as independent indicators for survivals in hepatocellular carcinoma patients.

Chromobox (CBX) proteins are important components of epigenetic regulation complexes known to play key roles in hepatocellular carcinoma (HCC). Little is known about the function of distinct CBXs in HCC. To address this issue, the study investigated the roles of CBXs in the prognosis of HCC using ONCOMINE, UALCAN, Human Protein Atlas, Kaplan-Meier Plotter, c-BioPortal databases. Over expressions of 8 CBXs members were found to be significantly associated with clinical cancer stages and pathological tumor grades in HCC patients. Besides, higher mRNA expressions of CBX1/2/3/6/8 were found to be significantly associated with shorter overall survival (OS) in HCC patients, while higher mRNA expression of CBX7 was associated with favorable OS. Multivariate analysis also showed that high mRNA expressions of CBX1/2/3/6/8 were independent prognostic factors for shorter OS of HCC patients. Moreover, high mutation rate of CBXs (51%) was also observed in HCC patients, and genetic alteration in CBXs was associated with shorter OS and disease-free survival (DFS) in HCC patients. Taken together, these results indicated that CBX1/2/3/6/8 could be prognostic biomarkers for survivals of HCC patients.