Table 3.

Summary of clinical and biological roles of complement proteins in hepatocellular carcinoma (HCC).

Complement proteins	Expression in HCC	Clinical implications in HCC	Biological functions	References
CFH	Decreased	Increases hepatocellular inflammation and injury Promotes enhanced tumorigenesis Poor overall and disease-free survival	Inactivates C3b and regulates activation of AP. Produced by epithelial endothelial cells	Weiler et al. (142) Laskowski et al. (119) Yang et al. (143)
CFHR3	Decreased	Increases cell proliferation and tumor burden Decreased cell apoptosis Poor overall and disease-free survival	Regulates WNT & NOTCH pathways. Prognostic predictor for targeted therapeutics in HCC	Liu et al. (147) Liu et al. (331) Pan et al. (149)
C2	Decreased	Worse prognosis time-to-recurrence of HCC Increases mortality and reduced survival times Promotes tumorigenesis and metastasis	Increases cytotoxicity of CD4+ T cells. Reduces M2 macrophage polarization. Regulates multiple signaling pathways.	Ning et al. (190) Fu et al. (191) Tian et al. (40)
CR1	Decreased	Increases hepatocellular inflammation and injury Increases grades of cirrhosis and HCC Contributes to decreased disease-free survival	Inhibits classical and AP pathways. Defective clearance of CICs. Potential therapeutic target in HCC	Chen et al. (183) Kanto et al. (229) Weisman et al. (234)
MBL/MBL2	Decreased	Enhances tumorigenesis and cancer burden Enhances PGE2 production and HCC progression Increases HSC activation and tumorigenesis Potential biomarker of diagnostic value	Promotes accumulation of MDSCs. Increases Treg function and activity Impairs CD8+ T cell cytotoxicity Enhances activation of HSCs	Rong et al. (241) Li et al. (243) Yoshino et al. (245) Gu et al. (247)
CFHL1	Decreased	Worse time-to-recurrence of HCC Increased cell proliferation and tumorigenesis Reduced overall and disease-free patient survival	Negatively regulates AP of C activation. Regulates C5b deposition & immunity. Correlates with CpG site methylations. Regulates WNT/NOTCH pathways	Zipfel & Skerka. (305) Heinen et al. (306) Yang et al. (143) Liu et al. (331)
C8A	Decreased	Worse time-to-recurrence of HCC. Increased cell proliferation and tumorigenesis. Reduced overall and disease-free patient survival	Promotes differentiation & thrombosis. Decreased levels of C8A correlate with early HCC	Yao et al. (312) Yin et al. (313) Mu et al. (315)
C4	Decreased	Contributes to augmented liver inflammation Diagnostic marker for HCV related HCC. Biomarker for HCV infection, fibrosis and HCC	Distinguishes HCC & cirrhosis with highest accuracy Low C4 levels promote fibrosis & HCC	Potter et al. (291) Ali et al. (295) Banerjee et al. (296)
CD59	Increased	Decreases complement-mediated cell lysis Decreases apoptosis and increased tumor burden Worse overall and disease-free survival	Increased resistance of cancer cells Regulates Smad7 formation and Smad2/3 phosphorylation. Modulates TGF-β signaling	Fishelson et al. (151) Watson et al. (156) Abdel-Latif et al. (161) Lan & Wu (166)
CD46	Increased	Increases tumor growth & decreases regression Shorter relapse periods and worse prognosis Decreases overall and disease-free survival	Decreases complement cytotoxicity. Promotes differentiation of Tregs. Modulates HCC via miRNA activities	Sherbenou et al. (320) Kinugasa et al. (324) Lu et al. (328)
C1q	Increased	Increases cancer cell migration and proliferation Increases tumorigenesis and tumor burden. Poor overall and disease-free survival	Contributes to tumor angiogenesis Promotes cancer cell metastasis Enhances invasiveness of cancer cells	Hong et al. (169) Bulla et al. (186) Hoffken et al. (180) Ho et al. (189)
C3	Increased	Increases chemoresistance to therapeutics Promotes angiogenesis and metastasis Potential biomarker of diagnosis & prognosis	Promotes immunosuppressive. TME Suppresses anti-tumor CD8+ T cells. Increases M2 macrophages & MDSCs	Pio et al. (195) Wang et al. (249) Leung et al. (203)
C5	Increased	Increases metastasis and EMT of cancer cells Modulates proliferative & apoptosis pathways Enhances dissemination of cancer tumor cells	Promotes immunosuppressive TME. Decreases CD8+ T cell cytotoxicity. Enhances functions of MDSCs	Dai et al. (210) Medler et al. (213) Kusmartsev et al. (218)
C4BP	Increased	Promotes progressive metastases & tumor burden Positively correlates with HCC and liver cirrhosis Poor prognosis and HCC chemoresistance	Persistently maintains necrotic core. Modulates cholangiocyte survival. Shields tumors from cytotoxic cells	Phillips et al. (284) Tomes et al. (285) Williams et al. (286)
MASP-2	Variable	Diagnostic marker for HCC No clear role defined for MASP-2	Potentially regulates fibrosis and HCC	Ding et al. (264) Unterberger et al. (266)