Taken together, our results suggest that SMAD6 variant 2, IFITM1, TBX15, and CHST4 may act as TSGs in HCC that are silenced by promoter hyper-methylation; meanwhile, CCL20 may be epigenetically activated in tumor through promoter hypo-methylation, and elevated expression may be associated with a poor prognosis in HCC. Here, CCL20 is linked to hepatocellular carcinoma.