Abstract: Objective: To compare the heterogeneity of human hepatocellular carcinoma HepG2 and Hep3B cells, and to explore the relationship between the heterogeneity and the biological characteristics of drug resistance, invasion and migration.Methods: HepG2 (p53 wild-type) and Hep3B (p53 deficient) cells were used as research subjects.The sensitivity of the two cell lines to cisplatin (DDP), paclitaxel (PTX), etoposide (VP-16)and sorafenib (So) was analyzed by tetramethylazolium salt colorimetric method (MTT).Cell counting kit-8(CCK-8)assay and plate clone formation assay were used to detect the cellular growth curve and clone formation ability.The migration and invasion abilitites of cells were detected by scratch and Transwell assay.Subcutaneous transplantation tumor models of human hepatocellular carcinoma in nude mice were established, and the growth and tumor emergence time of mice were recorded.The transplanted tumor tissues and each viscera with HE to observe the pathological changes.Western blotting was conducted to detect the expression differences of p53, myelocytic leukemia-1 (Mcl-1), Bcl-2 associated X protein (Bax), B-cell lymphoma (Bcl-2), major vault protein (MVP), multidrug-resistant protein 1(MDR1), matrix metalloproteinase-2 (MMP2), and E-cadherin in cells and tissues.Results: MTT results showed that Hep3B cells were less sensitive to chemotherapy drugs than HepG2 cells (P＜0.05, P＜0.01, P＜0.001) and Hep3B cells revealed stronger abilities in proliferation, migration and invasion (P＜0.05, P＜0.01, P＜0.001).In the model of subcutaneous tumor transplantation in nude mice, the body weight decreased significantly with the extension of time, the time of tumor emergence was also longer than that of HepG2(P＜0.001), and liver metastasis of cancer cells was observed in nude mice implanted with Hep3B.Compared with HepG2 cells, the protein expressions of Bax and p53 in Hep3B cells decreased, the protein expressions of Bcl-2, Mcl-1, MVP, MDR1 and Ecadherin significantly increased (P＜0.05, P＜0.001)and the expressions of p53, MMP2 and E-cadherin in transplanted tumor tissue were consistent with the expression trend of cells (P＜0.01, P＜0.001).Conclusion: Hep3B cells show more obvious drug resistance, anti-apoptosis, invasion and migration abilities.This study can provide experimental basis for the determination of two clinical treatments of hepatocellular carcinoma with different biological characteristics.