Effect of hypoxia-inducible factor 2α on chemoresistance of hepatocellular carcinoma

doi:10.12092/j.issn.1009-2501.2019.06.005

Abstract

Abstract:

AIM: To study the effect of hypoxia-inducible factor 2α (HIF-2α) on chemoresistance of hepatocellular carcinoma and its mechanism. METHODS: Six hepatocellular carcinoma cell lines were selected and the expression of HIF-2α were detected by Western blot. The HIF-2α lentiviral particles were produced and infected with HepG2 and PLC/PRF/5 cells to prepare a cell line stably expressing HIF-2α, and Western blot was used to verify its expression. Six conventional chemotherapy drugs (fluorouracil, cyclophosphamide, epirubicin hydrochloride, mitomycin, methotrexate, and sorafenib) in five concentrations were added to HepG2-HIF2α and Control cells. MTT assay was used to detect cell inhibition rate. To study the mechanism, Western blot was used to detect the expression of drug resistance genes MDR1, LRP and MRP1 in HIF-2α overexpressing HCC cells and the corresponding control cells. RESULTS:Western blot result showed that HIF-2α was expressed in 6 hepatocellular carcinoma cell lines. The ectopic expression of HIF-2α in lentivirus-infected HepG2 and PLC/PRF/5 cells were validated by Western blot. MTT results showed that the inhibitory rate of cyclophosphamide, methotrexate and sorafenib on HepG2-HIF-2α was significantly lower than control cells (P<0.05), suggesting that the expression of HIF-2α caused chemotherapy resistance. However, the inhibition rate of fluorouracil, epirubicin hydrochloride and mitomycin on HepG2-HIF-2α cells was not different from that of the control group (P>0.05). Western blot analysis further analyzed the cause of HIF-2α on the increase of chemotherapy resistance in hepatocellular carcinoma cells. The results showed that the expression levels of drug resistance-related genes MDR1, LRP and MRP1 were higher in HepG2-HIF-2α cells and PLC/PRF/5-HIF-2α cells than those in the control group (P<0.05). CONCLUSION: In hepatocellular carcinoma, HIF-2α can increase the chemotherapy resistance of hepatocellular carcinoma cells by up-regulating the expression of MDR1, LRP and MRP1 resistance genes.

Key words: hepatocellular carcinoma, HIF-2α, MDR1, LRP, MRP1

CLC Number:

R965.2

YANG Shucai，ZHANG Li，LIU Liping，DENG Weijie，ZHOU Jie，LIU Hui，ZHANG Baohu，JIN Tao. Effect of hypoxia-inducible factor 2α on chemoresistance of hepatocellular carcinoma[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(6): 630-636.

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