c-Jun N-terminal kinase inhibitor favors transforming growth factor-β to antagonize hepatitis B virus X protein-induced cell growth promotion in hepatocellular carcinoma.
c-Jun N-terminal kinase inhibitor favors transforming growth factor-β to antagonize hepatitis B virus X protein-induced cell growth promotion in hepatocellular carcinoma.
复制标题
c-Jun N末端激酶抑制剂有利于转化生长因子-β拮抗乙型肝炎病毒X蛋白诱导的肝细胞癌细胞生长促进作用
DOI：
10.3892/mmr.2015.4644
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发表时间：
2016-02
影响因子：
3.4
通讯作者：
Chen XP
中科院分区：
文献类型：
--
作者：
Wu YH;Ai X;Liu FY;Liang HF;Zhang BX;Chen XP
转化生长因子-β诱导高分化肝细胞癌细胞生长停滞，而乙肝病毒X蛋白(HBx)使转化生长因子-β信号在早期慢性乙型肝炎中的抑瘤作用减弱，但如何逆转HBx的致癌作用并维持转化生长因子-β的抑瘤作用仍有待研究。本研究探讨了转化生长因子-β和c-jun氨基末端激酶抑制剂对强制表达HBx的肝癌细胞生长的影响。研究发现，HBx通过激活JNK/PSMAD3L途径和抑制转化生长因子-βI型受体(TβRI)/PSMAD3C途径促进细胞生长。PSMAD3L/Smad4和pSMAD3C/Smad4复合体相互拮抗，调节c-Myc的表达。在没有HBx的情况下，转化生长因子-β通过激活T-βRI/pSMAD3C通路在高分化肝癌细胞中诱导细胞生长停滞。在HBx存在的情况下，转化生长因子-β对细胞生长没有影响。JNK抑制剂SP600125可显著逆转HBx的致癌作用，并促进转化生长因子-β恢复抑制HBx表达的高分化肝癌细胞的生长。总之，靶向JNK信号有利于转化生长因子-β阻断HBx诱导的高分化肝癌细胞的生长促进作用。作为抗病毒治疗的辅助手段，转化生长因子-β和抑制JNK信号转导通路的联合应用有望成为治疗乙肝病毒感染的肝细胞癌的有效手段。
Transforming growth factor (TGF)-β induces cell growth arrest in well-differentiated hepatocellular carcinoma (HCC) while hepatitis B virus X protein (HBx) minimizes the tumor suppression of TGF-β signaling in early chronic hepatitis B. However, how to reverse the oncogenic effect of HBx and sustain the tumor-suppressive action of TGF-β has yet to be investigated. The present study examined the effect of TGF-β and a c-Jun N-terminal kinase (JNK) inhibitor on cell growth in HCC cells with forced expression of HBx. It was found that HBx promoted cell growth via activation of the JNK/pSMAD3L pathway and inhibition of the transforming growth factor-beta type I receptor (TβRI)/pSMAD3C pathway. pSMAD3L/SMAD4 and pSMAD3C/SMAD4 complexes antagonized each other to regulate c-Myc expression. In the absence of HBx, TGF-β induced cell growth arrest through activation of the TβRI/pSMAD3C pathway in well-differentiated HCC cells. In the presence of HBx, TGF-β had no effect on cell growth. JNK inhibitor SP600125 significantly reversed the oncogenic action of HBx and favored TGF-β to regain the ability to inhibit the cell growth in HBx-expressing well-differentiated HCC cells. In conclusion, targeting JNK signaling favors TGF-β to block HBx-induced cell growth promotion in well-differentiated HCC cells. As an adjunct to anti-viral therapy, the combination of TGF-β and inhibition of JNK signaling is a potential therapy for HBV-infected HCC.