Inhibition of c-Jun NH2-Terminal Kinase Switches Smad3 Signaling from Oncogenesis to Tumor-Suppression in Rat Hepatocellular Carcinoma
Inhibition of c-Jun NH2-Terminal Kinase Switches Smad3 Signaling from Oncogenesis to Tumor-Suppression in Rat Hepatocellular Carcinoma
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DOI：
10.1002/hep.22860
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发表时间：
2009-06-01
期刊：
影响因子：
13.5
通讯作者：
Uemoto, Shinji
中科院分区：
文献类型：
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作者：
Nagata, Hiromitsu;Hatano, Etsuro;Uemoto, Shinji
转化生长因子-β信号转导途径既涉及肿瘤抑制，又涉及肿瘤发生。转化生长因子-β激活转化生长因子-βI型受体(T-βRI)和c-jun氨基末端激酶(JNK)，从而差异地将介质Smad3磷酸化为COOH末端磷酸化的Smad3(PSmad3C)和接头磷酸化的Smad3(PSmad3L)。依赖TβRI的pSmad3C传递肿瘤抑制的转化生长因子-β信号，而依赖JNK的pSmad3L促进人类慢性肝病的癌变。本研究的目的是阐明JNK抑制剂SP600125如何影响大鼠肝细胞癌的发生，同时重点研究Smad3的结构域特异性磷酸化。每周皮下注射SP600125或赋形剂11次，同时给予100ppm N-二乙基亚硝胺(DEN)，连续56天，最后一次注射DEN后28天处死大鼠，以评估肝癌的发展情况。SP600125治疗组大鼠肿瘤结节直径大于3 mm的个数和肝重/体重比显著低于赋形剂治疗组(7-9+/-0.8vs17.7+/-0.9vs6.30+/-1.2vs7.1+/-0.2%：p0.05)。SP600125可显著延长DEN诱导的肝细胞癌大鼠的中位生存期(113d比97d：对数等级P=0.0018)。暴露于DEN的大鼠肝细胞JNK/pSmad3L/c-Myc表达增强。然而，随着DEN诱导的肝细胞癌的发展，TβRI/pSmad3C/p21(WAF1)的表达受损。SP600125对JNK活性的特异性抑制抑制了受损肝细胞中的pSmad3L/c-Myc，增强了正常肝细胞中的pSmad3C/p21(WAF1)，发挥了肿瘤抑制作用。结论：在DEN治疗的大鼠体内，SP600125使肝细胞SMAD3介导的信号从肿瘤发生转向肿瘤抑制，提示JNK可能成为人肝癌发生发展的治疗靶点。(《肝病》2009；49：1944-1953)
Transforming growth factor beta (TGF-beta) signaling involves both tumor-suppression and oncogenesis. TGF-beta activates the TGF-beta type I receptor (T beta RI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). T beta RI-dependent pSmad3C transmits a tumor-suppressive TGF-beta signal, while JNK-dependent pSmad3L promotes carcinogenesis in human chronic liver disorders. The aim of this study is to elucidate how SP600125, a JNK inhibitor, affected rat hepatocellular carcinoma (HCC) development, while focusing on the domain-specific phosphorylation of Smad3. The rats received subcutaneous injections of either SP600125 or vehicle 11 times weekly together with 100 ppm N-diethylnitrosamine (DEN) administration for 56 days and were sacrificed in order to evaluate HCC development 28 days after the last DEN administration. The number of tumor nodules greater than 3 mm in diameter and the liver weight/body weight ratio were significantly lower in the SP600125-treated rats than those in the vehicle-treated rats (7-9 +/- 0.8 versus 17.7 +/- 0.9: P < 0.001; 6.3 +/- 1.2 versus 7.1 +/- 0.2%: P < 0.05). SP600125 significantly prolonged the median survival time in rats with DEN-induced HCC (113 versus 97 days: log-rank P = 0.0018). JNK/pSmad3L/c-Myc was enhanced in the rat hepatocytes exposed to DEN. However, T beta RI/pSmad3C/p21(WAF1) was impaired as DEN-induced HCC developed and progressed. The specific inhibition of JNK activity by SP600125 suppressed pSmad3L/c-Myc in the damaged hepatocytes and enhanced pSmad3C/p21(WAF1), acting as a tumor suppressor in normal hepatocytes. Conclusion: Administration of SP600125 to DEN-treated rats shifted hepatocytic Smad3-mediated signal from oncogenesis to tumor suppression, thus suggesting that JNK could be a therapeutic target of human HCC development and progression. (HEPATOLOGY 2009;49:1944-1953.)