Growth arrest and DNA damage 45G down‐regulation contributes to janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma
Growth arrest and DNA damage 45G down‐regulation contributes to janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma
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DOI：
10.1002/hep.26628
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发表时间：
2014-01
期刊：
影响因子：
13.5
通讯作者：
Li Zhang;Zhaojuan Yang;A. Ma;Yulan Qu;S. Xia;Dongxu Xu;Chao Ge;B. Qiu;Q. Xia;Jinjun Li;Yongzhong Liu
中科院分区：
文献类型：
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作者：
Li Zhang;Zhaojuan Yang;A. Ma;Yulan Qu;S. Xia;Dongxu Xu;Chao Ge;B. Qiu;Q. Xia;Jinjun Li;Yongzhong Liu
生长停滞和DNA损伤45 G（GADD 45 G）是一种在各种生物学过程中具有多种意义的应激传感器，在广泛的癌症中下调。然而，GADD 45 G对肝癌细胞的生物学效应及其相关机制尚不清楚。在本研究中，我们发现GADD 45 G在癌基因转化的小鼠肝细胞以及人类和小鼠HCC中普遍下调。GADD 45 G的异位表达强烈地引起HCC细胞的衰老并抑制体内肿瘤生长。此外，GADD 45 G诱导的衰老发生在HCC细胞中，与p53、p16 INK 4a（p16）和视网膜母细胞瘤（Rb）无关。相反，在经历衰老的细胞中观察到Janus激酶2（Jak 2）、酪氨酸激酶2（Tyk 2）和信号转导子和转录激活子3（Stat 3）激活的迅速抑制。由GADD 45 G表达引起的Jak‐ Stat 3活化受损与含SH 2结构域的蛋白酪氨酸磷酸酶-2（Shp 2）的活化相关。组成性激活的Stat 3或人端粒酶逆转录酶（hTERT）的表达以及Shp 2f的敲低有效地抵消了GADD 45 G诱导的衰老。更重要的是，在临床HCC标本中，我们发现GADD 45 G表达与肿瘤细胞中磷酸化Stat 3表达和疾病进展呈负相关。结论：GADD 45 G作为Jak‐ Stat 3通路的负调节剂发挥作用，并通过诱导细胞衰老来抑制HCC。GADD 45 G表达的减少或缺失可能是肿瘤细胞或癌前肝细胞绕过细胞衰老的关键事件。（肝病学2014;58：178-189）
Growth arrest and DNA damage 45G (GADD45G), a stress sensor with multiple implications in various biological processes, is down‐regulated in a broad spectrum of cancers. However, little is known about the biological effects of GADD45G on hepatocellular carcinoma (HCC) cells and the related mechanisms. In the present study, we found that GADD45G was commonly down‐regulated in oncogene‐transformed mouse liver cells and in human and mouse HCC. Ectopic expression of GADD45G robustly elicited senescence in HCC cells and suppressed tumor growth in vivo. Furthermore, GADD45G‐induced senescence occurred in HCC cells independently of p53, p16INK4a (p16), and retinoblastoma (Rb). Instead, the prompt inhibition of Janus kinase 2 (Jak2), tyrosine kinase 2 (Tyk2), and signal transducer and activator of transcription 3 (Stat3) activation was observed in cells undergoing senescence. Impairment of Jak‐Stat3 activation caused by GADD45G expression was associated with activation of SH2 domain‐containing protein tyrosine phosphatase‐2 (Shp2). Expression of constitutively activated Stat3 or human telomerase reverse transcriptase (hTERT), as well as knockdown of Shp2f, efficiently counteracted GADD45G‐induced senescence. More important, in clinical HCC specimens, we found that GADD45G expression was inversely correlated with phosphorylated Stat3 expression in tumor cells and disease progression. Conclusion: GADD45G functions as a negative regulator of the Jak‐Stat3 pathway and inhibits HCC by inducing cellular senescence. The decrease or absence of GADD45G expression may be a key event for tumor cells or premalignant liver cells to bypass cellular senescence. (Hepatology 2014;58:178–189)