SIP1 is a downstream effector of GADD45G in senescence induction and growth inhibition of liver tumor cells.
SIP1 is a downstream effector of GADD45G in senescence induction and growth inhibition of liver tumor cells.
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SIP1是GADD45G在肝肿瘤细胞衰老诱导和生长抑制中的下游效应子
DOI：
10.18632/oncotarget.5602
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Liu Y
中科院分区：
文献类型：
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作者：
Xu G;Zhang L;Ma A;Qian Y;Ding Q;Liu Y;Wang B;Yang Z;Liu Y
肿瘤抑制程序失活引起的细胞衰老逃避与肿瘤启动和治疗耐药性有关。我们的前期研究表明，生长停滞和DNA损伤45 G（GADD 45 G）的下调有助于肝细胞癌（HCC）的衰老旁路。在这里，我们报告的Smad相互作用蛋白-1（SIP 1）是转录激活和功能的关键GADD 45 G诱导的肿瘤细胞衰老。SIP 1的敲低显著消除了GADD 45 G对体内异种移植肝肿瘤生长的抑制作用。SIP 1在GADD 45 G活性中的重要作用在蛋白酶体抑制剂MG 132诱导的细胞衰老模型中得到进一步验证。我们进一步表明，JNK，而不是p38 MAPK激活参与GADD 45 G介导的SIP 1上调，JNK抑制抵消GADD 45 G诱导的细胞衰老。更重要的是，我们发现GADD 45 G和SIP 1的表达在原发性肝癌组织中同时下调。总之，我们的研究结果表明GADD 45 G-SIP 1轴的下调可能有助于细胞衰老逃避和HCC的发展。
Cellular senescence evasion caused by the inactivation of tumor suppressive programs is implicated in tumor initiation and therapeutic resistance. Our previous study has shown that the downregulation of growth arrest and DNA damage 45G (GADD45G) contributes to senescence bypass in hepatocellular carcinoma (HCC). Here, we report that the Smad-interacting protein-1 (SIP1) is transcriptionally activated and functions critically in the GADD45G-induced tumor cell senescence. Knockdown of SIP1 significantly abrogates the suppressive effects of GADD45G on the growth of xenografted liver tumor in vivo. The essential role of SIP1 in GADD45G activities is further validated in the model of the proteasome inhibitor MG132-induced cell senescence. We further show that JNK but not p38 MAPK activation is involved in the GADD45G-mediated SIP1 upregulation, and that JNK inhibition counteracts the GADD45G-induced cellular senescence. More importantly, we show that GADD45G and SIP1 expression are coincidently downregulated in primary human HCC tissues. Together, our results establish that the dowregulation of GADD45G-SIP1 axis may contribute to cellular senescence evasion and HCC development.