The LIM protein AJUBA promotes colorectal cancer cell survival through suppression of JAK1/STAT1/IFIT2 network
The LIM protein AJUBA promotes colorectal cancer cell survival through suppression of JAK1/STAT1/IFIT2 network
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LIM 蛋白 AJUBA 通过抑制 JAK1/STAT1/IFIT2 网络促进结直肠癌细胞存活
DOI：
10.1038/onc.2016.418
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发表时间：
2017-05-11
期刊：
影响因子：
8
通讯作者：
Hou, Z.
中科院分区：
文献类型：
--
作者：
Jia, H.;Song, L.;Hou, Z.
LIM蛋白AJUBA是一种参与调控细胞粘附、有丝分裂、DNA损伤、细胞分化、增殖、迁移和基因转录的支架蛋白。然而，其在肿瘤发生和进展中的作用尚不明确。在这里，我们报道了AJUBA在结直肠癌（CRC）中高表达，并通过抑制细胞凋亡促进结直肠癌细胞在培养和异种移植小鼠中的生长。AJUBA抑制IFIT2基因的表达，IFIT2基因是一种干扰素刺激基因，是一种已知的细胞凋亡诱导剂和肿瘤抑制因子，介导其对细胞凋亡的抵抗。机制研究表明，AJUBA特异性结合JAK1的FERM结构域，使JAK1与IFNγ受体分离，从而抑制STAT1磷酸化并伴随其核易位。临床上，结直肠癌标本中AJUBA水平与IFIT2、pSTAT1水平呈负相关。总之，这些研究表明，AJUBA可以通过抑制细胞凋亡来促进结直肠癌的生长，并可作为结直肠癌治疗的靶点和诊断的标记物。
The LIM protein AJUBA is a scaffold protein participating in the regulation of cell adhesion, mitosis, DNA damage, cell differentiation, proliferation, migration and gene transcription. However, its roles in tumorigenesis and progression are poorly defined. Here, we report that AJUBA is highly expressed in colorectal cancer (CRC) and promotes CRC cell growth in culture and in xenografted mice via an inhibition of apoptosis. AJUBA represses the expression of IFIT2 gene, an interferon-stimulated gene and a known apoptosis inducer and tumour suppressor to mediate its resistance to apoptosis. Mechanistic investigations reveal that AJUBA specifically binds the FERM domain of JAK1 to dissociate JAK1 from the IFNγ recepter, resulting in an inhibition of STAT1 phosporylation and concomitantly its nuclear translocation. Clinically, the level of AJUBA in CRC specimens is negatively correlated with the levels of IFIT2 and pSTAT1. Collectively, these studies demonstrate that AJUBA can promote CRC growth via inhibiting apoptosis and serve as a target for the therapeutics and a marker for diagnosis of CRC.