Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells
Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells
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DOI：
10.1593/neo.07971
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发表时间：
2008-03-01
期刊：
影响因子：
4.8
通讯作者：
Fang, Jing-Yuan
中科院分区：
文献类型：
--
作者：
Xiong, Hua;Zhang, Zhi-Gang;Fang, Jing-Yuan
STAT 3通路的缺失参与了几种癌症的肿瘤发生。然而，失调的STAT 3信号传导促进人类结直肠癌（CRC）进展的机制尚未阐明，也没有评估JAK（STAT 3的生理激活剂）的作用。为了研究JAK和STAT 3在CRC进展中的作用，我们用AG 490抑制JAK并用SiRNA耗尽STAT 3。我们的研究结果表明，STAT 3和JAK 1和2通过调节基因表达，如Bcl-2，p16（ink 4a），p21（waf 1/cip 1），p27（kip 1），E-cadherin，VEGF和MMPs参与CRC细胞的生长，存活，侵袭和迁移。重要的是，FAK不是STAT 3介导的调控所必需的，但在JAK下游发挥作用。此外，我们的数据表明，蛋白酶体介导的蛋白水解促进JAK 2的去磷酸化，因此，在CRC中负调节STAT 3信号传导。此外，免疫组化染色显示磷酸化STAT 3的核染色主要存在于腺瘤和腺癌中，并且磷酸化JAK 2免疫反应性与结直肠腺癌的分化呈正相关。因此，我们的研究结果阐明了JAK 1，2/STAT 3信号通路在CRC进展中的生物学意义，并为JAK/STAT 3通路可能成为CRC治疗的新的潜在靶点提供了新的证据。
Abnormalities in the STAT3 pathway are involved in the oncogenesis of several cancers. However, the mechanism by which dysregulated STAT3 signaling contributes to the progression of human colorectal cancer (CRC) has not been elucidated, nor has the role of JAK, the physiological activator of STAT3, been evaluated. To investigate the role of both JAK and STAT3 in CRC progression, we inhibited JAK with AG490 and depleted STAT3 with a SiRNA. Our results demonstrate that STAT3 and both JAK1 and 2 are involved in CRC cell growth, survival, invasion, and migration through regulation of gene expression, such as Bcl-2, p16(ink4a), p21(waf1/cip1), p27(kip1), E-cadherin, VEGF, and MMPs. Importantly, the FAK is not required for STAT3-mediated regulation, but does function downstream of JAK. In addition, our data show that proteasome-mediated proteolysis promotes dephosphorylation of the JAK2, and consequently, negatively regulates STAT3 signaling in CRC. Moreover, immunohistochemical staining reveals that nuclear staining of phospho-STAT3 mostly presents in adenomas and adenocarcinomas, and a positive correlation is found between phospho-JAK2 immunoreactivity and the differentiation of colorectal adenocarcinomas. Therefore, our findings illustrate the biologic significance of JAK1, 2/STAT3 signaling in CRC progression and provide novel evidence that the JAK/STAT3 pathway may be a new potential target for therapy of CRC.