TAB3 upregulates PIM1 expression by directly activating the TAK1-STAT3 complex to promote colorectal cancer growth
TAB3 upregulates PIM1 expression by directly activating the TAK1-STAT3 complex to promote colorectal cancer growth
复制标题
TAB3 通过直接激活 TAK1-STAT3 复合物上调 PIM1 表达，促进结直肠癌生长。
DOI：
10.1016/j.yexcr.2020.111975
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发表时间：
2020-06-01
影响因子：
3.7
通讯作者：
Yuan, Rongfa
中科院分区：
文献类型：
--
作者：
Li, Qing;Chen, Leifeng;Yuan, Rongfa
转化生长因子- β活化激酶1 （TAK1）结合蛋白3 （TAB3）和Moloney小鼠白血病病毒1 （PIM1）的前病毒整合位点与癌症的发生有关。在本研究中，我们研究了TAB3和PIM1在结直肠癌（CRC）中的关系，并确定了TAB3在PIM1介导的结直肠癌生长中的潜在作用和分子机制。我们发现TAB3和PIM1在结直肠癌组织中的表达水平呈正相关。在体外和体内，敲低TAB3可显著降低PIM1的表达，抑制结直肠癌的增殖。PIM1的上调挽救了TAB3敲低诱导的细胞增殖下降，而PIM1敲低则抑制了TAB3增强的CRC增殖。此外，TAB3通过STAT3信号通路调控PIM1的表达，证实了TAB3与CRC组织中磷酸化STAT3的表达呈正相关。高表达TAB3和磷酸化stat3的患者预后最差。在机制上，TAB3通过形成TAB3- tak1 -STAT3复合物，促进STAT3的磷酸化和活化，从而调控PIM1的表达。总之，我们发现了一个新的CRC调控回路，涉及TAB3-TAK1-STAT3复合物和PIM1，其功能障碍可能与CRC肿瘤发生有关。
Transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 3 (TAB3) and the proviral integration site for Moloney murine leukaemia virus 1 (PIM1) are implicated in cancer development. In this study, we investigated the relationship between TAB3 and PIM1 in colorectal cancer (CRC) and determined the potential role and molecular mechanism of TAB3 in PIM1-mediated CRC growth. We found that TAB3 and PIM1 expression levels were positively correlated in CRC tissues. The knockdown of TAB3 significantly decreased PIM1 expression and inhibited CRC proliferation in vitro and in vivo. The upregulation of PIM1 rescued the decreased cell proliferation induced by TAB3 knockdown, whereas PIM1 knockdown decreased TAB3-enhanced CRC proliferation. Additionally, TAB3 regulates PIM1 expression through the STAT3 signalling pathway and confirmed a positive correlation between TAB3 and phosphorylated-STAT3 expression in CRC tissues. Patients with high expression of TAB3 and phosphorylated-STAT3 had the worst prognosis. Mechanistically, TAB3 regulates PIM1 expression by promoting STAT3 phosphorylation and activation through the formation of the TAB3-TAK1-STAT3 complex. Overall, a novel CRC regulatory circuit involving the TAB3-TAK1-STAT3 complex and PIM1 was identified, the dysfunction of which may contribute to CRC tumorigenesis.