Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China; Department of Pathology,Second Affiliated Hospital of Nanchang University, Nanchang, China.
Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, China; Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China.
Exp Cell Res. 2020 Jun 1;391(1):111975. doi: 10.1016/j.yexcr.2020.111975. Epub 2020 Mar 27.
Transforming growth factor-β-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.
转化生长因子-β激活激酶 1（TAK1）结合蛋白 3（TAB3）和莫洛尼鼠白血病病毒 1 前病毒整合位点（PIM1）与癌症的发生有关。在这项研究中，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 CRC 生长中的潜在作用和分子机制。我们发现，CRC 组织中 TAB3 和 PIM1 的表达水平呈正相关。TAB3 敲低显著降低了 PIM1 的表达，并抑制了 CRC 的体外和体内增殖。PIM1 的上调挽救了 TAB3 敲低引起的细胞增殖减少，而 PIM1 的敲低则降低了 TAB3 增强的 CRC 增殖。此外，TAB3 通过 STAT3 信号通路调节 PIM1 的表达，并在 CRC 组织中证实了 TAB3 和磷酸化-STAT3 表达之间的正相关。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 磷酸化和激活来调节 PIM1 的表达。总的来说，鉴定了一种涉及 TAB3-TAK1-STAT3 复合物和 PIM1 的新型 CRC 调控回路，其功能障碍可能有助于 CRC 肿瘤发生。
