因发病率高和致死率高，结直肠癌成为威胁到人类健康的重要因素之一。RelA是 NF-κB信号通路中心转录因子，在肿瘤转移中起着重要作用。已有研究表明：EGFR信号通路能够激活NF-kB信号通路，然而RelA在此背景下调节分子机制有待进一步阐明。我们前期研究发现：EGFR信号通路激活促进细胞核中RelA与MIIP特异结合；进而PKCε活性介导了RelA与MIIP相互作用，并且PKCε能够磷酸化MIIP；MIIP敲低削弱EGF诱导的RelA乙酰化水平及转录活性，结直肠癌细胞侵袭转移。本项目拟研究：MIIP在EGFR信号通路激活背景下调节RelA乙酰化水平及转录活性，从分子、细胞和动物水平揭示结直肠癌肿瘤侵袭转移的作用机制；分析临床肿瘤样本MIIP磷酸化、RelA乙酰化与病人预后的相关性。本项目将阐明MIIP调节EGF-NF-κB信号通路的分子机制以及其在结直肠癌肿瘤中的作用。

Colorectal cancer (CRC) is a major worldwide health problem owing to its high prevalence and mortality rates. EGFR signaling is implicated in NF-κB activation. However, the concrete mechanisms by which the core transcriptional factor of NF-κB signaling pathway, RelA/p65 is regulated under EGFR activation remains to be further clarified. Currently, we have found that EGF stimulation induced PKCε-dependent interaction between MIIP and RelA in the nucleus, and MIIP was able to be phosphorylated by PKCε. In addition, depletion of MIIP blocked RelA Ac-K310 levels and thereby tumor cell invasion induced by EGF. These results suggest PKCε -MIIP-RelA signaling pathway would be importantly implicated in CRC tumor metastasis. In the present project, we are going to further investigate the molecular mechanism by which MIIP regulates RelA-mediated CRC tumor metastasis. In addition, we will utilize the cancer cell lines and mice tumor model to test the effects of PKCε -MIIP-RelA signaling pathway on CRC tumor metastasis. Finally, we will set forth to examine the relationship between status of MIIP phosphorylation, RelA Ac-K310 and patient survival. Taken together, here we expect to uncover the functional role of MIIP in EGF-induced RelA activation and the relevant effects on CRC tumor metastasis.