FAM64A调控IL-6-STAT3信号通路的分子机制及其在炎症-癌症转化中的功能

Activation of STAT3 is tightly regulated during various physiological processes, and aberrant STAT3 activation results in diseases. And IL-6-STAT3 signaling pathway has been proved to be important to promote inflammation-associated cancer development. To identify additional molecules that regulate IL-6-induced STAT3 activation, we screened an expression clone library by STAT3 reporter assay, and identified FAM64A as a candidate regulator of STAT3 activation. In our preliminary studies, we found that overexpression of FAM64A potentiated IL-6-induced STAT3 activation and transcriptions of STAT3 downstream target genes, while RNAi-based knockdown of FAM64A had opposite effects. Moreover, IL-6-induced transcription of STAT3 target genes was significantly inhibited in Fam64a-deficient mouse embryo fibroblasts (MEF). These results indicate FAM64A is involved in positive regulation of IL-6-STAT3 signaling. In this project, we will further investigate the novel mechanisms that FAM64A regulates IL-6-STAT3 signaling and utilize knockout mice to determine the functions of FAM64A in inflammation-associated cancer development. This study will help to understand the complicated regulation mechanisms of IL-6-STAT3 signaling as well as inflammation-associated tumorigenesis and identify potential molecular target for cancer therapy.

研究表明，IL-6-STAT3信号转导在慢性炎症相关的肿瘤发生中发挥非常关键的作用。该信号通路受到复杂严密的调控，其调控机制需要进一步深入研究。我们通过表达克隆实验筛选得到一个未报道的参与调控IL-6-STAT3信号通路的分子FAM64A。前期研究发现，过量表达FAM64A显著促进IL-6诱导的STAT3激活。相反地，下调内源性FAM64A的表达则抑制IL-6诱导的STAT3激活。另外，在小鼠胚胎成纤维细胞中，Fam64a的缺失显著抑制IL-6诱导的STAT3下游靶基因的转录。这些结果表明，FAM64A正向调控IL-6-STAT3信号转导。本研究旨在进一步阐明FAM64A调控IL-6-STAT3信号转导的具体分子机制，并利用基因敲除小鼠研究FAM64A在炎症-癌症转化中的功能。本研究将有助于了解STAT3活性调控的复杂过程及炎症-癌症恶性转化的分子机制，为肿瘤的治疗鉴定新的分子靶标。

转录因子STAT3在细胞生长、增殖和分化等一系列生理活动中起重要作用，其活性受到严格精细的调控。STAT3活性异常将导致多种疾病的发生，如肿瘤。本项目通过表达克隆实验筛选到一个调控IL-6-STAT3信号通路的蛋白FAM64A，并研究其调控STAT3活性的分子机制及其在炎症-癌症转化中的功能。过量表达FAM64A促进IL-6诱导的STAT3激活及下游靶基因的转录，敲低或敲除FAM64A的表达则显著抑制IL-6诱导的STAT3激活及下游靶基因的转录。进一步的研究发现，FAM64A在细胞核里与STAT3相互作用，促进STAT3与靶基因启动子结合，从而促进STAT3的转录活性。Fam64a缺失会显著抑制Th17细胞的分化，但对Th1、Th2和iTreg细胞的分化没有明显影响。实验性自身免疫性脑脊髓炎和硫酸葡聚糖钠诱导的肠炎模型显示，Fam64a缺失显著抑制EAE和肠炎的发生，减少组织中Th17细胞数量以及炎症因子的表达。Fam64a缺失也能显著抑制偶氮甲烷和硫酸葡聚糖钠诱导的肠炎相关癌的发生。此外，本项目也揭示了另外一个调控蛋白TRIM27调控STAT3活化的分子机制及其在炎症-癌症转化中的功能。这些研究揭示了STAT3活性调控的精细机制，发现了FAM64A和TRIM27在肠炎以及炎症-癌症转化中的新功能，为炎症性疾病和肿瘤的治疗鉴定了新的分子靶标。