PIR蛋白通过抑制Fas介导的凋亡信号通路促进结肠癌发生的机理

凋亡逃逸是肿瘤的一大特征,在其发生中起重要作用。深入研究肿瘤抗凋亡的机制对其治疗有重要意义。PIR蛋白在多种肿瘤中高表达。我们之前的研究表明PIR转录激活细胞周期调控蛋白E2F1，促进细胞增殖，但尚不清楚PIR是否与凋亡逃逸有关。我们预实验发现在PIR高表达的结肠癌细胞系中抑制PIR的表达能够激活死亡受体Fas介导的凋亡途径。进一步的实验证实，抑制PIR能促进转录因子NF-kB2结合于Fas的启动子区域，增强Fas的表达，进而诱导细胞凋亡。可见PIR抑制Fas的表达在肿瘤逃逸凋亡中起重要作用，这也可能是其促癌的重要机理之一。本项目拟进一步深入探究：PIR抑制NF-kB2-Fas信号轴的详细的分子机理；在细胞和动物模型中验证PIR通过抑制该信号轴促进结肠癌细胞存活及成瘤；从大样本临床数据中分析PIR与Fas的相关性及与结肠癌预后的关系。研究有望为PIR作为新的潜在的抗肿瘤靶点提供理论依据。

Evading apoptosis is a hallmark of tumor and is essential for tumorigenesis. Exploring anti-apoptosis mechanisms in depth is of great significance to tumor treatment. PIR protein is highly expressed in many tumors. Our previous study has shown that PIR transcriptionally activates E2F1, a cell cycle regulator，and consequently promotes cell proliferation. However, it is unclear whether PIR is involved in the escape of cancer cells from apoptosis. Our preliminary experiments found that inhibition of PIR in PIR highly-expressed colon cancer cells activated apoptosis by mediating the death receptor Fas. Further experiments confirmed that PIR inhibition enhanced the binding of transcriptional factor NF-kB2 to Fas promoter, which in turn promoted Fas expression and cell apoptosis. These results demonstrate that PIR may play an important role in the escape of cancer cells from apoptosis by inhibiting Fas expression, which may also be the key mechanism underlying PIR promotion of carcinogenesis. In this project we will further dissect the detailed molecular mechanism by which PIR inhibit NF-kB2-Fas axis, confirm the promoting effect of such inhibition on colon cancer cell survival and tumor formation by using cell lines and animal models. We will also analyze the correlation between PIR and Fas expressions and examine whether this correlation can be used to evaluate the prognosis of colorectal cancer by virtue of large-scale clinical data. Our investigation will provide convincing proof proving PIR as a emerging anti-tumor target.