新肿瘤抑制基因FGF14在结直肠癌中的作用机制和临床应用价值研究

Colorectal cancer is one of the top cancers and one of the leading causes of cancer related deaths worldwide, especially in China. However, the molecular mechanism of colorectal cancer is still unclear. Promoter hypermethylation-induced epigenetic silencing of tumor related genes played a key role in the initiation and development of colorectal cancer. Using Methyl-DNA immunoprecipitation, we identified a novel potential tumor suppressor gene FGF14. This gene was silent or down-regulated in colorectal cancer. Its expression could be restored after demethylation treatment. Overexpression of FGF14 suppressed colorectal cancer cell growth. These preliminary data suggested that FGF14 gene might be a novel potential tumor suppressor gene in colorectal cancer. Based on these results, we aim to study 1) the effect of FGF14 in colorectal cancer cells through in vitro and in vitro assays; 2) the molecule basis of potential tumor suppressive effect of FGF14; 3) clinical significance of FGF14 down-regulation and evaluation of FGF14 methylation as a biomarker in clinical application in colorectal cancer. Hence, this study may identify the tumor suppressive effect of FGF14 gene in colorectal cancer, clarify its molecular mechanism, and provide important scientific evidences for the evaluation of colorectal cancer related biomarkers in diagnosis and prognosis of colorectal cancer.

结直肠癌的发病率和死亡率在中国乃至全球居于恶性肿瘤前列，但其发生机制尚不清楚。启动子超甲基化所致肿瘤抑制基因失活在结直肠癌发生发展过程中起重要的作用。应用甲基化DNA免疫共沉淀技术，我们发现新的潜在肿瘤抑制基因FGF14。该基因在结直肠癌细胞中表达普遍下调或沉默，而去甲基化处理可使FGF14恢复表达。此外，在结直肠癌细胞株中过表达FGF14能显著抑制肿瘤细胞生长。上述前期结果提示FGF14基因是结直肠癌新的肿瘤抑制基因。在此基础上，本课题主要研究：1）通过体内和体外实验进一步证实FGF14对结直肠癌生长的作用；2）阐明FGF14抑制结直肠癌生长的分子机制；3）探讨FGF14表达沉默的临床意义和FGF14甲基化在结直肠癌早期诊断和预后判断中的临床应用价值。本项目的开展有望证实FGF14在结直肠癌中的肿瘤抑制作用，阐明其抑癌机制，并为找到结直肠癌早期诊断和预后判断新的分子标记提供重要科学依据。

结直肠癌的发病率和死亡率在中国乃至全球居于恶性肿瘤前列，但其发生机制尚不清楚。启动子超甲基化所致肿瘤抑制基因失活在结直肠癌发生发展过程中起重要的作用。应用甲基化DNA免疫共沉淀技术，我们发现新的潜在肿瘤抑制基因FGF14。.本课题主要研究内容为：1）通过体内和体外实验探讨FGF14对结直肠癌生长的作用；2）阐明FGF14抑制结直肠癌生长的分子机制。.本研究发现，FGF14在结直肠癌细胞及组织中表达均下调，甲基化酶抑制剂5-Aza能逆转FGF14的表达下调。过表达FGF14能抑制结直肠癌细胞活性及克隆形成，并能诱导细胞凋亡。此外，过表达FGF14能抑制小鼠肿瘤生长。我们进一步研究发现，FGF14主要通过诱导线粒体凋亡及抑制PI3K/AKT/mTOR通路发挥作用。.本项目初步证实FGF14在结直肠癌中的肿瘤抑制作用及其抑癌机制，为找到结直肠癌早期诊断和预后判断新的分子标记提供重要科学依据。