PCDH17通过JNK/Bcl-2信号通路增强胃癌和结直肠癌细胞对5-FU敏感性的机制研究

5-Fluorouracil (5-FU) remains a widely used chemotherapeutic drug in the treatment of a variety of gastric and colorectal carcinomas, however, the resistance to 5-FU has been recognised as an important problem for gastric and colorectal cancer therapy. Previously, we first reported that PCDH17, acted as a functional tumor suppressor gene in gastric and colorectal cancers. PCDH17 can not only induce the activation of JNK but also enhance the cytotoxicity of 5-FU through inducing phosphorylation of Bcl-2, promoting the release of cytochrome C and activating caspase-3 in gastric and colorectal cancer cells. Increasing evidence demonstrates that JNK-mediated multisite phosphorylation of the anti-apoptotic protein Bcl-2 is an important mechanism for augmenting the sensitivity of chemotherapeutic drugs. So，we hypothesized that PCDH17 increased the sensitivity of 5-FU via JNK/Bcl-2-mediated mitochondrial pathway. Based on our previous study, we will focus on JNK/Bcl-2, and discuss the possible relationship between PCDH17， JNK/Bcl-2-mediated mitochondrial pathway and the sensitivity of 5-FU through chemical inhibitors, RNAi and other molecular biological techniques. Finally, we try to clarify the possible molecular mechanism that PCDH17 potentiates the sensitivity of 5-FU in gastric and colorectal cancer cells, which may allow us to develop a promising therapeutic target to improve clinical outcomes of 5-FU for gastric and colorectal cancer.

5-FU是胃肠道肿瘤常用的化疗药物，但其导致的抗药性是肿瘤治疗的难题。我们前期的研究首次发现：PCDH17在胃肠道肿瘤中是一个抑癌基因，其不仅能够激活JNK的活化，还可以通过诱导Bcl-2的磷酸化、促进cytochrome C的释放和激活caspase-3来增强肿瘤细胞对5-FU的敏感性。但PCDH17增强5-FU敏感性的分子机制尚不清楚。大量研究证实：JNK介导的Bcl-2磷酸化是化疗药物增敏的重要机制。因此，我们推测：PCDH17通过JNK/Bcl-2介导的线粒体通路增强了5-FU的敏感性。本项目将在上述基础上，以JNK/Bcl-2为切入点，采用化学抑制剂和RNAi等分子生物学方法，通过体内外实验研究PCDH17、JNK/Bcl-2线粒体通路和5-FU敏感性三者之间的关系，从而阐明PCDH17增强胃癌和结直肠癌细胞对5-FU敏感性的分子机制，为胃癌和结直肠癌的治疗提供一种新的靶点。

5-FU是胃肠道肿瘤常用的化疗药物，但其导致的抗药性是肿瘤治疗的难题。我们前期的研究首次发现：PCDH17在胃肠道肿瘤中是一个抑癌基因，其不仅能够激活JNK的活化，还可以通过诱导Bcl-2的磷酸化、促进cytochrome C的释放和激活caspase-3来增强肿瘤细胞对5-FU的敏感性。但PCDH17增强5-FU敏感性的分子机制尚不清楚。本项目在前期基础上证实大量研究证实：PCDH17通过介导JNK/Bcl-2 磷酸化进而增强了胃癌和结直肠癌细胞对5-FU的化疗敏感性。本项目初步阐明了PCDH17增强胃癌和结直肠癌细胞对5-FU敏感性的分子机制，为胃癌和结直肠癌的治疗提供一种新的精准治疗预测靶点。