逆转胃癌中高表达YAP促增殖作用的研究

YAP(Yes-associated protein) was a downstream signal transducer of Hippo pathway,and was reported to be implicated in the regulation of several signal pathways,including cell proliferation and apoptosis;In our previous studies, we found an overexpression of YAP in gastric cancer,moreover,YAP gene silencing mediated by SiRNA inhibited proliferation and induced apoptosis in gastric cancer cell line,we suggested that overexpression of YAP might promote cell proliferation and play multiple roles in the pathogenesis of gastric cancer; However,YAP has been reported to have dual effects in the regulation of cell proliferation and apoptosis,it promoted cell proliferation as well as induced cell apoptosis;YAP exhibited an proliferating effect in gastric cancer,while the mechanism of loss of apoptotic effect and whether YAP had a proapoptotic effect in gastric cancer were unknown.Our studies would take PML as a starting point,probing into the mechanisms led to the loss of apoptotic effect of YAP in gastric cancer,trying to reverse the proliferating effect as to induce cell apoptosis,exploring the possibility of YAP as the gene therapy target for gastric cancer.

YAP(yes-associated protein)为Hippo通路下游的信号转导分子，参与机体多条信号转导通路的调节，包括细胞增殖与凋亡的调控，我们在前期的实验中发现，胃癌中存在着YAP的高表达，应用SiRNA介导YAP基因沉默可明显抑制胃癌细胞的增殖并诱导细胞凋亡，我们认为YAP的高表达促进胃癌细胞的增殖，参与胃癌的发生与发展；然而研究表明，YAP同时具有促进增殖及诱导凋亡的双重作用，在胃癌中，YAP表现为促增殖作用，但其诱导凋亡缺失的机制以及是否具有潜在的促凋亡作用未见文献报道；研究拟以PML为切入点，探讨胃癌中YAP诱导凋亡缺失的机制，并试图逆转高表达YAP促细胞增殖作用，使其转化为诱导细胞凋亡，并进一步阐述胃癌的发生机制以及YAP做为胃癌基因治疗靶点的可能性。

胃癌的发生发展是个多基因突变、多因素的结果，针对关键基因的靶向治疗则可通过抑制肿瘤生长，延缓肿瘤进程，延长患者生存期，改善生活质量，从而使患者达到较长期的“带癌生存”；YAP(yes-associated protein)为Hippo 通路下游的信号转导分子，参与机体多条信号转导通路的调节，包括细胞增殖与凋亡的调控，我们前期的研究发现YAP在胃癌中的表达上调，YAP高表达可能促进了胃癌的发生发展。因YAP在肿瘤中存在抑癌或致癌的双向作用，我们本研究中进一步探讨了YAP做为胃癌靶向治疗的可能性；在本研究中，我们发现1. PML在胃癌中的表达明显下降,高表达PML的胃癌细胞系诱导细胞的凋亡，抑制细胞增殖，提示PML可能参与了胃癌的发生；2.发现PML诱导细胞凋亡需与YAP相结合而实现，提示在胃癌细胞系中，高表达的YAP可能在PML存在下诱导细胞凋亡。3.高表达YAP增加胃癌细胞系对化疗药物诱导凋亡的抵抗性。由此我们认为YAP可能成为胃癌的基因治疗的靶点。