YAP/TAZ蛋白去泛素化机制及其靶分子AREG作为胰腺癌早期诊断标志物的研究

YAP/TAZ蛋白为Hippo信号通路的主要效应分子，人类双调蛋白（AREG）为其靶分子,在胰腺癌血清中高表达。YAP/TAZ蛋白的稳定性主要受泛素及去泛素化调节，但去泛素化机制尚不清楚。我们发现泛素特异性蛋白酶39（USP39）在胰腺癌中高表达，促进胰腺癌细胞增殖，阻滞细胞周期，抑制细胞凋亡，并上调ERK磷酸化水平；USP39沉默后YAP/TAZ表达水平下调；既往研究表明YAP能激活MAPK/ERK通路，且沉默ERK可加速YAP的降解。我们推测USP39是否通过去泛素化YAP/TAZ，导致YAP/TAZ稳定性增加，继而引起Hippo及MAPK/ERK通路的过度活化，最终导致胰腺癌的发生发展?本研究将通过多种分子生物学方法证实USP39是YAP/TAZ去泛素化的酶及其作用机制；探索AREG作为胰腺癌早期诊断的血清标志物可能性。为明确胰腺癌发生发展的分子机制、寻找早期诊断标志物开拓新思路。

YAP/TAZ proteins is the key effectors in Hippo signaling pathway, amphiregulin (AREG) is the downstream functional target of YAP/TAZ and highly expressed in serum of pancreatic cancer patients. The stability of YAP/TAZ proteins are mainly regulated by ubiquitination and deubiquitination, but deubiquitination mechanism is still unclear. Our previous studies found that ubiquitin specific protease 39 (USP39) expression was up-regulated in pancreatic cancer, and positively correlated with YAP/TAZ expression; Moreover, it could promote pancreatic cancer cell proliferation, cell cycle arrest, inhibition of apoptosis by sitimulating the MAPK/ERK pathway; Previous studies also showed that YAP could activate the MAPK pathway, and silencing ERK expression could accelerate the degradation of YAP. Therefore, we hypothesize that whether USP39 increase stability and expression of YAP/TAZ by promoting ubiquitination of YAP/TAZ, thereby over-activate Hippo and MAPK/ERK pathway, and finally, promote the development of pancreatic cancer? This study will confirm USP39 is ubiquitination enzymes of YAP/TAZ and their underlying mechanism by performing a variety of molecular biology methods; and explore the possibilities of serum AREG，the YAP / TAZ downstrea functional target, as an early noninvasive diagnostic marker of pancreatic cancer. Moreover, our study will clarify the molecular mechanisms in pancreatic cancer development, and shed new light on early diagnostic markers in pancreatic cancer.