WDR34调控Par3亚细胞定位及表达在胃癌上皮间质转化中的机制研究

Epithelial mesenchymal transition (EMT) plays an important role in the process of gastric cancer metastasis. The EMT of gastric cancer is associated with polarity proteins. However, whether the polarity protein Par3 contributes to the EMT of gastric cancer is seldom studied. Our preliminary study manifested that Par3 was abnormally localized in the nucleus and the expression has decreased in gastric cancer cells, which might be involved in the EMT process of gastric cancer. Meanwhile, the overexpression of WDR34, an intermediate chain of cytoplasmic dynein2, was associated with the EMT of gastric cancer. The preliminary data suggested that WDR34 bind to Par3. Based on newly published literature and our preliminary data, we hypothesized that the overexpression of WDR34 drives the translocation of Par3 from the tight junction of cell membrane into the nucleus and the down-regulates the expression of Par3 through the Hedgehog signaling pathway, which lead to the loss of cell polarity and EMT of gastric cancer. To verify this hypothesis, following studies are planned: 1. To verify that the aberrant location and decreased expression of Par3 promotes the EMT of gastric cancer. 2. To prove the overexpression of WDR34 promotes the EMT of gastric cancer. 3. To clarify that the overexpression of WDR34 drives the aberrant location and decreased expression of Par3, which impair the EMT of gastric cancer. Our study will provide new strategies and targets for the treatment of gastric cancer.

上皮间质转化（EMT）在胃癌侵袭转移过程中发挥重要作用。胃癌EMT与极性蛋白相关，但极性蛋白Par3是否参与胃癌EMT及其调控机制目前尚无报道。我们的预实验发现：Par3在胃癌细胞中异常定位于胞核且其表达量下降，并参与胃癌EMT；同时，细胞胞浆逆向转运动力蛋白中链WDR34与胃癌EMT相关，且WDR34与Par3相互作用。结合文献及预实验结果提出假设：胃癌细胞中WDR34的高表达促使Par3从胞膜逆向转运至胞核，导致胞膜中Par3减少，同时WDR34通过激活Hh信号负调控胃癌细胞中Par3的表达，从而导致胃癌细胞极性消失，进而增强胃癌EMT。为验证该假设，拟进行以下研究：1.验证Par3异常定位及低表达促进胃癌EMT；2.证实WDR34异常高表达增强胃癌EMT；3、阐明WDR34高表达致使Par3异常定位及低表达进而增强胃癌EMT的机制。本项目的顺利实施将为胃癌的治疗提供新的思路和靶点。

Gastric cancer (GC) is one of the common and malignant tumors. WDR34 is implicated in the development of multiple cancers. We proved that WDR34 expression was upregulated in GC tissues, while being positively correlated with the clinical stage. Knockdown of WDR34 inhibited GC cell viability and prevented the G1 to S cell cycle transformation. RNA sequencing revealed that WDR34 refers to the cell cycle regulation pathway and is associated with E2F1 expression in GC. It was further confirmed that silencing of WDR34 decreased cell growth in a xenograft model. Mechanically, we showed that WDR34 binds to PABPC1 and regulates its nucleocytoplasmic distribution. Furthermore, PABCP1 may act as an oncogene that directly binds E2F1 mRNA and maintains its stability. WDR34 protects the dynamic nucleocytoplasmic distribution of PABPC1, resulting in E2F1 mRNA stability and translation.Our findings suggest a novel role for WDR34 in GC tumorigenesis and potential therapeutic target for GC.