NLGN3激活RTKs-Gαi1/3通路促食管癌进展

探索食管癌发生、发展的新机制及靶向干预措施至关重要。预实验发现神经连接蛋白-3（NLGN3）及其信号通路中关键分子Gαi1/3在食管癌过表达，两者耦联多个受体酪氨酸激酶（RTKs）。食管癌细胞中IGF2BP1结合NLGN3 mRNA；而敲除IGF2BP1或LncRNA THOR显著下调NLGN3表达。Gαi1/3敲减/除抑制NLGN3下游信号及食管癌细胞生长。我们提出NLGN3激活RTKs-Gαi1/3通路促食管癌细胞生长。本项目将深入研究NLGN3促食管癌生长作用和机制；探究食管癌细胞中NLGN3表达调控的分子机制，明确THOR-IGF2BP1通路在其中的作用；解析NLGN3激活Gαi1/3-RTKs信号通路促食管癌细胞进展的信号机制；最后检测NLGN3-Gαi1/3和THOR-IGF2BP1通路基因在食管癌组织中表达，并分析它们与临床指标的相关性。为食管癌临床诊治突破提供新的潜在靶点。

It is extremely important to further explore underlying mechanisms of esophageal cancer progression and to develop targeted interventions. Our preliminary results show that neuroligin-3 (NLGN3) and Gαi1/3, the key proteins in NLGN3 signaling cascade, are overexpressed in human esophageal cancer tissues and cells. Both were associated with multiple receptor tyrosine kinases (RTKs). In addition, IGF2BP1 directly binds to NLGN3 mRNA in esophageal cancer cells, whereas IGF2BP1 or LncRNA THOR knockout (KO) significantly downregulated NLGN3 expression. Furthermore, Gαi1/3 knockdown or knockout blocked NLGN3-induced downstream signaling activation and esophageal cancer cell proliferation and migration. We propose that NLGN3 activates RTK-Gαi1/3 signaling to promote esophageal cancer cell progression. In the current proposal, studies will be performed to examine the role and the underlying mechanisms of NLGN3 in promoting esophageal cancer cell growth in vitro and in vivo. We will further explore the regulatory mechanism of NLGN3 expression in esophageal cancer cells, by focusing on the THOR-IGF2BP1 pathway; The signal mechanisms by which NLGN3 activates RTKs-Gαi1/3 cascade to promote esophageal cancer cell progression will be analyzed. Finally, we will detect the expression of NLGN3-Gαi1/3 and THOR-IGF2BP1 pathway genes in esophageal cancer tissues, and analyze their correlations with patients’ clinical features. The results of the study will provide novel potential targets for clinical diagnosis and treatment of esophageal cancer.