LncRNA HIF1A-AS1在酸性微环境诱导胰腺癌血管重塑中的作用及机制

血管重塑与肿瘤发生发展密切相关。前期发现，酸性微环境可诱导胰腺癌细胞HIF-1α/VEGFA表达上调，其培养上清增强人脐静脉内皮细胞（HUVEC）出芽及管腔形成，但内皮排列紊乱且通透性增大。此外，发现lncRNA HIF1A-AS1表达增加，抑制HIF1A-AS1可下调HIF-1α/VEGFA表达。由此推测，HIF1A-AS1/HIF-1α/VEGFA信号轴介导酸性微环境调控胰腺癌血管重塑。拟建立不同酸度胰腺癌细胞与HUVEC共培养体系及胰腺癌动物模型，观察上述信号轴对血管重塑的调控作用；通过FISH、RIP、RNA-pulldown等技术检测HIF1A-AS1对HIFα-1/VEGFA表达调控机制；在胰腺癌动物模型干预上述通路，观察胰腺癌血管重塑、生长及转移变化。本课题以血管重塑为切入点，探讨酸性微环境在胰腺癌发病中作用，为胰腺癌防治研究提供新靶点，有助于深入理解微环境对肿瘤发生中作用。

Vascular remodeling is closely correlated with tumorigenesis. Previously, we found that the acidic microenvironment promoted HIF-1α/VEGFA expression of pancreatic cancer cell. The supernatant of acidic-treated pancreatic cancer promoted sprout and tube formation of HUVEC, with inordinate arrangement of endothelial and enhanced permeability. Moreover, the lncRNA HIF1A-AS1 was also increased, while the down-regulation of HIF1A-AS1 obviously inhibited expression of HIF-1α/VEGFA. Therefore, we hypothesize that a HIF1A-AS1/HIF-1α/VEGFA axis may be involved in the angiogenesis under acidic microenvironment of pancreatic cancer. After cultured with different pH medium, the effects of HIF1A-AS1/HIF-1α/VEGFA axis on vascular remodeling were evaluated both in vitro and in vivo. FISH, RIP and RNA-pulldown experiments were applied to investigate the mechanism of HIF1A-AS1 on HIF-1α/VEGFA expression. Furthermore, the HIF1A-AS1/HIF-1α/VEGFA axis was manipulated to observe the vascular remodeling, growth and metastasis of pancreatic cancer in vivo. The present study will investigate the function of acidic microenvironment on tumorigenesis of pancreatic cancer, especially on angiogenesis. Moreover, the research will provide comprehensive data for the understanding of microenvironment on tumorigenesis and new strategy for prevention and treatment of malignant tumor.