Tumor-associated macrophages promote gastric cancer tumorigenesis via upregulation of miR-210

Abstract

Chronic inflammation is a crucial event in progression of gastric cancer Particularly tumor-associated macrophages (TAMs) are part of inflammatory circuits that promote tumorigenesis MicroRNAs (miRNAs) are involved in multiple biological activities as well as disease progression including cancer However little is known about the association between tumor miRNAs and TAMs Previously we compared the expression profile of miRNAs between gastric cancer cells alone and gastric cancer cells co-cultured with U937 and found that miR-210 expression in gastric cancer cells significantly increased after co-cultured In this study we sought to determine whether TAMs regulate tumor miR-210 and thus promoting tumorigenesis of gastric cancer We first verified the correlation between miR-210 and TAMs in gastric cancer and found that miR-210 was up-regulated by TAMs in co-culture experiments Furthermore we also observed a positive correlation between miR-210 expression and TAMs in gastric cancer specimens Overall survival in gastric cancer patients with higher CD204 expression was significantly reduced than patients with lower CD204 expression In addition inactivation of miR-210 attenuated TAMs-mediated gastric cancer cell migration Using MetaCore we found that NTN4 a regulator for cytoskeleton is a putative target gene of miR-210 Indeed miR-210 can block the luciferase activity of NTN4–3’UTR in gastric cancer cell Moreover expression of NTN4 was decreased in clinical specimens and gastric cancer cells after TAMs stimulation Combined high NTN4 expression and lower miR-210 expression is associated with better survival in gastric cancer patients Collectively these findings extend our understanding of the function of miR-210 in the inflammation system and this newly identified TAMs/miR-210/NTN4 pathway can be a prognostic factor for gastric cancer patient survival and a potential therapeutic target in gastric cancer treatment

Date of Award	2014 Aug 22
Original language	English
Supervisor	Yan-Shen Shan (Supervisor)