IL4R alpha and IL13R alpha 1 Are Involved in the Development of Human Gallbladder Cancer

Abstract

Background: Gallbladder cancer is commonly associated with inflammation, which indicates that inflammation-related cytokines and cytokine receptors are related to the progression of gallbladder cancers. Interleukin 4 (IL4) is a well-known cytokine that promotes the differentiation of naive helper T cells (Th0) to T helper type 2 cells (Th2). IL13 is a cytokine that is secreted by Th2 cells. IL4 and IL13 are closely related in immune responses. However, the role of IL4R alpha and IL13R alpha 1 signaling pathway has not been fully understood in the development of gallbladder cancer. Methods: In human gallbladder carcinomas, the expression of IL4R alpha and IL13R alpha 1 were evaluated with immunohistochemical staining in tissue microarray tissue sections. After knockdown of IL4R alpha or IL13R alpha 1, cell assays to measure the proliferation and apoptosis and Western blotting analysis were conducted in SNU308 human gallbladder cancer cells. Since Janus kinases2 (JAK2) was considered as one of the down-stream kinases under IL4R alpha and IL13R alpha 1 complex, the same kinds of experiments were performed in SNU308 cells treated with AZD1480, Janus-associated kinases2 (JAK2) inhibitor, to demonstrate the cytotoxic effect of AZD1480 in SNU308 cells. Results: Immunohistochemical expression of IL4R alpha was significantly associated with the expression of IL13R alpha 1 in human carcinoma tissue. In univariate analysis, nuclear expression of IL4R alpha, cytoplasmic expression of IL4R alpha, nuclear expression of IL13R alpha 1, and cytoplasmic expression of IL13R alpha 1 were significantly associated with shorter overall survival and shorter relapse-free survival. Multivariate analysis revealed nuclear expression of IL4R alpha as an independent poor prognostic indicator of overall survival and relapse-free survival. Then, we found that knockdown of IL4R alpha or IL13R alpha 1 decreased viability and induced apoptosis in SNU308 cells via activation of FOXO3 and similarly, AZD1480 decreased viability and induced apoptosis in SNU308 cells with dose dependent manner. Conclusions: Taken together, our results suggest that IL4R alpha and IL13R alpha 1 might be involved in the development of human gallbladder cancer cells and IL4R alpha and IL13R alpha 1 complex/JAK2 signaling pathway could be efficient therapeutic targets for gallbladder cancer treatment.