IL13R alpha 2 Is Involved in the Progress of Renal Cell Carcinoma through the JAK2/FOXO3 Pathway

초록

Previously, we reported a close relationship between type II IL4R alpha and IL13R alpha 1 complex and poor outcomes in renal cell carcinoma (RCC). In this study, we investigated the clinicopathologically significant oncogenic role of IL13R alpha 2, a kind of the independent receptor for IL13, in 229 RCC patients. The high expression of IL13R alpha 2 was closely related to relapse-free survival in specific cancers in univariate and multivariate analysis. Then, the oncogenic role of IL13R alpha 2 was evaluated by performing in vitro assays for cell proliferation, cell cycle arrest, and apoptosis in A498, ACHN, Caki1, and Caki2, four kinds of RCC cells after transfection of siRNA against IL13R alpha 2. Cell proliferation was suppressed, and apoptosis was induced in A498, ACHN, Caki1, and Caki2 cells by knockdown of IL13R alpha 2. Interestingly, the knockdown of IL13R alpha 2 decreased the phosphorylation of JAK2 and increased the expression of FOXO3. Furthermore, the knockdown of IL13R alpha 2 reduced the protein interaction among IL13R alpha 2, phosphorylated JAK2, and FOXO3. Since phosphorylation of JAK2 was regulated by IL13R alpha 2, we tried to screen a novel JAK2 inhibitor from the FDA-approved drug library and selected telmisartan, a clinically used medicine against hypertension, as one of the strongest candidates. Telmisartan treatment decreased the cell proliferation rate and increased apoptosis in A498, ACHN, Caki1, and Caki2 cells. Mechanistically, telmisartan treatment decreased the phosphorylation of JAK2 and increased the expression of FOXO3. Taken together, these results suggest that IL13R alpha 2 regulates the progression of RCC via the JAK2/FOXO3-signaling path pathway, which might be targeted as the novel therapeutic option for RCC patients.

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