IL4Rα and IL13Rα1 Are Involved in the Development of Human Gallbladder Cancer

Sung Woo Ahn; Chang Min Lee; Mi-Ae Kang; Usama Khamis Hussein; Ho Sung Park; Ae-Ri Ahn; Hee Chul Yu; Jae Do Yang; Yung-Hun Yang; Kyungmoon Park; Jongsung Lee; Kyu Yun Jang; See-Hyoung Park

doi:10.3390/jpm12020249

IL4Rα and IL13Rα1 Are Involved in the Development of Human Gallbladder Cancer

J Pers Med. 2022 Feb 9;12(2):249. doi: 10.3390/jpm12020249.

Authors

Sung Woo Ahn¹, Chang Min Lee², Mi-Ae Kang³, Usama Khamis Hussein^{4

5

6}, Ho Sung Park^{4

5

6}, Ae-Ri Ahn^{4

5

6}, Hee Chul Yu¹, Jae Do Yang¹, Yung-Hun Yang⁷, Kyungmoon Park², Jongsung Lee⁸, Kyu Yun Jang^{4

5

6}, See-Hyoung Park²

Affiliations

¹ Department of Surgery, Jeonbuk National University Medical School, Jeonju 54896, Korea.
² Department of Bio and Chemical Engineering, Hongik University, Sejong 30016, Korea.
³ Zoonolab Inc., Seoul 04799, Korea.
⁴ Department of Pathology, Jeonbuk National University Medical School, Jeonju 54896, Korea.
⁵ Research Institute of Clinical Medicine of Jeonbuk National University, Jeonju 54896, Korea.
⁶ Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54896, Korea.
⁷ Department of Biological Engineering, Konkuk University, Seoul 05029, Korea.
⁸ Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 03063, Korea.

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 IL4Rα and IL13Rα1 signaling pathway has not been fully understood in the development of gallbladder cancer.

Methods: In human gallbladder carcinomas, the expression of IL4Rα and IL13Rα1 were evaluated with immunohistochemical staining in tissue microarray tissue sections. After knockdown of IL4Rα or IL13Rα1, 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 IL4Rα and IL13Rα1 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 IL4Rα was significantly associated with the expression of IL13Rα1 in human carcinoma tissue. In univariate analysis, nuclear expression of IL4Rα, cytoplasmic expression of IL4Rα, nuclear expression of IL13Rα1, and cytoplasmic expression of IL13Rα1 were significantly associated with shorter overall survival and shorter relapse-free survival. Multivariate analysis revealed nuclear expression of IL4Rα as an independent poor prognostic indicator of overall survival and relapse-free survival. Then, we found that knockdown of IL4Rα or IL13Rα1 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 IL4Rα and IL13Rα1 might be involved in the development of human gallbladder cancer cells and IL4Rα and IL13Rα1 complex/JAK2 signaling pathway could be efficient therapeutic targets for gallbladder cancer treatment.

Keywords: AZD1480; IL13Rα1; IL4Rα; JAK2; gallbladder cancer.

Abstract

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