J Cancer 2020; 11(22):6571-6581. doi:10.7150/jca.48327 This issue

Research Paper

High level of interleukin-33 in cancer cells and cancer-associated fibroblasts correlates with good prognosis and suppressed migration in cholangiocarcinoma

Supaporn Yangngam1,2, Suyanee Thongchot2,3, Ananya Pongpaibul4, Kulthida Vaeteewoottacharn5, Somchai Pinlaor6, Peti Thuwajit2, Seiji Okada7, Marcela A. Hermoso8, Chanitra Thuwajit2,✉

1. Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
2. Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
3. Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University 10700, Thailand.
4. Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
5. Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
6. Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
7. Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan.
8. Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, CL 8380453 Chile.

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Citation:
Yangngam S, Thongchot S, Pongpaibul A, Vaeteewoottacharn K, Pinlaor S, Thuwajit P, Okada S, Hermoso MA, Thuwajit C. High level of interleukin-33 in cancer cells and cancer-associated fibroblasts correlates with good prognosis and suppressed migration in cholangiocarcinoma. J Cancer 2020; 11(22):6571-6581. doi:10.7150/jca.48327. Available from https://www.jcancer.org/v11p6571.htm

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Abstract

Interleukin 33 (IL-33) promotes cholangiocarcinoma (CCA) genesis in a mouse model, however, its function in human CCA has not been clearly understood. This study was aimed to investigate IL-33 level in CCA tissues and its clinicopathological correlations. The results revealed that IL-33 was found in both cancer cells and stromal cancer-associated fibroblast (CAFs) staining patterns which were divided into high (CH) and low level (CL) in cancer cells; and presence (FP) and absence (FA) in CAFs. Kaplan-Meier analysis showed that patients in the CL group were significantly correlated with a short 2-year survival time (P = 0.027). The CL/FP group had a shorter survival time compared to the other groups with statistical significance for 2-year (P = 0.030) and 5-year (P = 0.023) survivals. In contrast, CH/FP patients had significantly greater 2-year (P = 0.003) and 5-year (P = 0.003) survivals. Univariate and multivariate analysis confirmed that CL/FP was a significantly independent risk factor whereas CH/FP was a significant protective factor in CCA patients. High IL-33 expressing CCA cells had low migration, but they showed increased migration when IL-33 expression was knocked down. The low level of recombinant human IL-33 (rhIL-33) (0.002 - 2 ng/ml) could promote CCA cell migration, in contrast to the suppressive effect at a high dose (20 - 200 ng/ml). In conclusion, the combination of high IL-33 level in cancer cells and CAFs is a potentially good prognosis marker in CCA patients. The in vitro migration suppressive effect of IL-33 may be the potential mechanism supporting its role as a good prognostic marker in CCA patients. The obtained results strengthen IL-33 as a promising predictor and therapeutic target for CCA.

Keywords: Cholangiocarcinoma, IL-33, Prognosis, Survival time, Cancer-associated fibroblasts, Migration