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Targeting interleukin 6 signaling by monoclonal antibody siltuximab on cholangiocarcinoma
Author(s) -
Nguyen Mai Ly Thi,
Bui Khac Cuong,
Scholta Tim,
Xing Jun,
Bhuria Vikas,
Sipos Bence,
Wilkens Ludwig,
Nguyen Linh Toan,
Velavan Thirumalaisamy P,
Bozko Przemyslaw,
Plentz Ruben R
Publication year - 2021
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.15307
Subject(s) - carcinogenesis , wnt signaling pathway , cancer research , medicine , in vivo , immunohistochemistry , monoclonal antibody , interleukin , western blot , cancer , pathology , antibody , immunology , signal transduction , cytokine , biology , biochemistry , microbiology and biotechnology , gene
Background and Aim Cholangiocarcinoma has an unimproved prognosis. Interleukin 6 (IL‐6) has an oncogenic potential in some cancer diseases. However, the role of IL‐6 in cholangiocarcinoma carcinogenesis is not well understood. The current study investigated the role of IL‐6 signaling in cholangiocarcinoma carcinogenesis and efficacy of siltuximab treatment on cholangiocarcinoma in vitro and in vivo . Methods The expression of IL‐6 was analyzed on human cholangiocarcinoma cell lines and murine and human cholangiocarcinoma tissues, using reverse transcription real‐time polymerase chain reaction and immunohistochemistry. In addition, the effect of anti‐IL‐6 chimeric monoclonal antibody, siltuximab, was investigated in vitro by proliferation, migration, and two‐dimensional and three‐dimensional invasion assays and in vivo by xenograft mouse model. Western blot was applied to study the molecular alteration. Results Our result shows high expression of IL‐6 in human cholangiocarcinoma cells, and IL‐6 stimulants enhance cholangiocarcinoma cell proliferation. In addition, murine and human cholangiocarcinoma tissues express significantly higher levels of IL‐6, compared with adjacent non‐tumor tissues. On the cholangiocarcinoma engineered mouse model, IL‐6 level is associated with tumor volume. Taken together, our data indicate an oncogenic potential of IL‐6 in cholangiocarcinoma carcinogenesis. Siltuximab sufficiently abrogates IL‐6 signaling and inhibits cholangiocarcinoma progression in vitro and in vivo . The results additionally indicate a relative alteration of IL‐6 signaling and its molecular targets, such as STAT3, Wnt/β‐catenin, and mesenchymal markers. Conclusions Interleukin 6 plays an essential role in cholangiocarcinoma carcinogenesis, and siltuximab has the potential to be considered as a new treatment option for cholangiocarcinoma patients.