Mai Ly Thi Nguyen1,2,3, Khac Cuong Bui1,3,4,5, Tim Scholta1, Jun Xing1, Vikas Bhuria1, Bence Sipos6, Ludwig Wilkens7, Toan Nguyen Linh4, Thirumalaisamy P Velavan3,8,9, Przemyslaw Bozko1, Ruben R Plentz1,10. 1. Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany. 2. Department of Biochemistry, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam. 3. Vietnamese-German Centre for Medical Research (VG-CARE), Hanoi, Vietnam. 4. Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam. 5. Laboratory Animal Research Center, Vietnam Military Medical University, Hanoi, Vietnam. 6. Department of Internal Medicine VIII, Universitätsklinikum Tübingen, Tübingen, Germany. 7. Institute of Pathology, Nordstadt Krankenhaus, Hannover, Germany. 8. Institute of Tropical Medicine, Universitätsklinikum Tübingen, Tübingen, Germany. 9. Duy Tan University, Da Nang, Vietnam. 10. Department of Internal Medicine II, Klinikum Bremen Nord, Bremen, Germany.
Abstract
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.
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 humancholangiocarcinoma cell lines and murine and humancholangiocarcinoma 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 humancholangiocarcinoma cells, and IL-6 stimulants enhance cholangiocarcinoma cell proliferation. In addition, murine and humancholangiocarcinoma 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 cholangiocarcinomapatients.
Authors: Leticia Colyn; Gloria Alvarez-Sola; M Ujue Latasa; Carmen Berasain; Maite G Fernandez-Barrena; Matias A Avila; Iker Uriarte; Jose M Herranz; Maria Arechederra; George Vlachogiannis; Colin Rae; Antonio Pineda-Lucena; Andrea Casadei-Gardini; Federica Pedica; Luca Aldrighetti; Angeles López-López; Angeles López-Gonzálvez; Coral Barbas; Sergio Ciordia; Sebastiaan M Van Liempd; Juan M Falcón-Pérez; Jesus Urman; Bruno Sangro; Silve Vicent; Maria J Iraburu; Felipe Prosper; Leonard J Nelson; Jesus M Banales; Maria Luz Martinez-Chantar; Jose J G Marin; Chiara Braconi; Christian Trautwein; Fernando J Corrales; F Javier Cubero Journal: J Exp Clin Cancer Res Date: 2022-05-26
Authors: Daria Briukhovetska; Janina Dörr; Stefan Endres; Peter Libby; Charles A Dinarello; Sebastian Kobold Journal: Nat Rev Cancer Date: 2021-06-03 Impact factor: 69.800