Targeting interleukin 6 signaling by monoclonal antibody siltuximab on cholangiocarcinoma

J Gastroenterol Hepatol. 2021 May;36(5):1334-1345. doi: 10.1111/jgh.15307. Epub 2020 Nov 12.


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.

Keywords: Cholangiocarcinoma; IL-6; Siltuximab.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • Bile Duct Neoplasms / drug therapy*
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / pathology*
  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Cholangiocarcinoma / drug therapy*
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / pathology*
  • Disease Models, Animal
  • Gene Expression
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Male
  • Mice
  • Middle Aged
  • Molecular Targeted Therapy
  • STAT3 Transcription Factor
  • Signal Transduction / drug effects*
  • Wnt Proteins
  • beta Catenin


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Interleukin-6
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Wnt Proteins
  • beta Catenin
  • siltuximab