ADAM9 mediates the interleukin-6-induced Epithelial-Mesenchymal transition and metastasis through ROS production in hepatoma cells

Cancer Lett. 2018 May 1:421:1-14. doi: 10.1016/j.canlet.2018.02.010. Epub 2018 Feb 10.

Abstract

Interleukin (IL)-6 has been implicated in the invasion and metastasis of hepatocellular carcinoma (HCC). However, the molecular events that mediate this process are poorly understood. Here, we showed that IL-6 promoted the epithelial-mesenchymal transition (EMT) in HCC cell lines, and upregulated a disintegrin and metalloprotease 9 (ADAM9) expression by activating the JNK signaling pathway. ADAM9 was upregulated in human HCCs which promoted HCC cell invasion and the EMT by interacting with NADPH oxidase 1 and inducing reactive oxygen species generation. Knockdown of ADAM9 inhibited the IL-6-induced EMT. Additionally, ADAM9 expression was positively correlated with IL-6 and Snail expression in human HCC specimens. Taken together, our results showed that ADAM9 is an important mediator of IL-6-induced HCC cell migration and invasion, and may provide a novel therapeutic target for HCC management.

Keywords: A disintegrin and metalloprotease 9; Epithelial–mesenchymal transition; Hepatocellular carcinoma; Interleukin-6; ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism*
  • Animals
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Disease Progression
  • Epithelial-Mesenchymal Transition / physiology*
  • Female
  • Heterografts
  • Humans
  • Interleukin-6 / metabolism*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness / pathology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / physiology

Substances

  • IL6 protein, human
  • Interleukin-6
  • Membrane Proteins
  • Reactive Oxygen Species
  • ADAM Proteins
  • ADAM9 protein, human