Proinflammatory homeobox gene, ISX, regulates tumor growth and survival in hepatocellular carcinoma

Cancer Res. 2013 Jan 15;73(2):508-18. doi: 10.1158/0008-5472.CAN-12-2795. Epub 2012 Dec 5.


Chronic inflammation drives initiation of hepatocellular carcinoma (HCC), but the underlying mechanisms linking inflammation and tumor formation remain obscure. In this study, we compared the expression of interleukin (IL)-6 and cyclin D1 (CCND1) with the IL-6-induced homeobox gene ISX (intestine-specific homeobox) in 119 paired specimens of HCCs and adjacent normal tissues and also in paired specimens from 11 patients with non-HCCs. In pathologic analysis, ISX exhibited a tumor-specific expression pattern and a high correlation to patient survival time, tumor size, tumor number, and progression stage. Enforced expression of ISX accelerated cell proliferation and tumorigenic activity in hepatoma cells through CCND1 induction. In contrast, short hairpin RNA-mediated attenuation of ISX in hepatoma cells decreased cell proliferation and malignant transformation in vitro and in vivo. A high positive correlation existed in human hepatoma tumors between ISX and CCND1 expression. Together, our results highlight ISX as an important regulator in hepatoma progression with significant potential as a prognostic and therapeutic target in HCCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Cell Proliferation
  • Cyclin D1 / metabolism
  • E2F1 Transcription Factor / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, Homeobox*
  • Homeodomain Proteins / genetics*
  • Humans
  • Interleukin-6 / metabolism
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • RNA Interference
  • Transcription Factors / genetics*


  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Homeodomain Proteins
  • Interleukin-6
  • Isx protein, human
  • Transcription Factors
  • Cyclin D1