HOXB5 induces invasion and migration through direct transcriptional up-regulation of β-catenin in human gastric carcinoma

Biochem J. 2015 Dec 15;472(3):393-403. doi: 10.1042/BJ20150213. Epub 2015 Oct 14.

Abstract

HOX (homeobox) genes encode a family of transcriptional regulators, which have an important role in morphogenesis and differentiation during embryonic development. Their deregulated expression is involved in the carcinogenesis of many human solid tumours. In the present study, we show that HOXB5 mRNA was significantly overexpressed in gastric cancer tissues compared with adjacent normal tissues. HOXB5-up-regulated cancer cells showed increased invasion and migration activity, but no change in proliferation activity, whereas HOXB5-down-regulated cells showed decreased invasion and migration activity. Up-regulation of HOXB5 resulted in up-regulation of β-catenin, whereas inhibition of HOXB5 expression by siRNA led to the down-regulation of β-catenin. Moreover, a significant correlation between HOXB5 and CTNNB1 (β-catenin) mRNA expression was detected in gastric cancer tissues. Furthermore, we found that HOXB5 binds directly to the CTNNB1 promoter region and activates the transcriptional expression of β-catenin, as well as its downstream target genes, encoding cyclin D1 and c-Myc, leading to an increase in the invasion and migration activity of human gastric cancer cells. Thus HOXB5 may be an important regulator of the Wnt/β-catenin signalling pathway, thereby contributing to gastric cancer progression and metastasis.

Keywords: HOXB5; gastric cancer; invasion; migration; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement*
  • Cell Proliferation / genetics
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Homeodomain Proteins / biosynthesis*
  • Homeodomain Proteins / genetics
  • Humans
  • Neoplasm Invasiveness
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Transcription, Genetic*
  • Up-Regulation*
  • Wnt Signaling Pathway / genetics
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • CCND1 protein, human
  • CTNNB1 protein, human
  • HOXB5 protein, human
  • Homeodomain Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • beta Catenin
  • Cyclin D1