Surface-bound galectin-4 regulates gene transcription and secretion of chemokines in human colorectal cancer cell lines

Tumour Biol. 2017 Mar;39(3):1010428317691687. doi: 10.1177/1010428317691687.

Abstract

One long-term complication of chronic intestinal inflammation is the development of colorectal cancer. However, the mechanisms linking inflammation to the colorectal tumorigenesis are poorly defined. Previously, we have demonstrated that galectin-4 is predominantly expressed in the luminal epithelia of the gastrointestinal tract, and its loss of expression plays a key role in the colorectal tumorigenesis. However, the mechanism by which galectin-4 regulates inflammation-induced tumorigenesis is unclear. Here, we show that galectin-4 secreted by the colorectal cancer cell lines was bound to the cell surface. Neutralization of surface-bound galectin-4 with anti-galectin-4 antibody resulted in increased cell proliferation with concomitant secretion of several chemokines into the extracellular medium. Neutralization of the surface-bound galectin-4 also resulted in the up-regulation of transcription of 29 genes, several of which are components of multiple inflammation signaling pathways. In an alternate experiment, binding of recombinant galectin-4 protein to cell surface of the galectin-4-negative colorectal cancer cells resulted in increased p27, and decreased cyclin D1 and c-Myc levels, leading to cell cycle arrest and apoptosis. Together, these data demonstrated that surface-bound galectin-4 is a dual function protein-down-regulating cell proliferation and chemokine secretion in galectin-4-expressing colorectal cancer cells on one hand and inducing apoptosis in galectin-4-negative colorectal cancer cells on the other hand.

Keywords: Galectins; cancer; chemokines; colorectal cancer; galectin-4; inflammation.

MeSH terms

  • Apoptosis / genetics
  • Carcinogenesis / pathology*
  • Cell Cycle Checkpoints / genetics
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemokines / biosynthesis
  • Chemokines / metabolism*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Cyclin D1 / metabolism
  • Galectin 4 / metabolism*
  • Gene Expression Regulation, Neoplastic / physiology*
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Inflammation / pathology
  • Intestinal Mucosa / pathology*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism

Substances

  • CCND1 protein, human
  • Chemokines
  • Galectin 4
  • MYC protein, human
  • Proliferating Cell Nuclear Antigen
  • Proto-Oncogene Proteins c-myc
  • p27 antigen
  • Cyclin D1