MS4A12 is a colon-selective store-operated calcium channel promoting malignant cell processes

Cancer Res. 2008 May 1;68(9):3458-66. doi: 10.1158/0008-5472.CAN-07-5768.

Abstract

Using a data mining approach for the discovery of new targets for antibody therapy of colon cancer, we identified MS4A12, a sequence homologue of CD20. We show that MS4A12 is a cell surface protein. Expression analysis and immunohistochemistry revealed MS4A12 to be a colonic epithelial cell lineage gene confined to the apical membrane of colonocytes with strict transcriptional repression in all other normal tissue types. Expression is maintained upon malignant transformation in 63% of colon cancers. Ca(2+) flux analyses disclosed that MS4A12 is a novel component of store-operated Ca(2+) entry in intestinal cells. Using RNAi-mediated gene silencing, we show that loss of MS4A12 in LoVo colon cancer cells attenuates epidermal growth factor receptor-mediated effects. In particular, proliferation, cell motility, and chemotactic invasion of cells are significantly impaired. Cancer cells expressing MS4A12, in contrast, are sensitized and respond to lower concentrations of epidermal growth factor. In summary, these findings have implications for both the physiology of colonic epithelium as well as for the biology and treatment of colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium Channels / physiology*
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Chemokines / metabolism
  • Colon / metabolism*
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Disease Progression
  • Epidermal Growth Factor / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Models, Biological
  • Neoplasm Invasiveness
  • Organ Specificity
  • Protein Structure, Tertiary
  • RNA, Small Interfering / pharmacology

Substances

  • Calcium Channel Blockers
  • Calcium Channels
  • Chemokines
  • MS4A10 protein, human
  • Membrane Proteins
  • RNA, Small Interfering
  • Epidermal Growth Factor