MS4A12 is a colon-selective store-operated calcium channel promoting malignant cell processes.
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.
Koslowski
Michael
M
Department of Internal Medicine III, Division of Experimental and Translational Oncology, Johannes Gutenberg University, Mainz, Germany.
Sahin
Ugur
U
Dhaene
Karl
K
Huber
Christoph
C
Türeci
Ozlem
O
D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009928:Organ Specificity; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018925:Chemokines; C436717:MS4A10 protein, human; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor