title: Induction of CaSR expression circumvents the molecular features of malignant CaSR null colon cancer cells.
abstract: We recently reported on the isolation and characterization of calcium sensing receptor (CaSR) null human colon cancer cells (Singh et al., Int J Cancer 2013; 132: 1996-2005). CaSR null cells possess a myriad of molecular features that are linked to a highly malignant and drug resistant phenotype of colon cancer. The CaSR null phenotype can be maintained in defined human embryonic stem cell culture medium. We now show that the CaSR null cells can be induced to differentiate in conventional culture medium, regained the expression of CaSR with a concurrent reversal of the cellular and molecular features associated with the null phenotype. These features include cellular morphology, expression of colon cancer stem cell markers, expression of survivin and thymidylate synthase and sensitivity to fluorouracil. Other features include the expression of epithelial mesenchymal transition linked molecules and transcription factors, oncogenic miRNAs and tumor suppressive molecule and miRNA. With the exception of cancer stem cell markers, the reversal of molecular features, upon the induction of CaSR expression, is directly linked to the expression and function of CaSR because blocking CaSR induction by shRNA circumvented such reversal. We further report that methylation and demethylation of the CaSR gene promoter underlie CaSR expression. Due to the malignant nature of the CaSR null cells, inclusion of the CaSR null phenotype in disease management may improve on the mortality of this disease. Because CaSR is a robust promoter of differentiation and mediates its action through diverse mechanisms and pathways, inactivation of CaSR may serve as a new paradigm in colon carcinogenesis.
authors.affiliation: Department of Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University, School of Medicine, Springfield, IL.
authors.forename: Navneet
authors.initials: N
authors.lastname: Singh
authors.forename: Subhas
authors.initials: S
authors.lastname: Chakrabarty
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003470:Culture Media / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D044169:Receptors, Calcium-Sensing / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D014408:Biomarkers, Tumor; C095550:CASR protein, human; D003470:Culture Media; D035683:MicroRNAs; D044169:Receptors, Calcium-Sensing; D014157:Transcription Factors; D005472:Fluorouracil
keywords: CaSR; colon cancer; molecular phenotype