The loss of sarco/endoplasmic reticulum calcium transport ATPase 3 expression is an early event during the multistep process of colon carcinogenesis.
Calcium accumulation in the endoplasmic reticulum is accomplished by sarco/endoplasmic reticulum calcium transport ATPases (SERCA enzymes). To better characterize the role of SERCA3 in colon carcinogenesis, its expression has been investigated in colonic epithelium, benign lesions, adenomas, and adenocarcinomas. In addition, the regulation of SERCA3 expression was analyzed in the context of the adenomatous polyposis coli/beta-catenin/T-cell factor 4 (TCF4) pathway and of specificity protein 1 (Sp1)-like factor-dependent transcription. We report that SERCA3 expression increased along the crypts as cells differentiated in normal colonic mucosa and in hyperplastic polyps, was moderately and heterogeneously expressed in colonic adenomas with expression levels inversely correlated with the degree of dysplasia, was barely detectable in well and moderately differentiated adenocarcinomas, and was absent in poorly differentiated tumors. Inhibition of Sp1-like factor-dependent transcription blocked SERCA3 expression during cell differentiation, and SERCA3 expression was induced by the expression of dominant-negative TCF4 in colon cancer cells. These data link SERCA3 expression to the state of differentiation of colonic epithelial cells, and relate SERCA3 expression, already decreased in adenomas, to enhanced adenomatous polyposis coli/beta-catenin/TCF4-dependent signaling and deficient Sp1-like factor-dependent transcription. In conclusion, intracellular calcium homeostasis becomes progressively anomalous during colon carcinogenesis as reflected by deficient SERCA3 expression.
Service d'Anatomie et Cytologie Pathologiques, Hôpital Lariboisière, Paris, France.
Jean-Philippe
JP
Brouland
Pascal
P
Gélébart
Tünde
T
Kovàcs
Jocelyne
J
Enouf
Johannes
J
Grossmann
Béla
B
Papp
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000201:enzymology*; D003111:Colonic Polyps / Q000201:enzymology; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D014162:Transfection; D019076:Transgenes; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506949:ATP2A3 protein, human; D000252:Calcium-Transporting ATPases; D002118:Calcium