title: Induction of the adenoma-carcinoma progression and Cdc25A-B phosphatases by the trefoil factor TFF1 in human colon epithelial cells.
abstract: TFF1 is overexpressed in inflammatory diseases and human cancers of the digestive and urogenital systems. To examine the transforming potential of TFF1 in human colon epithelial cells, premalignant PC/AA/C1 adenoma cells (PC) derived from a patient with familial adenomatous polyposis (FAP) were transformed by the TFF1 cDNA and used as a model of the adenoma-carcinoma transition. Constitutive expression of TFF1 increased anchorage-independent cell growth in soft agar, and induced or potentiated the growth of colon PC-TFF1 and kidney MDCKts.src-TFF1 tumor xenografts in athymic mice. This resulted in reduction of thapsigargin-induced apoptosis and promotion of collagen type I invasion through several oncogenic pathways. Using the differential display approach to identify TFF1 target genes, we found that the dual specific phosphatases Cdc25A and B implicated in cell cycle transitions are strongly upregulated under active forms in both PC-TFF1 and HCT8/S11-TFF1 colon cancer cells. Accordingly, TFF1 expression is absent in normal human colon crypts but is induced in correlation with Cdc25a and b transcript levels and tumor grade in familial and sporadic colon adenomas and carcinomas. We propose that TFF1 and Cdc25A-B cooperate with other dominant oncogenic pathways to induce the adenoma and adenocarcinoma transitions. Agents that target TFF1/Cdc25 signaling pathways may be useful for treating patients with TFF1-positive solid tumors.
authors.affiliation: INSERM U. 673 and University of Paris VI, Molecular and Clinical Oncology of Solid tumors, Paris Cedex 12, France.
authors.forename: S
authors.initials: S
authors.lastname: Rodrigues
authors.forename: C M
authors.initials: CM
authors.lastname: Rodrigue
authors.forename: S
authors.initials: S
authors.lastname: Attoub
authors.forename: J F
authors.initials: JF
authors.lastname: Fléjou
authors.forename: E
authors.initials: E
authors.lastname: Bruyneel
authors.forename: M
authors.initials: M
authors.lastname: Bracke
authors.forename: S
authors.initials: S
authors.lastname: Emami
authors.forename: C
authors.initials: C
authors.lastname: Gespach
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003106:Colon / Q000166:cytology*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000378:metabolism; D018450:Disease Progression; D004285:Dogs; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D010641:Phenotype; D011230:Precancerous Conditions / Q000473:pathology; D014162:Transfection; D014183:Transplantation, Heterologous; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; C517004:CDC25A protein, human; C517008:CDC25B protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases