Induction and expression of betaig-h3 in pancreatic cancer cells.
betaig-h3 (TGFBI, keratoepithelin) was first identified as a transforming growth factor-beta1 (TGF-beta1)-inducible gene in a human lung adenocarcinoma cell line. It encodes for a secreted extracellular matrix (ECM) protein, which is thought to act on cell attachment and ECM composition. Mutations of the betaig-h3 gene are involved in several corneal dystrophies. Pancreatic cancers display multiple alterations in the TGF-beta signaling pathway and in TGF-beta response genes, such as overexpression of all three TGF-beta isoforms and Smad4 mutations. In this report, we determined that betaig-h3 mRNA levels were induced by TGF-beta1 in two out of five examined pancreatic cancer cell lines (CAPAN-1, PANC-1). In CAPAN-1 cells, which harbor a Smad4 mutation, betaig-h3 but not PAI-1 was induced by TGF-beta1, whereas in PANC-1 cells that express wild-type Smad4, TGF-beta1 induced both PAI-1 and betaig-h3. In human pancreatic tissues, there was a 32.4-fold increase in betaig-h3 mRNA levels in pancreatic cancers in comparison to normal control tissues. In situ hybridization analysis revealed that betaig-h3 mRNA was expressed mainly in the cancer cells within the pancreatic tumor mass. These findings suggest that betaig-h3 is induced by TGF-betas in pancreatic cancer cells even in the presence of Smad4 mutations, which might explain, in part, the increased betaig-h3 mRNA levels observed in pancreatic cancer cells in vivo.
Schneider
Dominik
D
Department of Visceral and Transplantation Surgery, University of Bern, Bern, Switzerland.
Kleeff
Jörg
J
Berberat
Pascal O
PO
Zhu
Zhaowen
Z
Korc
Murray
M
Friess
Helmut
H
Büchler
Markus W
MW
D000293:Adolescent; D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D016326:Extracellular Matrix Proteins; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051901:Smad4 Protein; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D000099222:betaIG-H3 Protein
D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein; C497796:SMAD4 protein, human; C508960:TGFB1 protein, human