Systematic analysis of the TGF-beta-Smad signaling pathway in gastrointestinal cancer cells.
The transforming growth factor-beta (TGF-beta)-Smad signaling pathway has an important role in carcinogenesis. To study the frequency and mechanism of functional impairment of this pathway in human gastrointestinal cancers, we used a reporter assay to examine the response of 38 cell lines (11 colorectal, 9 pancreatic, 10 gastric, and 8 hepatic cancers) to TGF-beta. We then analyzed TGF-beta type II receptor (T beta RII) gene, immunoblots of Smad4, and restoration of the pathway by rescuing T beta R or Smad. We observed impaired signaling in 91% of colorectal, 67% of pancreatic, and 40% of gastric cancer cell lines, but in none of the hepatic cancer cells. We suggest that this pathway does not function as a tumor suppressor in hepatic carcinogenesis. The impairment is due to inactivation of T beta RII and Smad4 in colorectal and pancreatic cancers. However, because the signal was not recovered by rescuing T beta R or Smad genes in TGF-beta-response-defective gastric cancer cell lines, we suggest that novel molecules or mechanisms are involved in the impaired pathway in some gastric cancers.
Ijichi
H
H
Department of Gastroenterology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. ijichi-2im@h.u-tokyo.ac.jp
Ikenoue
T
T
Kato
N
N
Mitsuno
Y
Y
Togo
G
G
Kato
J
J
Kanai
F
F
Shiratori
Y
Y
Omata
M
M
D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004789:Enzyme Activation; D005770:Gastrointestinal Neoplasms / Q000378:metabolism*; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011061:Poly A; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis*; D015398:Signal Transduction; D051901:Smad4 Protein; D015534:Trans-Activators / Q000096:biosynthesis*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D011061:Poly A; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II