Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer.
Loss of the tumor suppressive effect of transforming growth factor-beta (TGF-beta) has been commonly found at later stages in carcinogenic progression. Although the genes encoding TGF-beta receptors and Smads have been found genetically altered in certain human cancers, no mutation in Smad3 has been observed. Therefore, suppression of Smad3 expression may mediate key oncogenic properties of TGF-beta. First, we observed that 37.5% of human gastric cancer tissues showed low to undetectable levels of Smad3 and that in nine human gastric cancer cell lines examined, two showed deficient Smad3 expression. Introduction of Smad3 into human gastric cancer cells that did not express Smad3, restored TGF-beta responsiveness: induction of p21 and p15 gene expression, and growth inhibition in response to TGF-beta. Furthermore, these Smad3-expressing cells showed markedly decreased and delayed tumorigenicity in vivo. These findings suggest that Smad3 expression may have a critical role in tumor suppression in the early stages of gastric carcinogenesis.
Han
Sang-Uk
SU
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892-5055, USA.
Kim
Heung-Tae
HT
Seong
Do Hwan
DH
Kim
Yong-Suk
YS
Park
Yoon-Soo
YS
Bang
Yung-Jue
YJ
Yang
Han-Kwang
HK
Kim
Seong-Jin
SJ
D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005753:Gastric Mucosa / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity; D015398:Signal Transduction; D051900:Smad3 Protein; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000637:transplantation
D004268:DNA-Binding Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta