[Mechanism of resistance to growth inhibition by transforming growth factor-beta 1 (TGF-beta 1) in primary lung cancer and new molecular targets in therapy].
Transforming Growth Factor-beta 1 (TGF-beta 1) regulates the proliferation of normal epithelial cells, and resistance to TGF-beta 1 growth inhibition is a common feature of human cancers including lung cancer. In order to understand the mechanism of resistance to growth inhibition by TGF-beta 1 and to reverse the regulation of proliferation in lung cancer, we determined the genomic structure of the genes involved in the signal transduction pathway of TGF-beta 1 and performed an initial mutation survey of the complete coding region of the genes in lung cancer and cell lines with the resistance to growth inhibition by TGF-beta 1. First, a mutation analysis of the TGF-beta type II receptor (TGF-beta RII) was performed. Point mutations of the gene were detected in several colon cancers and an adenocarcinoma of the lung in the poly-A sequence. No mutations of Smad 2, 3, 4, 5 and TGF-beta type I receptor (TGF-beta IR) genes were detected in a series of the tumors we tested, although several mutations of Smad 2 and 4 were previously reported. Frequent alterations of the p15 gene and reduced expression of p21 we already reported from our previous studies. We also determined the genomic structure of the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), which is involved in activating TGF-beta 1, and performed an initial mutation survey of the complete coding sequences of the gene. A point mutation at exon 40 was found in one lung adenocarcinoma cell line. In summary, alterations in the many genes involved in the signal transduction of TGF-beta 1 were found and may mediate the loss of TGF-beta 1 responsiveness in lung cancer. The molecular targets for the regulation of the proliferation of lung cancer are thought to be p15, p21 and the transcriptional regulators.
Gemma
A
A
4th Dept. of Internal Medicine, Nippon Medical School.
Uematsu
K
K
Hagiwara
K
K
Takenoshita
S
S
Kudoh
S
S
D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017527:Receptor, IGF Type 2 / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D017527:Receptor, IGF Type 2; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta