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Mutations and reduced expression of the transforming growth factor-beta receptor II gene in rat lung adenocarcinomas
T Tsujiuchi1, Y Sasaki, M Tsutsumi
1Department of Oncological Pathology, Cancer Center, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan. ttujiuch@nmu-gw.naramed-u.ac.jp
Abstract:
Mutations and expression of the transforming growth factor-beta receptor type II (TGF-beta RII) gene were investigated in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats. Males of the Wistar strain, 6 weeks old, were given 2000 ppm of BHP in their drinking water for 12 weeks and then maintained without further treatment until killed at week 25. Total RNA was extracted from 12 adenocarcinomas and mutations in TGF-beta RII were investigated by RT-PCR-restriction-SSCP analysis followed by sequencing analysis. Two out of 12 adenocarcinomas showed band shifts, indicative of mutations (16.7%). One was a CTG-to-TTG (Leu to Leu) transition at codon 308 without amino acid alteration and the other a frameshift deletion of one of two guanines at nucleotides 1434 to 1435 (codon 477 to 478). Semi-quantitative RT-PCR analysis demonstrated significantly reduced TGF-beta RII expression in adenocarcinomas, as compared with normal lung tissue. These results suggest that TGF-beta RII alterations may play a role in the acquisition of growth advantage by lung adenocarcinomas induced by BHP in rats.
Insights
Transforming growth factor-beta receptor type II (TGF-beta RII) gene mutations and reduced expression were found in rat lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine (BHP). These TGF-beta RII alterations may contribute to tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Toxicology
Background:
- Lung adenocarcinomas can arise from exposure to chemical carcinogens.
- The transforming growth factor-beta (TGF-beta) signaling pathway plays a critical role in cell growth and differentiation.
- TGF-beta receptor type II (TGF-beta RII) is a key component of this pathway.
Purpose of the Study:
- To investigate mutations and expression levels of the TGF-beta RII gene in rat lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine (BHP).
- To determine the potential role of TGF-beta RII alterations in the development of BHP-induced lung cancer.
Main Methods:
- Wistar rats were exposed to BHP in drinking water for 12 weeks.
- Lung adenocarcinomas were surgically removed at 25 weeks.
- Total RNA was extracted for analysis.
- Mutations in TGF-beta RII were analyzed using RT-PCR-restriction-SSCP and sequencing.
- Gene expression was quantified using semi-quantitative RT-PCR.
Main Results:
- Mutations in the TGF-beta RII gene were identified in 2 out of 12 (16.7%) lung adenocarcinomas.
- Identified mutations included a silent transition at codon 308 and a frameshift deletion at codons 477-478.
- Significantly reduced TGF-beta RII expression was observed in tumor tissues compared to normal lung tissue.
Conclusions:
- Alterations in the TGF-beta RII gene, including mutations and reduced expression, occur in BHP-induced rat lung adenocarcinomas.
- These molecular changes in TGF-beta RII may contribute to the neoplastic transformation and growth advantage of lung tumors.
- The findings highlight the potential involvement of TGF-beta RII in chemical carcinogenesis of the lung.
