Alterations of the LKB1 Gene in Lung Adenocarcinomas Induced by N-Nitrosobis(2-Hydroxypropyl)amine in Rats

Abstract

Objective: Germ line mutations of the LKB1 gene cause the autosomal dominant Peutz-Jeghers syndrome (PJS), and PJS has also been associated with an increased risk of developing cancers, suggesting LKB1 may act as a tumor suppressor in PJS. By contrast, LKB1 mutations are rare events in most sporadic tumors in non-PJS patients, except for lung cancers. To better understand the involvement of LKB1 gene alterations during lung carcinogenesis, we investigated the LKB1 gene mutations and expressions in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats. Methods: Male Wistar rats, 6 weeks old, were given 2,000 ppm BHP in their drinking water for 12 weeks and maintained without further treatment until they were sacrificed at 25 weeks. A total of 15 lung adenocarcinomas were obtained, and genomic DNA was extracted for the search of mutations using polymerase chain reaction (PCR)-single strand conformation polymorphism analysis. To assess altered expressions of the LKB1 gene, reverse transcription-PCR analysis was also performed. Results: No mutations were found throughout exons 1–9 in any of the tumors. Aberrant transcripts bearing deletions of nucleotides 216–1459, 289–1302, 268–1261, or 257–1378 were detected in 5 of 15 adenocarcinomas (33.3%). Conclusion: These results suggest that alterations of the LKB1 gene might be involved in the development of lung adenocarcinomas induced by BHP in rats.

Liver kinase B1 suppresses metastasis and angiogenesis of lung cancer: involvement of the Shh signaling pathway

“…Whereas, inactivation of LKB1 due to point mutation or deletion frequently appears in lung cancer, especially in NSCLC, with more than 30% mutation, ranking the third in lung cancer after TRP53 and Kras [16,17]. Interestingly, LKB1 acts as an important barrier in tumorigenesis of lung cancer, controlling its initiation, metastasis and differentiation [17][18][19]. LKB1 is also reported to suppress the growth and metastasis of lung cancer cells [19,20].…”