Laboratory of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, Higashiosaka, Japan.
Pathobiology. 2010;77(4):225-9. doi: 10.1159/000305355. Epub 2010 Jul 7.
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.
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.
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%).
These results suggest that alterations of the LKB1 gene might be involved in the development of lung adenocarcinomas induced by BHP in rats.
LKB1 基因的种系突变导致常染色体显性遗传的 Peutz-Jeghers 综合征（PJS），而 PJS 也与癌症风险增加相关，提示 LKB1 可能在 PJS 中作为肿瘤抑制因子发挥作用。相比之下，LKB1 突变在非 PJS 患者的大多数散发性肿瘤中很少见，除了肺癌。为了更好地理解 LKB1 基因改变在肺癌发生过程中的作用，我们研究了 N-亚硝基双（2-羟丙基）胺（BHP）诱导的大鼠肺腺癌中 LKB1 基因突变和表达。
6 周龄雄性 Wistar 大鼠饮用 2000 ppm BHP 的水 12 周，直至 25 周处死前不再进行进一步处理。共获得 15 个肺腺癌，提取基因组 DNA 进行聚合酶链反应（PCR）-单链构象多态性分析以寻找突变。为评估 LKB1 基因表达的改变，还进行了逆转录-PCR 分析。
在任何肿瘤中均未发现外显子 1-9 的突变。在 15 个腺癌中的 5 个中检测到携带核苷酸 216-1459、289-1302、268-1261 或 257-1378 缺失的异常转录本（33.3%）。
这些结果表明，LKB1 基因的改变可能参与了 BHP 诱导的大鼠肺腺癌的发生。
