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Carcinogen‐induced tumors in SFN ‐transgenic mice harbor a characteristic mutation spectrum of human lung adenocarcinoma
Author(s) -
Kim Yunjung,
ShibaIshii Aya,
Ramirez Karina,
Muratani Masafumi,
Sakamoto Noriaki,
Iijima Tatsuo,
Noguchi Masayuki
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14081
Subject(s) - adenocarcinoma , carcinogenesis , cancer research , lung cancer , oncogene , biology , carcinogen , genetically modified mouse , lung , transgene , cancer , gene , pathology , cell cycle , medicine , genetics
Abstract The landscape of genetic alterations in disease models such as transgenic mice or mice with carcinogen‐induced tumors has provided a huge amount of information that has shed light on the process of tumorigenesis in human non‐small‐cell lung cancer ( NSCLC ). We have previously identified stratifin ( SFN ) as a potent oncogene, and generated SFN ‐transgenic (Tg‐ SPC ‐ SFN +/− ) mice, which express human SFN ( hSFN ) only in the lung. Here, we have found that carcinogen nicotine‐derived nitrosaminoketone ( NNK )‐induced tumors developing in Tg‐ SPC ‐ SFN +/− mice show a similar histology to human lung adenocarcinoma and exhibit high hSFN expression. In order to compare the genetic characteristics of Tg‐ SPC ‐ SFN +/− tumors and human lung adenocarcinoma, the former were subjected to whole‐exome sequencing. Interestingly, Tg‐ SPC ‐ SFN +/− tumors showed the distinct distribution of exonic mutations and high number of mutated genes and transversion. Moreover, Tg‐ SPC ‐ SFN +/− tumors showed 73 genes that were commonly detected in more than 2 tumors, mutations of which were also found in human lung adenocarcinoma. The expression levels of some of these genes were significantly associated with the clinical outcome of lung adenocarcinoma patients. Additionally, mutated genes in Tg‐ SPC ‐ SFN +/− tumors were closely associated with key canonical pathways such as PI 3K/ AKT signaling and apoptosis signaling. These results suggest that SFN overexpression is a universal abnormality in human lung adenocarcinogenesis and Tg‐ SPC ‐ SFN +/− tumors recapitulate key features of major human lung adenocarcinoma. Therefore, Tg‐ SPC ‐ SFN +/− mice provide a useful model for clarifying the molecular mechanism underlying lung adenocarcinogenesis.

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