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FAM111B enhances proliferation of KRAS‐driven lung adenocarcinoma by degrading p16

Lung cancer is a common type of cancer that represents a health problem worldwide; lung adenocarcinoma (LUAD) is a major subtype of lung cancer. Although several treatments for LUAD have been developed, the mortality rate remains high because of uncontrollable progression. Further biological and cli...

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Published in:Cancer science 2020-07, Vol.111 (7), p.2635-2646
Main Authors: Kawasaki, Keisuke, Nojima, Satoshi, Hijiki, Sachiko, Tahara, Shinichiro, Ohshima, Kenji, Matsui, Takahiro, Hori, Yumiko, Kurashige, Masako, Umeda, Daisuke, Kiyokawa, Hiroki, Kido, Kansuke, Okuzaki, Daisuke, Morii, Eiichi
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Language:English
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Summary:Lung cancer is a common type of cancer that represents a health problem worldwide; lung adenocarcinoma (LUAD) is a major subtype of lung cancer. Although several treatments for LUAD have been developed, the mortality rate remains high because of uncontrollable progression. Further biological and clinicopathological studies are therefore needed. Here, we investigated the role of family with sequence similarity 111 member B (FAM111B), which is highly expressed in papillary‐predominant LUAD; however, its role in cancer is unclear. An immunohistochemical analysis confirmed that papillary‐predominant adenocarcinomas exhibited higher expression of FAM111B, compared with lepidic‐predominant adenocarcinomas. Additionally, FAM111B expression was significantly correlated with clinical progression. In vitro functional analyses using FAM111B‐knockout cells demonstrated that FAM111B plays an important role in proliferation and cell cycle progression of KRAS‐driven LUAD under serum‐starvation conditions. Furthermore, FAM111B regulated cyclin D1‐CDK4‐dependent cell cycle progression by degradation of p16. In summary, we revealed the clinical importance of FAM111B in human tumor tissues, as well as its function as a degradative enzyme. Therefore, FAM111B has potential as a clinicopathological prognostic marker for LUAD. We screened family with sequence similarity 111 member B (FAM111B), the precise functional role of which in cancers is not clear, as the molecule is highly expressed in papillary‐predominant lung adenocarcinoma. Immunohistochemical analysis confirmed that papillary‐predominant adenocarcinoma had higher expression of FAM111B compared with lepidic‐predominant adenocarcinoma, and FAM111B expression levels were significantly correlated with patients’ clinical progression. In vitro functional analyses using FAM111B‐knockout (FAM111B‐KO) cells demonstrated that FAM111B plays an important role in proliferation and cell cycle progression of LUAD with the KRAS mutation, specifically under the conditions of serum starvation, and it was revealed that FAM111B negatively regulates CyclinD1‐CDK4‐dependent cell cycle progression by functioning as a degrading enzyme to control p16 expression level.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.14483