Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer
- Authors
- Roh, Jae-il; Lee, Jaehoon; Sung, Young-Hoon; Oh, Jahyun; Hyeon, Do Young; Kim, Yujin; Lee, Seungeon; Devkota, Sushil; Kim, Hye Jeong; Park, Bomin; Nam, Taewook; Song, Yaechan; Kim, Yonghwan; Hwang, Daehee; Lee, Han-Woong
- Issue Date
- Sep-2020
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- ONCOGENE, v.39, no.36, pp 5876 - 5887
- Pages
- 12
- Journal Title
- ONCOGENE
- Volume
- 39
- Number
- 36
- Start Page
- 5876
- End Page
- 5887
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/1251
- DOI
- 10.1038/s41388-020-01399-5
- ISSN
- 0950-9232
1476-5594
- Abstract
- KRAS-mutant non-small cell lung cancer (NSCLC) is a major lung cancer subtype that leads to many cancer-related deaths worldwide. Although numerous studies on KRAS-mutant type NSCLC have been conducted, new oncogenic or tumor suppressive genes need to be detected because a large proportion of NSCLC patients does not respond to currently used therapeutics. Here, we show the tumor-promoting function of a cell cycle-related protein, PIERCE1, in KRAS-mutant NSCLC. Mechanistically, PIERCE1 depletion inhibits cell growth and AKT phosphorylation (pAKT) at S473, which is particularly observed in KRAS-mutant lung cancers. Analyses of AKT-related genes using microarray, immunoblotting, and real-time quantitative PCR indicated that PIERCE1 negatively regulates the gene expression of the AKT suppressor, TRIB3, through the CHOP pathway, which is a key regulatory pathway for TRIB3 expression. Similarly, in vivo analyses of PIERCE1 depletion in the KRAS mutation-related lung cancer mouse models revealed the suppressive effect of PIERCE1 knockout in urethane- and KRAS(G12D)-induced lung tumorigenesis with decreased pAKT levels observed in the tumors. Tissue microarrays of human lung cancers indicated the expression of PIERCE1 in 83% of lung cancers and its correlation with pAKT expression. Thus, we illustrate how PIERCE1 depletion may serve as a therapeutic strategy against KRAS-mutant NSCLC and propose the clinical benefit of PIERCE1.
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