Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer

Autor: Young-Hoon Sung, Seungeon Lee, Yaechan Song, Do Young Hyeon, Jae-Hoon Lee, Yujin Kim, Jae-il Roh, Hye Jeong Kim, Bomin Park, Yonghwan Kim, Taewook Nam, Jahyun Oh, Han Woong Lee, Daehee Hwang, Sushil Devkota
Rok vydání: 2020
Předmět:
0301 basic medicine
Cancer Research
Lung Neoplasms
Microarray
Cell
Cell Cycle Proteins
Biology
medicine.disease_cause
Models
Biological
Article
Proto-Oncogene Proteins p21(ras)
Mice
03 medical and health sciences
0302 clinical medicine
Carcinoma
Non-Small-Cell Lung
Cell Line
Tumor
Biomarkers
Tumor
Genetics
medicine
Animals
Humans
Lung cancer
neoplasms
Molecular Biology
Protein kinase B
Cell Proliferation
Mice
Knockout
Tissue microarray
Cell growth
Prognosis
medicine.disease
respiratory tract diseases
Gene Expression Regulation
Neoplastic
Disease Models
Animal
Cell Transformation
Neoplastic
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Mutation
Cancer research
KRAS
Carcinogenesis
Proto-Oncogene Proteins c-akt
Non-small-cell lung cancer
Signal Transduction
Cell signalling
Zdroj: Oncogene
ISSN: 1476-5594
0950-9232
Popis: 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 KRASG12D-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.
Databáze: OpenAIRE
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