Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer
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ABSTRACT:
PROVIDER: PRJNA561353 | ENA |
REPOSITORIES: ENA
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Project description:KRAS-mutant non-small cell lung cancer (NSCLC) is one of the main subtypes across lung cancers. Despite the enormous studies on KRAS-mutant NSCLC, new therapeutic targets need to be identified because current therapies are insufficient. Here we show the tumor promoting function of PIERCE1 in the KRAS-mutant NSCLC. Mechanistically, PIERCE1 depletion inhibits cell growth and AKT phosphorylation (pAKT) at S473, particularly in KRAS-mutant lung cancer. Analyses of AKT-related genes show that PIERCE1 negatively regulates gene expression of AKT suppressor TRIB3 through CHOP pathway. Correspondingly, four independent in vivo approaches in lung cancer mouse models related to KRAS mutations reveal the tumor suppressive effect of PIERCE1 depletion suggesting its therapeutic potential. Tissue microarray of human lung cancer showed that PIERCE1 is expressed in 83% of lung cancers and is linked to pAKT expression. This illustrates how PIERCE1 depletion acts as a novel therapeutics against KRAS-mutant NSCLC.
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Project description: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.
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