Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis.

ABSTRACT: BACKGROUND:Chitinase 3 like 1 protein (Chi3L1) is expressed in several cancers, and a few evidences suggest that the secreted Chi3L1 contributes to tumor development. However, the molecular mechanisms of intracellular Chi3L1 are unknown in the lung tumor development. METHODS:In the present study, we generated Chi3L1 knockout mice (Chi3L1KO(-/-)) using CRISPR/Cas9 system to investigate the role of Chi3L1 on lung tumorigenesis. RESULTS:We established lung metastasis induced by i.v. injections of B16F10 in Chi3L1KO(-/-). The lung tumor nodules were significantly reduced in Chi3L1KO(-/-) and protein levels of p53, p21, BAX, and cleaved-caspase 3 were significantly increased in Chi3L1KO(-/-), while protein levels of cyclin E1, CDK2, and phsphorylation of STAT3 were decreased in Chi3L1KO(-/-). Allograft mice inoculated with B16F10 also suppressed tumor growth and increased p53 and its target proteins including p21 and BAX. In addition, knockdown of Chi3L1 in lung cancer cells inhibited lung cancer cell growth and upregulated p53 expression with p21 and BAX, and a decrease in phosphorylation of STAT3. Furthermore, we found that intracellular Chi3L1 physically interacted and colocalized with p53 to inhibit its protein stability and transcriptional activity for target genes related with cell cycle arrest and apoptosis. In lung tumor patient, we clinically found that Chi3L1 expression was upregulated with a decrease in p53 expression, as well as we validated that intracellular Chi3L1 was colocalized, reversely expressed, and physically interacted with p53, which results in suppression of the expression and function of p53 in lung tumor patient. CONCLUSIONS:Our studies suggest that intracellular Chi3L1 plays a critical role in the lung tumorigenesis by regulating its novel target protein, p53 in both an in vitro and in vivo system.

SUBMITTER: Park KR 

PROVIDER: S-EPMC7055043 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature