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 (Chi3L1 KO(−/−) ) 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 Chi3L1 KO(−/−) . The lung tumor nodules were significantly reduced in Chi3L1 KO(−/−) and protein levels of p53, p21, BAX, and cleaved-caspase 3 were significantly increased in Chi3L1 KO(−/−) , while protein levels of cyclin E1, CDK2, and phsphorylation of STAT3 were decreased in Chi3L1 KO(−/−) . 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.

Gene Expression Profiling and Protein Analysis Reveal Suppression of the C-Myc Oncogene and Inhibition JAK/STAT and PI3K/AKT/mTOR Signaling by Thymoquinone in Acute Myeloid Leukemia Cells

“…The NGS results showed downregulation of JAK/STAT and PI3K/AKT/mTOR genes in TQ-treated cells. The results also revealed significant downregulation in genes that induced the activation of JAK/STAT and PI3K/AKT/mTOR pathways ( Figure 11 ) such as chemokine (C–C motif) ligand 2 ( CCL2 ) [ 36 ], colony-stimulating factor 1 receptor ( CSF1R ) [ 37 ], CXC chemokine receptor 2 ( CXCR2 ) [ 38 ], interleukin 6 receptor (IL6R) [ 39 ], G protein-coupled receptors (GPCRs) [ 40 ], and chitinase 3 like 1 protein (Chi3L1) [ 41 ]. These findings suggest that TQ induces apoptosis and inhibits cancer cell proliferation by inhibiting the JAK/STAT and PI3K/AKT/mTOR signaling pathways.…”

Paralysis of the cytotoxic granule machinery is a new cancer immune evasion mechanism mediated by chitinase 3-like-1

“…18 19 It is also unclear whether high levels of CHI3L1 can inhibit NK cells, hindering their role as sentinels and enabling the development of CHI3L1-mediated metastatic disease. [20][21][22][23][24][25] As opposed to their prime role in controlling metastasis formation, NK cells have been generally considered as minor players in the control of solid tumors. 26 However, this concept has been challenged by the use of ADCC-inducing monoclonal antibodies (eg, Trastuzumab, Cetuximab), immune-checkpoint blockers, NK cell engagers, and chimeric receptors that enhance NK cell cytotoxicity and redirect them to treat solid malignancies.…”

Diagnostic Value of Chitinase-3-like Protein 1 and Keratin 5 in Bronchoalveolar Lavage Fluid of Lung Cancer

“…and can be used as an inflammatory biomarker [21,22] . YKL40 has also been found to be associated with a high risk of cancer progression and future cancer development [9,10,23] KRT5 is widely expressed in cancer tissues and can promote cancer cell growth, migration [11,24] and increase mortality in cancer patients. Xiao et al [25] found KRT5 to be valuable in the diagnostic differential of lung adenocarcinoma and lung squamous cell carcinoma.…”

“…In recent years, the detection of biomarkers in alveolar lavage fluid or serum is a new method for the early diagnosis of lung cancer, which is promising due to its simplicity, reproducibility and low invasiveness [8] . Recent studies have shown that Chitinase-3-like protein 1 (YKL-40) and Keratin 5 (KRT5) play an important role in the staging, differential diagnosis and prognosis of lung cancer [9][10][11] , but most of the studies have been conducted on a single tumor marker and there are few reports on the simultaneous detection of the expression levels of both in alveolar lavage fluid. The aim of this study was to explore the value of YKL40 and KRT5 in Bronchoalveolar Lavage Fluid (BALF) for the early diagnosis of lung cancer.…”