Caspase Recruitment Domain Containing Protein 9 Suppresses Non-Small Cell Lung Cancer Proliferation and Invasion via Inhibiting MAPK/p38 Pathway

Abstract

PurposeCaspase recruitment domain containing protein 9 (CARD9) has been demonstrated to be a pro-tumor factor in various cancers. However, our previous study found a significant decrease of CARD9 in malignant pleural effusion compared with benign pleural effusion. So we investigated the role of CARD9 in non-small cell lung cancer (NSCLC) and its working mechanism. Materials and MethodsImmunohistochemistry, western blot, and quantitative real-time polymerase chain reaction were used to detect the expression of CARD9 in specimens of NSCLC patients. The Cancer Genome Atlas (TCGA) databasewas also used to analyze the expression of CARD9 in NSCLC and its predicting value for prognosis. Immunofluorescence was used for CARD9 cellular location. Cell growth assay, clonal formation assay, wound healing assay, matrigel invasion assay, and flow cytometry were used to test cell proliferation, migration, invasion, apoptosis, and cycle progression of NSCLC cells with CARD9 knockdown or CARD9 overexpression. Co-immunoprecipitation was used to identify the interaction between CARD9 and B-cell lymphoma 10 (BCL10). SB203580 was used to inhibit p38 activation.ResultsCARD9 was decreased in NSCLC tissues compared with normal tissues; low CARD9 expression was associated with poor survival. CARD9 was expressed both in tumor cells and macrophages. Downregulation of CARD9 in NSCLC cells enhanced the abilities of proliferation, invasion and migration via activated MAPK/p38 signaling, while overexpression of CARD9 presented antitumor effects. BCL10 was identified to interact with CARD9.ConclusionWe demonstrate that CARD9 is an independent prognostic factor in NSCLC patients and inhibits proliferation, migration, and invasion by suppressing MAPK/p38 pathway in NSCLC cells.

CARD9 as a potential therapeutic target in lung cancer

“…Pan and co-workers also identified CARD9 as a potential prognostic indicator in lung cancer [30]. Contrary to previous findings [1,13], CARD9 expression was reduced in lung cancer and exhibited anti-tumor activity in this study.…”

“…CARD9 protein was also found to be expressed in lung cancer cell lines PC9, H1299, and HBE [30], suggesting its potential participation in tumorigenesis. In vitro experiments showed that CARD9 knockdown in PC9 cells significantly promoted cell proliferation, invasion, migration, and inhibited cell apoptosis.…”

Mycobiota and C-Type Lectin Receptors in Cancers: Know thy Neighbors

“…However, there is growing evidence that CARD9 appears to play an anti-cancer role in lung cancer. It was demonstrated that CARD9 expression was reduced in NSCLC tissues compared to normal tissues, and low CARD9 expression was related to poor survival ( Pan et al, 2020 ). CARD9 was expressed in both tumor cells and macrophages, and the downregulation of CARD9 in NSCLC cells enhanced proliferation, invasion, and migration through the activation of MAPK/p38 signaling, while the overexpression of CARD9 presented anti-tumor effects.…”