NLR family CARD domain containing 5 promotes hypoxia-induced cancer progress and carboplatin resistance by activating PI3K/AKT via carcinoembryonic antigen related cell adhesion molecule 1 in non-small cell lung cancer

ABSTRACT

It is well known that non-small cell lung cancer (NSCLC) is a malignant tumor with high incidence in the world. We aimed to clarify a possible target and identify its precise molecular biological mechanism in NSCLC. NLR family CARD domain containing 5 (NLRC5) is widely expressed in tissues and exerts a vital role in anti-tumor immunity. We determined NLRC5 expression by RT-qPCR and western blot assay. The role of NLRC5 in the development of NSCLC was assessed by a loss-of-function assay. CCK-8, Annexin-V-FITC/PI Apoptosis Detection Kit, Transwell, and wound healing assays were used to determine the cell functions. Drug resistance-related proteins were analyzed by western blot assay. Furthermore, the modulation of NLRC5 on carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression and subsequent PI3K/AKT signaling was assessed. In this study, a hyper-expression of NLRC5 was found in NSCLC tissues and cell lines. Knockdown of NLRC5 suppressed cell viability, invasion, and migration, and furthermore promoted cell apoptosis in NSCLC cells. Moreover, under normoxia or hypoxia treatment, the upregulation of NLRC5 was related to carboplatin resistance. NLRC5 silencing increased carboplatin-resistant cell chemosensitivity, as evidenced by the increase in the cell inhibition rate and decrease in drug resistance-related protein expression. Mechanistically, NLRC5 knockdown inhibited the expression of CEACAM1 and subsequently blocked the PI3K/AKT signaling pathway. In conclusion, NLRC5 promotes the malignant biological behaviors of NSCLC cells by activating the PI3K/AKT signaling pathway via the regulation of CEACAM1 expression under normoxia and hypoxia.

KEYWORDS:

• NLRC5
• CEACAM1
• resistance
• hypoxia
• NSCLC

Acknowledgements

All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data used to support the findings of this study are available from the corresponding author upon request.

Author’s contributions

Yu Dong: Conceptualization, Methodology, Writing – original draft preparation;

Tao Xu, Dongfan Li, and Hua Guo: Formal analysis and investigation;

Xusheng Du, Guangshun Li, and Jiakuan Chen: Funding acquisition;

Bo Wang, Peng Wang, and Gang Yu: Resources;

Xuan Zhao and Ruiqi Xue: Supervision.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21655979.2022.2086375

Additional information

Funding

This study was funded by the Natural Science Basic Research Program of Shaanxi (2021JM-561).