Carboxypeptidase N2 as a Novel Diagnostic and Prognostic Biomarker for Lung Adenocarcinoma

Ting Xu; Zhe Zhang; Hongqiang Chen; Ruili Cai; Qian Yang; Qi Liu; Yahan Fan; Wenbin Liu; Chunyan Yao

doi:10.3389/fonc.2022.843325

Carboxypeptidase N2 as a Novel Diagnostic and Prognostic Biomarker for Lung Adenocarcinoma

Front Oncol. 2022 May 23:12:843325. doi: 10.3389/fonc.2022.843325. eCollection 2022.

Authors

Ting Xu¹, Zhe Zhang², Hongqiang Chen^{3

4}, Ruili Cai^{5

6}, Qian Yang¹, Qi Liu¹, Yahan Fan¹, Wenbin Liu^{3

4}, Chunyan Yao¹

Affiliations

¹ Department of Blood Transfusion, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
² Department of Breast and Thyroid Surgery, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
³ Department of Environmental Health, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China.
⁴ Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China.
⁵ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
⁶ Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.

Abstract

Carboxypeptidase N2 (CPN2) is a plasma metallo-protease that cleaves basic amino acids from the C-terminal of peptides and proteins. Emerging evidence showed that carboxypeptidases perform many diverse functions in the body and play key roles in tumorigenesis. However, the clinical significance and biological functions of CPN2 in lung adenocarcinoma remain unclear. Our study aimed to explore the potential role and functions of CPN2 in lung adenocarcinoma. The results showed that the transcription level of CPN2 was significantly increased in the tumor tissues of lung adenocarcinoma patients compared to the adjacent normal tissues in The Cancer Genome Atlas cohort (P < 0.05). The survival plots showed that the overall survival of patients with a high expression of CPN2 was significantly lower than that of patients with a low expression of CPN2, both in the Kaplan-Meier database and the clinical sample cohort (P < 0.05). The tissue microarray analysis found that CPN2 protein expression was significantly positively correlated with node status and tumor stage as well as tumor malignancy (P < 0.05). Further univariate and multivariate Cox regression analyses showed that CPN2 may act as an independent prognostic factor in patients with lung adenocarcinoma (P < 0.05). In addition, the analysis of co-expression genes from LinkedOmics showed that CPN2 was positively associated with many genes of fibrillar collagen family members and the PI3K-Akt pathway. The gene set enrichment analysis showed that a higher expression of CPN2 may participate in mTOR, TGF-BETA, NOTCH, TOLL-like-receptor, WNT, and MAPK signaling pathway in lung adenocarcinoma. Notably, the knockdown of CPN2 significantly inhibited the ability of cell proliferation, clone formation, invasion, and migration. Our findings suggested that the upregulation of CPN2 is associated with a worse clinical outcome in lung adenocarcinoma and cancer-related pathways, which laid the foundation for further research on CPN2 during carcinogenesis.

Keywords: CPN2; biomarker; diagnosis; lung adenocarcinoma; prognosis.