Anpep, also known as alanyl aminopeptidase, membrane (ANPEP)/CD13, is an aminopeptidase that has diverse functions. It is involved in the renin-angiotensin system, converting angiotensin (Ang) III to Ang IV [3]. It is also associated with extracellular matrix remodeling in fibrosis [2]. It plays a role in various physiological functions such as cell proliferation, differentiation, migration, angiogenesis, invasion, and metastasis [8].

In esophageal adenocarcinoma, elevated ANPEP/CD13 expression indicates shorter patient survival and a more invasive cancer cell phenotype in vitro, and down-regulation by short hairpin RNA vector reduces colony formation, migration, and invasion of EAC cells [1]. In gallbladder squamous cell/adenosquamous carcinomas and adenocarcinomas, a marked reduction in ANPEP levels was seen in cancer relative to normal adjacent tissue, and lack of ANPEP was correlated with larger tumors, higher TNM staging, invasion, metastasis, and poor patient outcomes [4]. In non-alcoholic fatty liver disease, ANPEP was strongly associated with the disease based on plasma proteome profiling [2]. In microvascular complications of type 2 diabetes, certain ANPEP gene polymorphisms were associated with a lower risk of diabetic retinopathy and nephropathy [5]. In Parkinson's disease, ANPEP (CD13) is overexpressed [6]. Regarding viral infections, ANPEP-knockout pigs showed that aminopeptidase N (APN) encoded by ANPEP is a receptor for porcine deltacoronavirus (PDCoV) in porcine alveolar macrophages but not necessary for infection of lung-derived fibroblast cells [7].

In summary, Anpep is involved in multiple biological processes and is associated with various diseases including cancer, liver disease, diabetes-related microvascular complications, and Parkinson's disease. The use of genetic models like ANPEP-knockout pigs has been valuable in revealing its role in viral infections, and studies on gene polymorphisms and expression changes in diseases have enhanced our understanding of its function in disease development.

References:

1. Goltsov, Alexei A, Maru, Dipen M, Katkhuda, Riham, Futreal, P Andrew, Hofstetter, Wayne L. 2023. ANPEP/CD13 Expression as a Marker of Lymphovascular Invasion and Survival in Esophageal Adenocarcinoma. In The Annals of thoracic surgery, 118, 241-251. doi:10.1016/j.athoracsur.2023.09.036. https://pubmed.ncbi.nlm.nih.gov/37806335/

2. Niu, Lili, Geyer, Philipp E, Wewer Albrechtsen, Nicolai J, Hofmann, Susanna M, Mann, Matthias. 2019. Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease. In Molecular systems biology, 15, e8793. doi:10.15252/msb.20188793. https://pubmed.ncbi.nlm.nih.gov/30824564/

3. Kim, Jong-Heon, Afridi, Ruqayya, Cho, Eunji, Ryu, Hoon, Suk, Kyoungho. 2022. Soluble ANPEP Released From Human Astrocytes as a Positive Regulator of Microglial Activation and Neuroinflammation: Brain Renin-Angiotensin System in Astrocyte-Microglia Crosstalk. In Molecular & cellular proteomics : MCP, 21, 100424. doi:10.1016/j.mcpro.2022.100424. https://pubmed.ncbi.nlm.nih.gov/36220603/

4. Liu, Ziru, Yang, Zhulin, Xiong, Li, Zou, Qiong, Yuan, Yuan. 2020. ACO2 and ANPEP as novel prognostic markers for gallbladder squamous cell/adenosquamous carcinomas and adenocarcinomas. In International journal of clinical oncology, 25, 1346-1355. doi:10.1007/s10147-020-01651-8. https://pubmed.ncbi.nlm.nih.gov/32249333/

5. Korvyakova, Ya E, Azarova, I E, Markina, D D, Solodilova, M A, Polonikov, A V. 2024. Polymorphisms of ANPEP Gene Are Associated with Microvascular Complications of Type 2 Diabetes. In Bulletin of experimental biology and medicine, 178, 79-85. doi:10.1007/s10517-024-06286-7. https://pubmed.ncbi.nlm.nih.gov/39576474/

6. Lowes, Hannah, Robertson, Fiona, Pyle, Angela, Santibanez-Koref, Mauro, Hudson, Gavin. 2020. The Human Coronavirus Receptor ANPEP (CD13) Is Overexpressed in Parkinson's Disease. In Movement disorders : official journal of the Movement Disorder Society, 35, 2134-2136. doi:10.1002/mds.28354. https://pubmed.ncbi.nlm.nih.gov/33070335/

7. Stoian, Ana, Rowland, Raymond R R, Petrovan, Vlad, Cigan, Mark, Prather, Randall S. 2019. The use of cells from ANPEP knockout pigs to evaluate the role of aminopeptidase N (APN) as a receptor for porcine deltacoronavirus (PDCoV). In Virology, 541, 136-140. doi:10.1016/j.virol.2019.12.007. https://pubmed.ncbi.nlm.nih.gov/32056711/

8. Lendeckel, Uwe, Karimi, Farzaneh, Al Abdulla, Ruba, Wolke, Carmen. 2023. The Role of the Ectopeptidase APN/CD13 in Cancer. In Biomedicines, 11, . doi:10.3390/biomedicines11030724. https://pubmed.ncbi.nlm.nih.gov/36979703/