Areg, also known as amphiregulin, is a member of the epidermal growth factor (EGF) family. It acts as an extracellular ligand for the EGF receptor (EGFR) and also functions as an intracellular signaling molecule. Areg is involved in multiple biological processes such as cell survival, tissue growth, and it has been linked to pathways like Hippo-YAP [1]. It plays a vital role in immunity, inflammation, and tissue repair, and is expressed in various cell types including epithelial, mesenchymal, and multiple leukocyte populations [5].

In psoriasis, IL-17A promotes keratinocyte proliferation through activating the YAP-AREG axis. Inhibiting this axis with IL-17A antagonist secukinumab suppresses the pathway in human psoriatic skin [1]. In esophageal squamous cell carcinoma, co-culture with cancer-associated fibroblasts upregulates AREG, which promotes cancer progression via EGFR-Erk/p38 MAPK signaling [2]. In melanoma, nuclear AREG affects a low-proliferative phenotype and contributes to drug resistance, and knocking down AREG makes resistant cells more sensitive to treatment [3]. In non-alcoholic steatohepatitis, Areg-producing regulatory T cells promote liver fibrosis and insulin resistance, and deleting Areg in these T cells reduces NASH-induced liver fibrosis [4]. In pancreatic cancer, AREG mediates epithelial-mesenchymal transition via the EGFR/ERK/NF-κB signaling pathway, and knocking down AREG inhibits cell migration, invasion, and tumor growth [6]. Also, miR-33a-3p can regulate METTL3-mediated AREG stability to inhibit pancreatic cancer invasion and metastasis [7].

In conclusion, Areg is a multifunctional molecule involved in various biological processes and disease conditions. Gene-knockout or conditional-knockout mouse models and other loss-of-function experiments have revealed its role in diseases like psoriasis, cancer, and non-alcoholic steatohepatitis. Understanding Areg's functions through these models provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Yu, Zengyang, Yu, Qian, Xu, Hui, Guo, Chunyuan, Shi, Yuling. 2022. IL-17A Promotes Psoriasis-Associated Keratinocyte Proliferation through ACT1-Dependent Activation of YAP-AREG Axis. In The Journal of investigative dermatology, 142, 2343-2352. doi:10.1016/j.jid.2022.02.016. https://pubmed.ncbi.nlm.nih.gov/35304250/

2. Nakanishi, Takashi, Koma, Yu-Ichiro, Miyako, Shoji, Yokozaki, Hiroshi, Kakeji, Yoshihiro. 2024. AREG Upregulation in Cancer Cells via Direct Interaction with Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression Through EGFR-Erk/p38 MAPK Signaling. In Cells, 13, . doi:10.3390/cells13201733. https://pubmed.ncbi.nlm.nih.gov/39451251/

3. Seefried, Felix, Haller, Lucia, Fukuda, Shinji, Bosserhoff, Anja Katrin, Kuphal, Silke. 2022. Nuclear AREG affects a low-proliferative phenotype and contributes to drug resistance of melanoma. In International journal of cancer, 151, 2244-2264. doi:10.1002/ijc.34254. https://pubmed.ncbi.nlm.nih.gov/36054710/

4. Savage, Thomas M, Fortson, Katherine T, de Los Santos-Alexis, Kenia, Schwabe, Robert F, Arpaia, Nicholas. 2024. Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis. In Immunity, 57, 303-318.e6. doi:10.1016/j.immuni.2024.01.009. https://pubmed.ncbi.nlm.nih.gov/38309273/

5. Zaiss, Dietmar M W, Gause, William C, Osborne, Lisa C, Artis, David. . Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. In Immunity, 42, 216-226. doi:10.1016/j.immuni.2015.01.020. https://pubmed.ncbi.nlm.nih.gov/25692699/

6. Wang, Li, Wang, Lili, Zhang, Hui, Wu, Huanwen, Liang, Zhiyong. 2020. AREG mediates the epithelial‑mesenchymal transition in pancreatic cancer cells via the EGFR/ERK/NF‑κB signalling pathway. In Oncology reports, 43, 1558-1568. doi:10.3892/or.2020.7523. https://pubmed.ncbi.nlm.nih.gov/32323797/

7. Su, Xiaowen, Lai, Tiantian, Tao, Yue, Mao, Yong, Hu, Hao. 2023. miR-33a-3p regulates METTL3-mediated AREG stability and alters EMT to inhibit pancreatic cancer invasion and metastasis. In Scientific reports, 13, 13587. doi:10.1038/s41598-023-39506-7. https://pubmed.ncbi.nlm.nih.gov/37604948/