TMEM176A, a transmembrane protein-encoding gene, is involved in multiple biological processes. It has been linked to the regulation of ERK signaling pathway, which is crucial in cell growth, proliferation, and apoptosis. Additionally, it may play a role in the immune response, as it is related to antigen presentation in dendritic cells and has implications in the modulation of the tumor immune microenvironment [1,4,2]. Genetic models such as knockout or conditional knockout mouse models could potentially be valuable for further exploring its functions.

In cancer studies, overexpression of TMEM176A in pancreatic cancer cells suppressed cell proliferation, invasion, migration, and induced apoptosis by inhibiting ERK signaling, suggesting it acts as a tumor suppressor in pancreatic cancer [1]. In lung cancer, restoration of TMEM176A expression induced cell apoptosis, G2/M phase arrest, and inhibited colony formation, cell proliferation, migration, and invasion, and its methylation activated ERK signaling and sensitized cells to an ATM inhibitor [3]. In hepatocellular carcinoma, esophageal squamous cell cancer, and colorectal cancer, methylation of the TMEM176A promoter was associated with reduced expression, and restoration of its expression inhibited cancer cell growth, invasion, and migration, and induced apoptosis [7,8,9]. However, in glioblastoma cells, it acted as a tumor-promoting factor, and its function was suppressed by an ERK1/2 inhibitor [6].

In non-cancer research, TMEM176A and TMEM176B were required in conventional dendritic cells for optimal antigen processing and presentation to CD4+ T cells [4]. Also, their overexpression was found in chronic spinal cord injury, suggesting a role in inhibiting protective immune responses [5].

In conclusion, TMEM176A plays diverse roles in biological processes, especially in cancer and immune-related functions. Through studies on model-based research, it is evident that TMEM176A can act as either a tumor suppressor or promoter depending on the cancer type, mainly through its regulation of the ERK signaling pathway. In the immune system, it is involved in antigen presentation and potentially in the modulation of immune responses post-spinal cord injury. Understanding TMEM176A functions helps in uncovering disease mechanisms and may provide new therapeutic targets.

References:

1. Guo, Yulin, Cao, Feng, Hu, Shun, Li, Ang, Li, Fei. . TMEM176A acts as a tumor suppressor gene in pancreatic cancer by inhibiting ERK signaling. In Discovery medicine, 30, 145-153. doi:. https://pubmed.ncbi.nlm.nih.gov/33593482/

2. Guo, Siyu, Liu, Xinkui, Zhang, Jingyuan, Zhou, Wei, Wu, Jiarui. 2023. Integrated analysis of single-cell RNA-seq and bulk RNA-seq unravels T cell-related prognostic risk model and tumor immune microenvironment modulation in triple-negative breast cancer. In Computers in biology and medicine, 161, 107066. doi:10.1016/j.compbiomed.2023.107066. https://pubmed.ncbi.nlm.nih.gov/37263064/

3. Li, Hongxia, Yang, Weili, Zhang, Meiying, Hu, Liming, Guo, Mingzhou. 2021. Methylation of TMEM176A, a key ERK signaling regulator, is a novel synthetic lethality marker of ATM inhibitors in human lung cancer. In Epigenomics, 13, 1403-1419. doi:10.2217/epi-2021-0217. https://pubmed.ncbi.nlm.nih.gov/34558311/

4. Lancien, Melanie, Bienvenu, Geraldine, Salle, Sonia, Cuturi, Maria Cristina, Louvet, Cedric. 2021. Dendritic Cells Require TMEM176A/B Ion Channels for Optimal MHC Class II Antigen Presentation to Naive CD4+ T Cells. In Journal of immunology (Baltimore, Md. : 1950), 207, 421-435. doi:10.4049/jimmunol.2000498. https://pubmed.ncbi.nlm.nih.gov/34233909/

5. Picotto, Gabriela, Morse, Leslie R, Nguyen, Nguyen, Saltzman, Jonah, Battaglino, Ricardo. 2019. TMEM176A and TMEM176B Are Candidate Regulators of Inhibition of Dendritic Cell Maturation and Function after Chronic Spinal Cord Injury. In Journal of neurotrauma, 37, 528-533. doi:10.1089/neu.2019.6498. https://pubmed.ncbi.nlm.nih.gov/31354034/

6. Liu, Zhiguo, An, Haixia, Song, Peng, Chen, Kai, Pang, Qi. 2018. Potential targets of TMEM176A in the growth of glioblastoma cells. In OncoTargets and therapy, 11, 7763-7775. doi:10.2147/OTT.S179725. https://pubmed.ncbi.nlm.nih.gov/30464524/

7. Li, Hongxia, Zhang, Meiying, Linghu, Enqiang, Hu, Liming, Guo, Mingzhou. 2018. Epigenetic silencing of TMEM176A activates ERK signaling in human hepatocellular carcinoma. In Clinical epigenetics, 10, 137. doi:10.1186/s13148-018-0570-4. https://pubmed.ncbi.nlm.nih.gov/30400968/

8. Wang, Ying, Zhang, You, Herman, James G, Linghu, Enqiang, Guo, Mingzhou. 2017. Epigenetic silencing of TMEM176A promotes esophageal squamous cell cancer development. In Oncotarget, 8, 70035-70048. doi:10.18632/oncotarget.19550. https://pubmed.ncbi.nlm.nih.gov/29050260/

9. Gao, Dan, Han, Yingjie, Yang, Yang, Lu, Zhi John, Guo, Mingzhou. 2017. Methylation of TMEM176A is an independent prognostic marker and is involved in human colorectal cancer development. In Epigenetics, 12, 575-583. doi:10.1080/15592294.2017.1341027. https://pubmed.ncbi.nlm.nih.gov/28678648/