Anxa2, also known as Annexin A2, is a pleiotropic calcium-dependent phospholipid-binding protein. It is involved in various cellular processes such as vesicular transport, antioxidant defense, and actin remodeling [6]. It is also associated with pathways like the plasminogen-mediated proteolytic pathway, as the ANXA2/S100A10 complex serves as an oncogenic plasminogen receptor [5]. Anxa2's abnormal expression is related to many diseases, highlighting its biological importance. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In esophageal squamous cell carcinoma (ESCC), overexpression of ANXA2 promotes cell migration, invasion, and metastasis in vitro and in vivo through activating the MYC-HIF1A-VEGF cascade. Phosphorylation of ANXA2 at Tyr23 by SRC leads to its nuclear translocation and enhances ESCC metastatic potential [1]. In non-alcoholic steatohepatitis (NASH), p-STAT3 promotes Anxa2 expression at the transcription level, activating Caspase-1-mediated hepatocyte pyroptosis and fibrosis [2]. In triple-negative breast cancer (TNBC), ANXA2 upregulates the phosphorylation of HSF1, resulting in the transcriptional activation of ATG7, which is crucial to ATG7-mediated autophagy and tumor aggressiveness. ANXA2 knockdown can enhance sensitivity to doxorubicin in TNBC treatment [3]. In gastric cancer, the EphA2-YES1-ANXA2 pathway promotes cancer progression and metastasis, with YES1 phosphorylating ANXA2 at Tyr24 to activate it and increase its nuclear distribution [4].

In conclusion, Anxa2 plays essential roles in multiple biological processes and is closely associated with various diseases including cancers and NASH. Studies using KO/CKO mouse models (or in vivo models in general) have revealed its significant functions in promoting cancer cell migration, invasion, metastasis, and in regulating cell death and autophagy processes, providing potential therapeutic targets for these diseases.

References:

1. Ma, Sai, Lu, Chen-Chen, Yang, Li-Yan, Zhang, Yu, Wang, Ming-Rong. 2018. ANXA2 promotes esophageal cancer progression by activating MYC-HIF1A-VEGF axis. In Journal of experimental & clinical cancer research : CR, 37, 183. doi:10.1186/s13046-018-0851-y. https://pubmed.ncbi.nlm.nih.gov/30081903/

2. Feng, Yun, Li, Wenhua, Wang, Zhuoya, Li, Zhenghong, Dong, Yuwei. 2022. The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis. In Journal of translational medicine, 20, 497. doi:10.1186/s12967-022-03692-1. https://pubmed.ncbi.nlm.nih.gov/36324154/

3. Koh, Minsoo, Lim, Hyesol, Jin, Hao, Lee, Myung-Shik, Moon, Aree. 2024. ANXA2 (annexin A2) is crucial to ATG7-mediated autophagy, leading to tumor aggressiveness in triple-negative breast cancer cells. In Autophagy, 20, 659-674. doi:10.1080/15548627.2024.2305063. https://pubmed.ncbi.nlm.nih.gov/38290972/

4. Mao, Linfeng, Yuan, Weijie, Cai, Kaimei, Chen, Zhikang, Chen, Zihua. 2021. EphA2-YES1-ANXA2 pathway promotes gastric cancer progression and metastasis. In Oncogene, 40, 3610-3623. doi:10.1038/s41388-021-01786-6. https://pubmed.ncbi.nlm.nih.gov/33941853/

5. Bharadwaj, Alamelu G, Kempster, Emma, Waisman, David M. 2021. The ANXA2/S100A10 Complex-Regulation of the Oncogenic Plasminogen Receptor. In Biomolecules, 11, . doi:10.3390/biom11121772. https://pubmed.ncbi.nlm.nih.gov/34944416/

6. Partevian, Suzanna A, Slominsky, Petr A, Shadrina, Maria I, Alieva, Anelya Kh. 2025. ANXA2 Protein and Its Role in Neurodegeneration Processes. In Life (Basel, Switzerland), 15, . doi:10.3390/life15030402. https://pubmed.ncbi.nlm.nih.gov/40141747/