ANXA2, also known as Annexin A2, is a pleiotropic calcium-dependent phospholipid-binding protein. It is involved in multiple cellular processes such as vesicular transport, antioxidant defense, and actin remodeling [5]. ANXA2 has been implicated in various pathways, including those related to cancer progression and neurodegeneration. Genetic models, especially KO/CKO mouse models, can be valuable in further exploring its functions.

In cancer research, in esophageal squamous cell carcinoma (ESCC), overexpression of ANXA2 promoted cell migration, invasion, and metastasis in vitro and in vivo through activation of the MYC-HIF1A-VEGF cascade [1]. In triple-negative breast cancer (TNBC), ANXA2 was crucial to ATG7-mediated autophagy, leading to tumor aggressiveness, and its knockdown increased sensitivity to doxorubicin [3]. In gastric cancer, the EphA2-YES1-ANXA2 pathway promoted cancer progression and metastasis [4]. In breast cancer, the FOXD1-dependent RalA-ANXA2-Src complex promoted circulating tumor cell (CTC) formation via activating the ERK1/2 signal [8]. In bladder cancer, a novel tsRNA promoted malignancy by regulating ANXA2 phosphorylation [7]. In non-alcoholic steatohepatitis (NASH), the p-STAT3/ANXA2 axis promoted caspase-1-mediated hepatocyte pyroptosis and fibrosis [2]. In epilepsy, ANXA2 was upregulated in relevant models, and its knockdown decreased epileptic susceptibility and GluA1 phosphorylation [6].

In conclusion, ANXA2 is a multifunctional protein involved in numerous biological processes. Studies using KO/CKO mouse models (not explicitly mentioned in these references but in general terms) could potentially further clarify its role. The research on ANXA2 has significant implications for understanding the mechanisms of various diseases, especially cancer, NASH, and epilepsy, providing potential targets for treatment.

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. 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/

6. Ma, Limin, Wu, Qingyuan, Yuan, Jinxian, Liang, Minxue, Chen, Yangmei. 2023. Inhibition of ANXA2 activity attenuates epileptic susceptibility and GluA1 phosphorylation. In CNS neuroscience & therapeutics, 29, 3644-3656. doi:10.1111/cns.14295. https://pubmed.ncbi.nlm.nih.gov/37302990/

7. Ying, Xiaoling, Hu, Wenyu, Huang, Yapeng, Wu, Wenqi, Ji, Weidong. 2024. A Novel tsRNA, m7G-3' tiRNA LysTTT, Promotes Bladder Cancer Malignancy Via Regulating ANXA2 Phosphorylation. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2400115. doi:10.1002/advs.202400115. https://pubmed.ncbi.nlm.nih.gov/38894581/

8. Long, Yufei, Chong, Tuotuo, Lyu, Xiaoming, Chen, Ceshi, Li, Xin. 2022. FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer. In Journal of experimental & clinical cancer research : CR, 41, 301. doi:10.1186/s13046-022-02504-0. https://pubmed.ncbi.nlm.nih.gov/36229838/