Anxa4, encoding Annexin A4, is a calcium ion (Ca2+)- and phospholipid-binding protein of the Annexin family. It has been implicated in various biological processes, such as cell migration, proliferation, and apoptosis, and is associated with multiple signaling pathways including PI3K/Akt/eNOS, JAK-STAT3, and NF-κB [1,2,4]. It also seems to be involved in innate immunity, which might link atrial fibrillation and cancer [3]. Genetic models, like gene knockout mouse models, can help further clarify its functions.

In preeclampsia, Anxa4 expression is downregulated in placentas and placenta-derived extravillous cytotrophoblasts. Overexpression of Anxa4 in human trophoblast cells promotes cell proliferation and invasion, inhibits apoptosis, and upregulates PI3K, p-Akt, and p-eNOS, while knockdown has the opposite effects. Inhibition of the PI3K/Akt pathway abrogates the Anxa4 overexpression-mediated effects. In an N-nitro-l-arginine methyl ester-induced preeclampsia rat model, Anxa4 overexpression alleviates preeclampsia progression [1]. In basal-like breast cancer, Anxa4 expression is upregulated in tumor tissues. High Anxa4 expression is associated with poor survival. Anxa4 can activate JAK-STAT3 signaling by interacting with ANXA1, modulating cyclin D1 expression and G1/S progression, and promoting tumor growth in vivo. Inhibition of Anxa4 slows tumor growth [2].

In summary, Anxa4 plays crucial roles in cell-related biological processes like proliferation, invasion, and apoptosis. Model-based research, especially in preeclampsia and basal-like breast cancer, has revealed its significance in these disease conditions. These findings suggest Anxa4 could be a potential target for treating related diseases [1,2].

References:

1. Xu, Yalan, Sui, Lili, Qiu, Bintao, Liu, Juntao, Zhang, Xiaohong. 2019. ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia. In American journal of physiology. Cell physiology, 316, C481-C491. doi:10.1152/ajpcell.00404.2018. https://pubmed.ncbi.nlm.nih.gov/30673304/

2. Li, Lei, Zhang, Rong, Liu, Ying, Zhang, Gong. 2020. ANXA4 Activates JAK-STAT3 Signaling by Interacting with ANXA1 in Basal-Like Breast Cancer. In DNA and cell biology, 39, 1649-1656. doi:10.1089/dna.2020.5570. https://pubmed.ncbi.nlm.nih.gov/32552056/

3. Yan, Tao, Zhu, Shijie, Shi, Yu, Wang, Chunsheng, Guo, Changfa. 2021. Pan-Cancer Analysis of Atrial-Fibrillation-Related Innate Immunity Gene ANXA4. In Frontiers in cardiovascular medicine, 8, 713983. doi:10.3389/fcvm.2021.713983. https://pubmed.ncbi.nlm.nih.gov/34540918/

4. Liu, Juanjuan, Wang, Huimin, Zheng, Mingjun, Zhang, Xue, Lin, Bei. 2020. p53 and ANXA4/NF‑κB p50 complexes regulate cell proliferation, apoptosis and tumor progression in ovarian clear cell carcinoma. In International journal of molecular medicine, 46, 2102-2114. doi:10.3892/ijmm.2020.4757. https://pubmed.ncbi.nlm.nih.gov/33125094/