Foxf2, a member of the forkhead box transcription factors, serves as a transcriptional regulator. It plays crucial roles in embryonic development, metabolism, and is associated with diseases like stroke, gastroparesis, and various cancers. It is involved in pathways such as Wnt/β -catenin and TGF -β/SMAD signaling, and genetic models, especially KO/CKO mouse models, are valuable for studying its functions [1].

In mouse models, Foxf2 knockout leads to shortened and malformed cochleae, reduced expression of Eya1 and Pax3 essential for cochlear development, indicating its key role in cochlear development [5]. Osteoprogenitor-specific Foxf2 knockout mice exhibit a high bone mass phenotype due to increased bone formation, revealing its repression of bone formation via Wnt2b/β -catenin signaling [4]. In prostate cancer models, increasing prostatic stromal Foxf2 suppresses tumor growth and metastasis by enhancing antitumor immunity, and its expression in human prostate stroma inversely correlates with the Gleason grade [2]. In breast cancer, FOXF2 oppositely regulates stemness in luminal and basal-like breast cancer cells through the Wnt/β -catenin pathway [3]. In esophageal squamous cell carcinoma, overexpression of FOXF2 inhibits cell proliferation and M2 polarization of tumor-associated macrophages via modulating the RNF144A-FTO axis [6].

In summary, Foxf2 is essential for embryonic development, especially in cochlear and palate development, and bone formation regulation. In disease areas, it has significant impacts on cancer progression, including prostate, breast, and esophageal cancers. The use of KO/CKO mouse models has been instrumental in uncovering these functions, providing insights into potential therapeutic targets for related diseases.

References:

1. He, Weihan, Kang, Yuanbo, Zhu, Wei, Ren, Caiping, Guo, Weihua. 2020. FOXF2 acts as a crucial molecule in tumours and embryonic development. In Cell death & disease, 11, 424. doi:10.1038/s41419-020-2604-z. https://pubmed.ncbi.nlm.nih.gov/32503970/

2. Jia, Deyong, Zhou, Zhicheng, Kwon, Oh-Joon, Creighton, Chad J, Xin, Li. 2022. Stromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity. In Nature communications, 13, 6828. doi:10.1038/s41467-022-34665-z. https://pubmed.ncbi.nlm.nih.gov/36369237/

3. Zhang, Xiao, Zhang, Rui, Hou, Chen, Zhai, Qiong-Li, Feng, Yu-Mei. 2022. FOXF2 oppositely regulates stemness in luminal and basal-like breast cancer cells through the Wnt/beta-catenin pathway. In The Journal of biological chemistry, 298, 102082. doi:10.1016/j.jbc.2022.102082. https://pubmed.ncbi.nlm.nih.gov/35660418/

4. Tanaka, Tomoyuki, Takahashi, Akira, Kobayashi, Yutaka, Carlsson, Peter, Inose, Hiroyuki. 2022. Foxf2 represses bone formation via Wnt2b/β-catenin signaling. In Experimental & molecular medicine, 54, 753-764. doi:10.1038/s12276-022-00779-z. https://pubmed.ncbi.nlm.nih.gov/35668101/

5. Bademci, Guney, Abad, Clemer, Incesulu, Armagan, Walz, Katherina, Tekin, Mustafa. . FOXF2 is required for cochlear development in humans and mice. In Human molecular genetics, 28, 1286-1297. doi:10.1093/hmg/ddy431. https://pubmed.ncbi.nlm.nih.gov/30561639/

6. Han, Tianci, Tong, Wei, Xie, Junwei, Guo, Xiaoqi, Zhang, Liang. 2024. FOXF2 suppressed esophageal squamous cell carcinoma by reducing M2 TAMs via modulating RNF144A-FTO axis. In International immunopharmacology, 143, 113422. doi:10.1016/j.intimp.2024.113422. https://pubmed.ncbi.nlm.nih.gov/39447407/