Wif1, short for Wnt inhibitory factor 1, is a secreted antagonist of the Wnt signaling pathway. By directly interacting with various Wnt ligands, it prevents their binding to membrane-bound receptors, thus playing a crucial role in embryonic development and tissue homeostasis [4]. Epigenetic promoter methylation of Wif1, which leads to its transcriptional silencing and subsequent up-regulation of Wnt signaling, is often observed during cancer progression [4].

In prostate cancer, Wif1 inhibits Wnt/β-catenin signaling by binding to Wnt ligands, reducing c-Myc and Cyclin D1 expression. It also promotes apoptosis by down-regulating anti-apoptotic proteins like Bcl-2 and up-regulating pro-apoptotic proteins such as Bax. Additionally, Wif1 suppresses epithelial-mesenchymal transition (EMT) and metastasis [1]. In cervical cancer, methylation of the Wif1 promoter leads to its down-regulation and activation of the Wnt/β-catenin signaling, suggesting it functions as a tumor suppressor [2]. Similarly, in endometrial cancer, Wif1 promoter hypermethylation promotes cancer progression by down-regulating Wif1, activating the Wnt/β-catenin pathway, and influencing cell proliferation and apoptosis [3]. In NSCLC, Wif1 hypermethylation is a potential biomarker, being more predominant in squamous cell carcinoma (SCC) [5]. In the context of kidney disease, loss of CLDN5 in podocytes down-regulates Wif1, activating the WNT signaling pathway, and systemic delivery of Wif1 can suppress disease progression [6]. In neural and glioma stem cells, Wif1 is upregulated by BMP4, and it decreases the cell cycle and proliferation of neural stem cells (NSCs) and glioma cells [7]. In skin, Wif1 suppresses the generation of suprabasal cells in acanthotic skin and the growth of basal cell carcinomas upon overexpression [8].

In summary, Wif1 is a key inhibitor of the Wnt signaling pathway with significant implications in multiple disease areas such as cancer, kidney disease, and neural-related disorders. Through various in vivo and functional studies, its role in tumor suppression, cell cycle regulation, and tissue homeostasis has been revealed, highlighting its potential as a therapeutic target in these diseases.

References:

1. Xia, Zhiliang, Du, Dan, Zhang, Zhi, Guo, Xiong, He, Ziqiu. 2024. WIF1 and DKK3 in prostate cancer: from molecular pathways to therapeutic targets: a narrative review. In Translational andrology and urology, 13, 2601-2616. doi:10.21037/tau-24-304. https://pubmed.ncbi.nlm.nih.gov/39698576/

2. Wang, Ying, Yuan, Shifa, Ma, Jing, Zhang, Fengzhen, Wang, Xiaomei. . WIF1 was downregulated in cervical cancer due to promoter methylation. In Acta biochimica Polonica, 70, 419-423. doi:10.18388/abp.2020_6700. https://pubmed.ncbi.nlm.nih.gov/37306343/

3. Zhang, Baohua, Ji, Jing, Hu, Mingzhu, Fu, Yu, Li, Lan. . WIF1 promoter hypermethylation induce endometrial carcinogenesis through the Wnt/β-catenin signaling pathway. In American journal of reproductive immunology (New York, N.Y. : 1989), 90, e13743. doi:10.1111/aji.13743. https://pubmed.ncbi.nlm.nih.gov/37491917/

4. Poggi, Lucia, Casarosa, Simona, Carl, Matthias. 2018. An Eye on the Wnt Inhibitory Factor Wif1. In Frontiers in cell and developmental biology, 6, 167. doi:10.3389/fcell.2018.00167. https://pubmed.ncbi.nlm.nih.gov/30574494/

5. Guo, Hao, Zhou, Shuni, Tan, Lili, Wu, Zhenfeng, Ran, Ruizhi. . Clinicopathological significance of WIF1 hypermethylation in NSCLC, a meta-analysis and literature review. In Oncotarget, 8, 2550-2557. doi:10.18632/oncotarget.13707. https://pubmed.ncbi.nlm.nih.gov/27911280/

6. Sun, Hui, Li, Hui, Yan, Jie, Zhao, Shengtian, Gong, Yongfeng. 2022. Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease. In Nature communications, 13, 1600. doi:10.1038/s41467-022-29277-6. https://pubmed.ncbi.nlm.nih.gov/35332151/

7. Xu, Congdi, Hu, Xinyu, Fan, Yantao, Gao, Zhengliang, Cai, Chunhui. . Wif1 Mediates Coordination of Bone Morphogenetic Protein and Wnt Signaling in Neural and Glioma Stem Cells. In Cell transplantation, 31, 9636897221134540. doi:10.1177/09636897221134540. https://pubmed.ncbi.nlm.nih.gov/36324293/

8. Becker, Marco, Bauer, Julia, Pyczek, Joanna, Uhmann, Anja, Hahn, Heidi. 2020. WIF1 Suppresses the Generation of Suprabasal Cells in Acanthotic Skin and Growth of Basal Cell Carcinomas upon Forced Overexpression. In The Journal of investigative dermatology, 140, 1556-1565.e11. doi:10.1016/j.jid.2019.11.030. https://pubmed.ncbi.nlm.nih.gov/31987884/