MFAP2, or Microfibril Associated Protein 2, is an extracellular matrix protein that interacts with fibrillin to regulate microfibril function. It is involved in multiple biological processes and has been associated with pathways such as TGF-β/Smad3, FAK-AKT, Wnt/β-catenin, and Notch1, playing a significant role in various diseases, especially cancer [1,3,5,6,7]. Genetic models like gene knockout (KO) and conditional knockout (CKO) mouse models can be valuable for further studying its functions.

In liver fibrosis, knockdown of MFAP2 in a CCl4-induced mouse model inhibited HSC proliferation, decreased collagen deposits, alleviated hepatic fibrosis by inhibiting HSC activation and inducing apoptosis, suggesting it promotes HSCs activation through FBN1/TGF-β/Smad3 pathway [1]. In colorectal cancer, in vivo and in vitro studies with MFAP2 silencing showed inhibition of cell migration, invasion, and metastasis, uncovering a MFAP2-CLK3 signaling axis [2]. In ovarian cancer, knockdown of MFAP2 in mice inhibited xenograft tumor growth, indicating that it promotes cell proliferation and glycolysis via modulating FOXM1/β-catenin signaling pathway [3]. In gastric cancer, MFAP2-knockdown in drug-resistant cell lines improved cisplatin sensitivity as MFAP2 enhanced cisplatin resistance by inducing autophagy [4]. In esophageal squamous cell carcinoma (ESCC), upregulation of MFAP2 promoted metastasis and invasion in vitro and in vivo, while knockdown reduced these processes via FAK-AKT signaling pathway [5]. In oral squamous cell carcinoma (OSCC), MFAP2 promoted oncogenic autophagy, cell invasion, migration, proliferation, and tumor growth in vivo, and its knockdown could potentially serve as a biomarker [6]. In osteosarcoma, MFAP2 knockdown in U2OS cells reduced cell viability, migration, and invasion, and inhibited tumor growth in a xenograft model, revealing it as an upstream regulator of the Notch1 pathway promoting EMT [7]. In hepatocellular carcinoma, downregulation of MFAP2 in vitro inhibited cell proliferation and migration [8].

In conclusion, MFAP2 plays crucial roles in promoting the progression of multiple cancers and liver fibrosis. Studies using KO/CKO mouse models or other loss-of-function experiments have revealed its functions in cell proliferation, invasion, metastasis, and fibrosis-related processes, providing potential therapeutic targets for these diseases.

References:

1. Sun, Yonghong, Chen, Xingxing, Chen, Lili, Li, Chunming, Zhou, Yongning. 2023. MFAP2 promotes HSCs activation through FBN1/TGF-β/Smad3 pathway. In Journal of cellular and molecular medicine, 27, 3235-3246. doi:10.1111/jcmm.17884. https://pubmed.ncbi.nlm.nih.gov/37635348/

2. Xue, Meng, Mi, Shuyi, Zhang, Zizhen, Wei, Wei, Lou, Guochun. 2022. MFAP2, upregulated by m1A methylation, promotes colorectal cancer invasiveness via CLK3. In Cancer medicine, 12, 8403-8414. doi:10.1002/cam4.5561. https://pubmed.ncbi.nlm.nih.gov/36583532/

3. Zhao, Ling-Qin, Sun, Wei, Zhang, Ping, Fang, Chen-Yan, Zheng, Ai-Wen. 2022. MFAP2 aggravates tumor progression through activating FOXM1/β-catenin-mediated glycolysis in ovarian cancer. In The Kaohsiung journal of medical sciences, 38, 772-780. doi:10.1002/kjm2.12546. https://pubmed.ncbi.nlm.nih.gov/35546486/

4. Li, Meng, Zhang, Hong-Yi, Zhang, Rong-Gui. 2023. MFAP2 enhances cisplatin resistance in gastric cancer cells by regulating autophagy. In PeerJ, 11, e15441. doi:10.7717/peerj.15441. https://pubmed.ncbi.nlm.nih.gov/37304872/

5. Deng, Yiran, Huang, Xu, Yang, Yiran, Ma, Lifang, Wang, Jiayi. . MFAP2 upregulation promotes ESCC metastasis via FAK-AKT signaling pathway. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 38, e70266. doi:10.1096/fj.202402411R. https://pubmed.ncbi.nlm.nih.gov/39698924/

6. Zhang, Hao, Shen, Si, Feng, Chong, Chen, Gang, Wang, Xinxing. . MFAP2 promotes the progression of oral squamous cell carcinoma by activating the Wnt/β-catenin signaling pathway through autophagy. In Acta biochimica et biophysica Sinica, 55, 1445-1455. doi:10.3724/abbs.2023079. https://pubmed.ncbi.nlm.nih.gov/37592847/

7. Jiang, Shan, Zheng, Ziang, Yuan, Bo, Lei, Yue, Liang, Haidong. 2024. MFAP2 induces epithelial-mesenchymal transformation of osteosarcoma cells by activating the Notch1 pathway. In Translational cancer research, 13, 2847-2859. doi:10.21037/tcr-23-2035. https://pubmed.ncbi.nlm.nih.gov/38988940/

8. Zhu, Xiang, Cheng, Ye, Wu, Fan, Ma, Shijie, Cao, Hongyong. . MFAP2 Promotes the Proliferation of Cancer Cells and Is Associated With a Poor Prognosis in Hepatocellular Carcinoma. In Technology in cancer research & treatment, 19, 1533033820977524. doi:10.1177/1533033820977524. https://pubmed.ncbi.nlm.nih.gov/33280519/