TFF3, also known as trefoil factor 3 or intestinal trefoil factor, is a secreted protein involved in various biological processes. It plays a role in mucosal function and repair, and is associated with pathways such as HIF-1α/VEGFA, STAT3/PTGS2, and Hippo signaling. TFF3 is of great biological importance in processes like cell proliferation, migration, invasion, angiogenesis, and in maintaining metabolic balance [1,2,3,4]. Genetic models, especially knockout (KO) mouse models, are valuable for studying TFF3.

In a Tff3 -deficient mouse model exposed to a high-fat diet, male mice had reduced body weight and better glucose utilization after 17 weeks, and both male and female mice showed reduced lipid accumulation in the liver, indicating Tff3's involvement in metabolic pathways [4]. In colorectal cancer, TFF3 knockout led to decreased clonogenic survival of CRC cells, revealing its role in promoting cancer cell survival [6]. In anti-estrogen treated ER + mammary carcinoma, TFF3 was identified as an epigenetically regulated driver of dormancy-associated behaviors, and its inhibition could potentially alleviate the challenges of anti-estrogen-induced dormancy [5].

In conclusion, TFF3 has diverse functions in mucosal repair, metabolism, and cancer-related processes. Studies using KO mouse models have provided insights into its role in metabolic regulation, cancer cell survival, and tumor dormancy. These findings contribute to understanding the mechanisms of diseases such as fatty liver, colorectal cancer, and ER + mammary carcinoma, and may offer potential therapeutic targets.

References:

1. Wang, Xiaoan, Qin, Han. . TFF3 promotes pituitary tumor cell migration and angiogenesis via VEGFA. In Acta neurobiologiae experimentalis, 82, 237-243. doi:10.55782/ane-2022-022. https://pubmed.ncbi.nlm.nih.gov/35833823/

2. Cui, Hong-Yong, Wang, Shi-Jie, Song, Fei, Jiang, Jian-Li, Chen, Zhi-Nan. 2021. CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression. In Signal transduction and targeted therapy, 6, 268. doi:10.1038/s41392-021-00677-2. https://pubmed.ncbi.nlm.nih.gov/34262017/

3. Zhang, Shuwei, Tan, Yan Qin, Zhang, Xi, Pandey, Vijay, Lobie, Peter E. 2024. TFF3 drives Hippo dependent EGFR-TKI resistance in lung adenocarcinoma. In Oncogene, 44, 753-768. doi:10.1038/s41388-024-03244-5. https://pubmed.ncbi.nlm.nih.gov/39658649/

4. Šešelja, Kate, Bazina, Iva, Vrecl, Milka, Pirman, Tatjana, Baus Lončar, Mirela. 2022. Tff3 Deficiency Protects against Hepatic Fat Accumulation after Prolonged High-Fat Diet. In Life (Basel, Switzerland), 12, . doi:10.3390/life12081288. https://pubmed.ncbi.nlm.nih.gov/36013467/

5. Chen, Shu, Zhang, Xi, Basappa, Basappa, Pandey, Vijay, Lobie, Peter E. 2025. TFF3 facilitates dormancy of anti-estrogen treated ER+ mammary carcinoma. In Communications medicine, 5, 45. doi:10.1038/s43856-024-00710-9. https://pubmed.ncbi.nlm.nih.gov/39984660/

6. Yang, Ting, Fu, Xin, Tian, Ruo-Fei, Han, Ji-Ming, Wang, Shi-Jie. 2023. TFF3 promotes clonogenic survival of colorectal cancer cells through upregulation of EP4 via activation of STAT3. In Translational cancer research, 12, 1503-1515. doi:10.21037/tcr-22-2552. https://pubmed.ncbi.nlm.nih.gov/37434683/