CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression

Cui，Hong Yong1; Wang，Shi Jie1; Song，Fei1,2; Cheng，Xu3; Nan，Gang1; Zhao，Yu1; Qian，Mei Rui1; Chen，Xi1,4; Li，Jia Yue1; Liu，Fen Ling1; Zhu，Yu Meng1; Tian，Ruo Fei1; Wang，Bin1; Wu，Bin5; Zhang，Yang1; Sun，Xiu Xuan1; Guo，Ting1; Yang，Xiang Min1; Zhang，Hai1; Li，Ling1; Xu，Jing1,6; Bian，Hui Jie1; Jiang，Jian Li1; Chen，Zhi Nan1

2021-12-01

10.1038/s41392-021-00677-2

Signal Transduction and Targeted Therapy   影响因子和分区

2095-9907

2059-3635

Major gaps in understanding the molecular mechanisms of colorectal cancer (CRC) progression and intestinal mucosal repair have hampered therapeutic development for gastrointestinal disorders. Trefoil factor 3 (TFF3) has been reported to be involved in CRC progression and intestinal mucosal repair; however, how TFF3 drives tumors to become more aggressive or metastatic and how TFF3 promotes intestinal mucosal repair are still poorly understood. Here, we found that the upregulated TFF3 in CRC predicted a worse overall survival rate. TFF3 deficiency impaired mucosal restitution and adenocarcinogenesis. CD147, a membrane protein, was identified as a binding partner for TFF3. Via binding to CD147, TFF3 enhanced CD147-CD44s interaction, resulting in signal transducer and activator of transcription 3 (STAT3) activation and prostaglandin G/H synthase 2 (PTGS2) expression, which were indispensable for TFF3-induced migration, proliferation, and invasion. PTGS2-derived PGE2 bound to prostaglandin E2 receptor EP4 subtype (PTGER4) and contributed to TFF3-stimulated CRC progression. Solution NMR studies of the TFF3-CD147 interaction revealed the key residues critical for TFF3 binding and the induction of PTGS2 expression. The ability of TFF3 to enhance mucosal restitution was weakened by a PTGS2 inhibitor. Blockade of TFF3-CD147 signaling using competitive inhibitory antibodies or a PTGS2 inhibitor reduced CRC lung metastasis in mice. Our findings bring strong evidence that CD147 is a novel receptor for TFF3 and PTGS2 signaling is critical for TFF3-induced mucosal restitution and CRC progression, which widens and deepens the understanding of the molecular function of trefoil factors.

SCI

英语

其他

WOS:000675240800002

2-s2.0-85109961104

Scopus

1.National Translational Science Center for Molecular Medicine and Department of Cell Biology,Fourth Military Medical University,Xi’an,China
2.Department of Urology,Shenzhen Institute of Translational Medicine,The First Affiliated Hospital of Shenzhen University,Shenzhen Second People’s Hospital,Shenzhen,China
3.Medical Research Institute,School of Medicine,Wuhan University,Wuhan,China
4.College of Chemistry and Materials Science,Northwest University,Xi’an,China
5.National Facility for Protein Science Shanghai,Zhangjiang Lab,Shanghai Advanced Research Institute,Chinese Academy of Sciences,Shanghai,China
6.Medical Research Center,Southern University of Science and Technology Hospital,Shenzhen,China

Cui，Hong Yong,Wang，Shi Jie,Song，Fei,et al. CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression[J]. Signal Transduction and Targeted Therapy,2021,6(1).

Cui，Hong Yong.,Wang，Shi Jie.,Song，Fei.,Cheng，Xu.,Nan，Gang.,...&Chen，Zhi Nan.(2021).CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression.Signal Transduction and Targeted Therapy,6(1).

Cui，Hong Yong,et al."CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression".Signal Transduction and Targeted Therapy 6.1(2021).