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Updated: Oct 28, 2025
In vitro Organoid Culture of Primary Mouse Colon Tumors
Published on: May 17, 2013
CD147 receptor is essential for TFF3-mediated signaling regulating colorectal cancer progression
Hong-Yong Cui1, Shi-Jie Wang1, Fei Song1,2
1National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi'an, China.
Abstract:
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.
Insights
Trefoil factor 3 (TFF3) promotes colorectal cancer (CRC) progression and hinders intestinal repair by activating CD147 signaling. Targeting this pathway may offer new therapeutic strategies for gastrointestinal disorders.
Area of Science:
- Molecular mechanisms of cancer biology
- Gastrointestinal disease research
- Cellular repair processes
Background:
- Colorectal cancer (CRC) progression and intestinal repair mechanisms remain incompletely understood.
- Trefoil factor 3 (TFF3) is implicated in CRC and mucosal repair, but its precise roles are unclear.
- Existing knowledge gaps hinder therapeutic development for gastrointestinal disorders.
Purpose of the Study:
- To elucidate the molecular mechanisms by which TFF3 influences colorectal cancer aggressiveness and intestinal mucosal repair.
- To identify novel therapeutic targets for CRC and gastrointestinal disorders based on TFF3 function.
Main Methods:
- Investigated TFF3 expression in CRC and correlated it with patient survival rates.
- Utilized TFF3-deficient models to assess its role in mucosal restitution and tumor development.
- Identified CD147 as a TFF3 binding partner using biochemical and biophysical methods.
- Analyzed downstream signaling pathways including CD147-CD44s interaction, STAT3 activation, and PTGS2 expression.
- Examined the role of prostaglandin E2 (PGE2) and its receptor PTGER4 in TFF3-mediated effects.
- Employed solution NMR to determine the structural basis of TFF3-CD147 interaction.
- Tested the efficacy of inhibiting TFF3-CD147 signaling and PTGS2 in preclinical models of CRC metastasis.
Main Results:
- Upregulated TFF3 in CRC correlates with poorer patient survival.
- TFF3 deficiency impairs intestinal mucosal repair and reduces tumor formation.
- CD147 acts as a receptor for TFF3, enhancing CD147-CD44s interaction.
- TFF3-induced CD147 signaling activates STAT3 and upregulates PTGS2, promoting CRC cell migration, proliferation, and invasion.
- PTGS2-derived PGE2 signaling through PTGER4 contributes to TFF3-driven CRC progression.
- Structural analysis identified key residues for TFF3 binding and PTGS2 induction.
- Inhibiting TFF3-CD147 signaling or PTGS2 significantly reduced CRC lung metastasis in vivo.
Conclusions:
- CD147 is a novel receptor for TFF3, mediating its effects in colorectal cancer and intestinal repair.
- PTGS2 signaling is a critical downstream mediator of TFF3 function in both mucosal restitution and CRC progression.
- Targeting the TFF3-CD147-PTGS2 axis presents a promising therapeutic strategy for colorectal cancer and related gastrointestinal disorders.
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