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.
Highlights
INTRODUCTION While survival rates incolorectal cancer (CRC) have improved, CRC is still one of the leading causes of cancer-related deaths worldwide
Augmented Trefoil factor 3 (TFF3) expression in CRC promotes cancer progression and correlates with poor survival To identify the potential key players in mucosal restitution and CRC progression, we assessed the gene expression pattern in 163 tissue samples from patients with CRC from TCGA and 517 normal colorectal tissue samples derived from TCGA and the GTEx data portal (Supplementary Fig. 1a) and the differentially expressed genes (DEGs) [adjusted p-value < 1e − 20 (n = 5820)] were selected for further investigation of their effects on overall survival (Supplementary Fig. 1b, c)
Using fresh CRC tissues, we identified CD147, a glycosylated protein with a molecular weight in the range of 33 to 66 KDa depending on the degree of glycosylation; CD147 was found to be critical for TFF3-induced cell migration, invasion, metastasis, and proliferation
Summary
INTRODUCTION While survival rates inCRC have improved, CRC is still one of the leading causes of cancer-related deaths worldwide. Increased expression of TFF peptides is observed after injury in the gastrointestinal tract.[1,2] Research suggests that TFF3, which is expressed mainly by intestinal goblet cells, plays an important role in protecting the intestinal mucosa from a variety of injuries and is essential for effective mucosal restitution by facilitating cell migration and inhibiting apoptosis and anoikis.[3] Studies have reported that TFF3 expression is increased during the development and progression of human cancer, including CRC.[4,5] In addition, in vitro studies, have shown that TFF3 stimulates survival, proliferation, invasion, and metastasis, and inhibits apoptosis of CRC cells,[6,7,8,9] indicating that TFF3 regulates key functional characteristics of oncogenesis. The precise molecular mechanism by which TFF3 regulates CRC progression remains unclear
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