TYMS-TM4SF4 axis promotes the progression of colorectal cancer by EMT and upregulating stem cell marker.

Abstract

BACKGROUND: The expression of thymidylate synthase (TYMS) is significantly up-regulated in various cancers and associated with the poor prognosis of patients. However, the role of TYMS in the progression of colorectal cancer (CRC) is unclear. METHODS: Cell function assay, biology information analysis, and RNA sequencing were used to investigate the role of TYMS in the progression of CRC and underlining molecular mechanism. SPSS22.0 statistical software and GraphPad Prism 5 (Graphpad software) were used for statistical analysis. RESULTS: Our results showed that TYMS expression was higher in CRC tissues than that in non-tumor colorectal mucosa tissues. TYMS knockdown inhibited the proliferation, migration and invasion of HCT116 and HT29 cells, and the spheroid formation of HCT116 cells. The underling mechanism demonstrated that TYMS promoted the progression of CRC by regulating EMT-related proteins including E-cadherin, Vimentin, MMP-9 and stem cell biomarkers including CD133 and CD44. Furthermore, DEG sequencing showed that TYMS knockdown enriched the pathways of metastasis and metabolism by GO and KEGG analysis. We identified TM4SF4 was the downstream target of TYMS in CRC cells. TM4SF4 overexpression increased migration and invasion of CRC cells by regulating EMT and CD133 expression. CONCLUSIONS: Our findings suggest that TYMS-TM4SF4 axis may promote the progression of CRC by EMT and upregulating stem cell markers.