TFF3 promotes clonogenic survival of colorectal cancer cells through upregulation of EP4 via activation of STAT3

Abstract

Background While growing evidence indicates the importance of TFF3 in cancer, the molecular mechanism of its action in cancer remains largely unknown. Clonogenic survival is a key ability for tumor cells, which is interpreted as a trait of cancer cells with tumor-initiating capabilities. We investigated the effect and the underlying mechanisms of TFF3 on the clonogenic survival of colorectal cancer (CRC) cells. Methods Expression of TFF3 in CRC tissues and matched paracancerous tissues was determined by western blotting. Colony formation assays were performed to evaluate the clonogenic survival ability of CRC cells. PTGER4 mRNA expression was detected by quantitative polymerase chain reaction. PTGER4 promoter activity was determined by luciferase reporter assay. STAT3 nuclear localization was investigated using immunofluorescence staining. Expression of TFF3 and EP4 in CRC tissues was determined by immunohistochemistry. Results TFF3 knockout led to decreased clonogenic survival of CRC cells, while overexpression of TFF3 resulted in the opposite effect. EP4 was found to be upregulated by TFF3 at both the mRNA and protein level. Moreover, EP4 antagonist abrogated TFF3-mediated clonogenic survival of CRC cells. PGE2 and EP4 agonist could restore the effect of TFF3 knockout on the clonogenic survival of CRC cells. Furthermore, TFF3 promoted STAT3 activation and nuclear localization. Activated STAT3 bound to PTGER4 promoter, the gene encoding for EP4, and facilitated PTGER4 transcription. Conclusions TFF3 promotes clonogenic survival of CRC cells via upregulating EP4 expression.

Detecting phenotype-specific tumor microenvironment by merging bulk and single cell expression data to spatial transcriptomics

“…CEACAM5 is overexpressed in nearly 70 percent of epithelial malignancies including colorectal cancer (CRC) ( [49]) and has lead to the growth of a novel antibody-drug for the treatment of CEACAM5-positive Epithelial Tumors ( [50]). TFF3 is recently demonstrated to be a promoter of clonogenic survival in CRC cells ( [51]). Many genes are particularly upregulated DEGs detected in Tumor MUC2+, including genes associated with the immune system such as IGKC and IGHCA1, and genes related to heavy metal processing such as MT1G and MT1E.…”