Human telomerase reverse transcriptase recruits the β-catenin/TCF-4 complex to transactivate chemokine (C-C motif) ligand 2 expression in colorectal cancer.

Affiliation

Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China. Electronic address: [Email]

Abstract

OBJECTIVE : Various molecular mechanisms are involved in the pathogenesis of colorectal cancer (CRC), one of the leading fatal diseases. Although human telomerase reverse transcriptase (hTERT) is critical in promoting CRC development, its regulatory mechanism is still elusive. Chemokine (C-C motif) ligand 2 (CCL2) is important to CRC pathogenesis, but the upstream regulation of CCL2 requires further investigation. Therefore, we aim to investigate the crosstalk mechanism between hTERT and CCL2 and its involvement in the pathogenesis of CRC.
METHODS : The expression relationship between hTERT and CCL2 was verified in CRC and adjacent tissues by immunohistochemistry. Lentiviruses or plasmids were used to regulate hTERT and CCL2 expression. The roles of hTERT and CCL2 in cell growth and migration were studied using CCK8 and transwell assays. The interaction between hTERT and CCL2 was detected by a luciferase reporter assay, immunofluorescence and ChIP assays. The β-catenin/TCF-4 complex was confirmed by COIP.
RESULTS : Both hTERT and CCL2 expression levels were markedly increased in CRC tissues compared to the adjacent stroma. Moreover, myeloid-derived suppressor cells (MDSCs) were found in tumor areas with higher expression levels of hTERT and CCL2. hTERT promoted HCT116 cell migration and invasion by increasing CCL2 expression. Mechanistically, ectopic hTERT facilitated the nuclear translocation of canonical β-catenin and the formation of a complex with downstream effector TCF-4, which eventually activated the CCL2 promoter.
CONCLUSIONS : hTERT may promote CRC by recruiting β-catenin/TCF-4 complex to transactivate CCL2 expression, which is a novel crosstalk mechanism likely involved in the pathogenesis of CRC.

Keywords

Chemokine (C-C motif) ligand 2,Human telomerase reverse transcriptase,Metastasis,Tumor promotion,Wnt signaling pathway,

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