A positive feedback loop between Wnt/β‐catenin signaling and hTERT regulates the cancer stem cell‐like traits in radioresistant nasopharyngeal carcinoma cells

Abstract

Radioresistance may be induced by cancer stem cells (CSCs), while the biological traits of CSCs need to be retained by telomerase. The telomerase activity mainly depends on the transcriptional regulation of human telomerase reverse transcriptase (hTERT). Moreover, Wnt/β‐catenin signaling is also considered essential for maintaining the CSC phenotypes. In the previous study, we discovered that the radioresistant nasopharyngeal carcinoma cells CNE‐2R displayed CSC‐like traits, as well as high expression of hTERT and β‐catenin, but whether hTERT and β‐catenin were involved in regulating the CSC‐like traits and radiosensitivity of CNE‐2R cells remained unclear. In this study, our results suggested that hTERT could positively regulate the expression of CSC‐related proteins, as well as the cytoplasm‐ and nucleus‐β‐catenin, but it could not markedly regulate the expression of total β‐catenin in CNE‐2R cells. Meanwhile, Wnt/β‐catenin signaling had a positive regulatory effect on the expression of hTERT and CSC‐related proteins. Moreover, there was a β‐catenin/hTERT protein complex in CNE‐2R cells, indicating that β‐catenin could directly interact with hTERT protein. Our results also revealed that silencing hTERT or suppressing Wnt/β‐catenin signaling could attenuate telomerase activity and radioresistance of CNE‐2R cells; while suppressing Wnt/β‐catenin signaling, the telomerase activity and radioresistance could be reversed through overexpressing hTERT. Taken together, we have outlined a positive feedback loop between Wnt/β‐catenin signaling and hTERT in CNE‐2R cells, which can regulate the telomerase activity and CSC‐like traits, thus regulating the radiosensitivity. Therefore, blocking Wnt/β‐catenin signaling transduction and interfering with hTERT expression may be a promising approach for targeting radioresistant nasopharyngeal carcinoma cells with CSC‐like traits.

The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development

“…In particular, TERT has been shown to bind SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) factor, which is a chromatin remodeler, and to induce the expression of Wnt-responsive genes such as MYC proto-oncogene (MYC) and the vascular endothelial growth factor (VEGF) thus promoting cell transformation [ 35 , 36 , 37 ]. On the other hand, the Wnt/β-catenin signaling has been reported to regulate the telomerase activity and the acquisition of cancer stem cell-like phenotype in the radioresistant nasopharyngeal carcinoma cell line CNE-2R through a positive feedback loop [ 38 ]. Other non-canonical functions of TERT include the ability to induce overexpression of the epidermal growth factor receptor (EGFR) in human mammary epithelial cells and DNA methyltransferases (DNMTs) in human fibroblasts as well as the downregulation of pro-apoptotic genes in diverse human cancer-derived cell lines [ 39 , 40 , 41 , 42 ].…”

The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development

“…In particular, TERT has been shown to bind SMARCA4 factor, which is a chromatin remodeller, and to induce the expression of Wnt-responsive genes such as MYC and the vascular endothelial growth factor (VEGF) thus promoting cell transformation [35][36][37]. On the other hand, the Wnt/β-catenin signalling has been reported to regulate the telomerase activity and the acquisition of cancer stem cell-like phenotype in the radioresistant nasopharyngeal carcinoma cell line CNE-2R through a positive feedback loop [38]. Other non-canonical functions of TERT include the ability to induce overexpression of the epidermal growth factor receptor (EGFR) in human mammary epithelial cells and DNA methyltransferases (DNMTs) in human fibroblasts as well as downregulation of proapoptotic genes in diverse human cancer derived cell lines [39][40][41][42].…”

Abnormal Glycosylation of Cancer Stem Cells and Targeting Strategies

“…Expression of ST6 beta-galactoside alpha-2,6-sialyltransferase 1(ST6GAL1), which adds alpha2-6 lined sialic acid to glycosylated protein, is also upregulated in cancer malignancies specially in CSCs (79,80). ST6GAL1 expression corelated with other CSC markers in colorectal carcinoma (38,39) Renewal, cell proliferation and differentiation (27,40) samples from patient and induced chemoresistance (81). In ovarian cancer, ST6GAL1 expression is regulated by SOX2, a well-known stem cell transcription factor (82).…”