Enhanced expression of ten‐eleven translocation 1 reverses gemcitabine resistance in cholangiocarcinoma accompanied by a reduction in P‐glycoprotein expression

Abstract

Increasing evidence revealed that ten‐eleven translocation 1 (TET1) plays an important role in tumorigenesis and chemoresistance, but its functions in gemcitabine resistance in cholangiocarcinoma (CCA) remain unknown. This study aims to investigate the effect of TET1 on gemcitabine resistance in CCA and the possible effect on P‐glycoprotein (P‐gp) expression encoded by multidrug resistance (MDR) genes. We established two kinds of gemcitabine‐resistant CCA cell lines and confirmed its specific features. The expression of TET1 and P‐gp was evaluated in gemcitabine‐resistant CCA cells and their parental cells at mRNA and protein level by quantitative RT‐PCR and western blot analysis. After transfecting the gemcitabine‐resistant CCA cell lines with TET1 gene or siRNA, the cell viability test was obtained to verify the effect of TET1 on the sensitivity of CCA cells to gemcitabine. And then, the possible effect of TET1 on the expression of P‐gp was examined by western blot analysis. Xenograft tumor experiment was conducted to confirm the association between TET1 and P‐gp expression under gemcitabine chemoresistance. The associations between clinical outcomes of CCA patients with chemotherapy and TET1 expression were analyzed in 82 patients. The results showed that TET1 expression was significantly decreased, and P‐gp expression was increased in gemcitabine‐resistant CCA cells. Additionally, overexpression of TET1 augmented the sensitivity of CCA cells to gemcitabine and induced the decreased expression of P‐gp in gemcitabine‐resistant CCA cells. Furthermore, multivariate Cox regression analysis indicated that TET1 expression and TNM stage were independent risk factors (P < 0.001) for the clinical outcomes of CCA patients with chemotherapy. Additionally, Kaplan‐Meier survival and the log‐rank test showed that decreased expression of TET1 was associated with poorer prognosis of CCA patients with chemotherapy. These findings suggest that TET1 expression reverses gemcitabine resistance in CCA accompanied by a reduction in P‐gp expression. Thus, TET1 may be a promising target to overcome chemoresistance in CCA.

Prognostic role of high TET1 expression in patients with solid tumors

“…[ 22 ] As a result, SOCS1 dysfunction triggers MMP9 upregulation, which increases HCC cell growth, invasion, and metastasis. [ 22 ] A study from Wang et al [ 11 ] demonstrated that TET1 reverses gemcitabine resistance in cholangiocarcinoma (CCA), with overexpression of TET1 leading to increased sensitivity of CCA cells to gemcitabine. Furthermore, multivariate Cox regression analysis showed that TET1 expression was an independent risk factor ( P < .001) for the clinical results of CCA patients with chemotherapy.…”

“…Furthermore, multivariate Cox regression analysis showed that TET1 expression was an independent risk factor ( P < .001) for the clinical results of CCA patients with chemotherapy. [ 11 ] In addition, Kaplan--Meier survival and the log-rank test showed that decreased expression of TET1 was associated with poorer prognosis of CCA patients with chemotherapy. [ 11 ] Thus, TET1 may be a promising target to overcome chemoresistance in CCA.…”

“…[ 11 ] In addition, Kaplan--Meier survival and the log-rank test showed that decreased expression of TET1 was associated with poorer prognosis of CCA patients with chemotherapy. [ 11 ] Thus, TET1 may be a promising target to overcome chemoresistance in CCA. [ 11 ] Ciesielski et al [ 16 ] also identified TET1 expression in endometrial cancer as an independent prognostic factor.…”

“…Many clinical studies have revealed that the expression of TET1 is closely associated with survival rates in cancer patients with solid tumors, including gastric cancer, [ 15 , 18 , 24 ] cholangiocarcinoma, [ 11 ] hepatocellular cancer, [ 22 ] lung cancer, [ 14 , 21 ] breast cancer, [ 10 , 12 , 17 , 20 ] endometrial cancer, [ 16 ] renal cell cancer, [ 19 ] colorectal cancer, [ 13 ] and ovarian cancer. [ 23 ] Nevertheless, the consistency of the prognostic effect of TET1 remains unclear.…”

Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma

“…However, the literature regarding the use of gene therapy to chemosensitize CCA is scarce. Overexpression of ten-eleven translocation 1 (TET1), a methylcytosine dioxygenase that catalyzes DNA demethylation, enhances the sensitivity of CCA to gemcitabine, accompanied by a decrease in MDR1 expression [67]. In addition, overexpression of miR-199a-3p in the presence of cisplatin could decrease the proliferation rate and increase apoptosis of CCA cells, probably by regulating the expression of its target gene mTOR and reducing that of MRP1 [68].…”