Activation of Wnt/β-catenin signalling pathway induces chemoresistance to interferon-α/5-fluorouracil combination therapy for hepatocellular carcinoma

Abstract

Type I IFN receptor type 2 (IFNAR2) expression correlates significantly with clinical response to interferon (IFN)-a/5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC). However, some IFNAR2-positive patients show no response to the therapy. This result suggests the possibility of other factors, which would be responsible for resistance to IFN-a/5-FU therapy. The aim of this study was to examine the mechanism of anti-proliferative effects of IFN-a/5-FU therapy and search for a biological marker of chemoresistance to such therapy. Gene expression profiling and molecular network analysis were used in the analysis of nonresponders and responders with IFNAR2-positive HCC. The Wnt/b-catenin signalling pathway contributed to resistance to IFN-a/ 5-FU therapy. Immunohistochemical analysis showed positive epithelial cell adhesion molecule (Ep-CAM) expression, the target molecule of Wnt/b-catenin signalling, only in non-responders. In vitro studies showed that activation of Wnt/b-catenin signalling by glycogen synthesis kinase-3 inhibitor (6-bromoindirubin-3 0 -oxime (BIO)) induced chemoresistance to IFN-a/5-FU. BrdU-based cell proliferation ELISA and cell cycle analysis showed that concurrent addition of BIO and IFN-a/5-FU significantly to hepatoma cell cultures reduced the inhibitory effects of the latter two on DNA synthesis and accumulation of cells in the S-phase. The results indicate that activation of Wnt/b-catenin signalling pathway induces chemoresistance to IFN-a/5-FU therapy and suggest that Ep-CAM is a potentially useful marker for resistance to such therapy, especially in IFNAR2-positive cases.

Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade

“…Our results obtained by evaluation of cell cycle kinetics revealed that cells with high Smad4 expression were arrested in the G2-M phase under 5-FU treatment, owing to inhibition of the CDC2/cyclin B/survivin cascade. Accumulation of cells in the G1/S phase may result in resistance to 5-FU treatment, which is consistent with previous studies (34)(35)(36). Smad4 reduced the CDC2/cyclin B complex and survivin in both the CT26 and SW620 cells, through the downregulation of the PI3K/Akt pathway, resulting in cell cycle arrest and cell apoptosis.…”

Ep-CAM is a significant prognostic factor in pancreatic cancer patients by suppressing cell activity

“…In this study, we divided enrolled patients into Ep-CAM high and low-expression group by four of Ep-CAM expression scoring and this cut-off line was based on the previous reports (Gastl et al, 2000;Varga et al, 2004;Fong et al, 2008;Noda et al, 2009). However, as shown in Figure 2, it might not be appropriate to set the cut-off line at four because there were many patients scoring between 4 and 6.…”

“…Immunohistochemistry and evaluation of staining For immunohistochemical staining of Ep-CAM expression, we used the method as previously described (Noda et al, 2009). For negative controls, sections were treated the same way except that they were incubated with Tris-buffered saline instead of the primary antibody and normal pancreatic duct epithelium present in each section and Ep-CAM-transfected pancreatic cancer cell lines (MiaPaCa-2 and PSN1) were used as positive controls.…”

“…In brief, the proportion score described the estimated fraction of positively stained tumor cells (0, none; 1, o10%; 2, 10-50%; 3, 50-80% and 4, 480%) and the intensity score represented the estimated staining intensity (0, no staining; 1, weak; 2, moderate; 3, strong). The total score was ranging from 0 to 12, and Ep-CAM positive cases represented those with a total score 44 according to previous reported creiteria (Gastl et al, 2000;Varga et al, 2004;Fong et al, 2008;Noda et al, 2009). For the evaluation of heterogeneity in pancreatic cancer, the average score of triplicate tissues from each patient was used.…”

Glycogen synthase kinase 3β inhibitor (2′Z,3′E)-6-bromo-indirubin-3′-oxime enhances drug resistance to 5-fluorouracil chemotherapy in colon cancer cells

“…However, inhibition of GSK-3β leads to cell-cycle progression and resistance to apoptosis in other certain  www.cjcrbj.com types of tumors. What is more, emerging evidence indicated that some GSK-3β inhibitors influenced chemotherapy sensitivity [9,10] . Therefore, the function of GSK-3β and clinical application of GSK-3β inhibitors need to be carefully investigated for the potential harmful effects.…”