TY - JOUR
T1 - Activation of WntΒ-catenin signalling pathway induces chemoresistance to interferon-α5-fluorouracil combination therapy for hepatocellular carcinoma
AU - Noda, T.
AU - Nagano, H.
AU - Takemasa, I.
AU - Yoshioka, S.
AU - Murakami, M.
AU - Wada, H.
AU - Kobayashi, S.
AU - Marubashi, S.
AU - Takeda, Y.
AU - Dono, K.
AU - Umeshita, K.
AU - Matsuura, N.
AU - Matsubara, K.
AU - Doki, Y.
AU - Mori, M.
AU - Monden, M.
N1 - Funding Information:
This work was supported by a grant-in-aid for cancer research from the Ministry of Culture and Science, the Ministry of Health, Labour and Welfare in Japan.
PY - 2009/5/19
Y1 - 2009/5/19
N2 - Type I IFN receptor type 2 (IFNAR2) expression correlates significantly with clinical response to interferon (IFN)-α5-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-α5-FU therapy. The aim of this study was to examine the mechanism of anti-proliferative effects of IFN-α5-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 non-responders and responders with IFNAR2-positive HCC. The WntΒ-catenin signalling pathway contributed to resistance to IFN-α5-FU therapy. Immunohistochemical analysis showed positive epithelial cell adhesion molecule (Ep-CAM) expression, the target molecule of WntΒ-catenin signalling, only in non-responders. In vitro studies showed that activation of WntΒ-catenin signalling by glycogen synthesis kinase-3 inhibitor (6-bromoindirubin-3′-oxime (BIO)) induced chemoresistance to IFN-α5-FU. BrdU-based cell proliferation ELISA and cell cycle analysis showed that concurrent addition of BIO and IFN-α5-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 WntΒ-catenin signalling pathway induces chemoresistance to IFN-α5-FU therapy and suggest that Ep-CAM is a potentially useful marker for resistance to such therapy, especially in IFNAR2-positive cases.
AB - Type I IFN receptor type 2 (IFNAR2) expression correlates significantly with clinical response to interferon (IFN)-α5-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-α5-FU therapy. The aim of this study was to examine the mechanism of anti-proliferative effects of IFN-α5-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 non-responders and responders with IFNAR2-positive HCC. The WntΒ-catenin signalling pathway contributed to resistance to IFN-α5-FU therapy. Immunohistochemical analysis showed positive epithelial cell adhesion molecule (Ep-CAM) expression, the target molecule of WntΒ-catenin signalling, only in non-responders. In vitro studies showed that activation of WntΒ-catenin signalling by glycogen synthesis kinase-3 inhibitor (6-bromoindirubin-3′-oxime (BIO)) induced chemoresistance to IFN-α5-FU. BrdU-based cell proliferation ELISA and cell cycle analysis showed that concurrent addition of BIO and IFN-α5-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 WntΒ-catenin signalling pathway induces chemoresistance to IFN-α5-FU therapy and suggest that Ep-CAM is a potentially useful marker for resistance to such therapy, especially in IFNAR2-positive cases.
UR - http://www.scopus.com/inward/record.url?scp=67349198077&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67349198077&partnerID=8YFLogxK
U2 - 10.1038/sj.bjc.6605064
DO - 10.1038/sj.bjc.6605064
M3 - Article
C2 - 19401692
AN - SCOPUS:67349198077
SN - 0007-0920
VL - 100
SP - 1647
EP - 1658
JO - British journal of cancer
JF - British journal of cancer
IS - 10
ER -
