Katsumi Terashita1, Makoto Chuma2, Yutaka Hatanaka3, Kanako Hatanaka3, Tomoko Mitsuhashi3, Hideki Yokoo4, Takumi Ohmura5, Hiroyuki Ishizu6, Shunji Muraoka7, Atsushi Nagasaka8, Takahiro Tsuji9, Yoshiya Yamamoto10, Nobuaki Kurauchi11, Norihiko Shimoyama12, Hidenori Toyoda13, Takashi Kumada13, Yuji Kaneoka14, Atsuyuki Maeda14, Koji Ogawa1, Mitsuteru Natsuizaka1, Hirofumi Kamachi4, Tatsuhiko Kakisaka4, Toshiya Kamiyama4, Akinobu Taketomi4, Yoshihiro Matsuno3, Naoya Sakamoto1. 1. Departments of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan. 2. Departments of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan. 3. Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan. 4. Department of Gastroenterological Surgery I, Hokkaido University Hospital, Sapporo, Japan. 5. Department of Gastroenterology, Sapporo-Kosei General Hospital, Sapporo, Japan. 6. Department of Surgery, Sapporo-Kosei General Hospital, Sapporo, Japan. 7. Department of Pathology, Sapporo-Kosei General Hospital, Sapporo, Japan. 8. Department of Gastroenterology, Sapporo Municipal Hospital, Sapporo, Japan. 9. Department of Pathology, Sapporo Municipal Hospital, Sapporo, Japan. 10. Department of Gastroenterology, Hakodate Municipal Hospital, Hakodate, Japan. 11. Department of Surgery, Hakodate Municipal Hospital, Hakodate, Japan. 12. Department of Pathology, Hakodate Municipal Hospital, Hakodate, Japan. 13. Departments of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan. 14. Department of Surgery, Ogaki Municipal Hospital, Ogaki, Japan.
Abstract
BACKGROUND/AIM: Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignant tumours, so the identification of molecular targets for ICC is an important issue. Zinc finger E-box binding homeobox 1 (ZEB1) is a key inducer of epithelial-mesenchymal transition (EMT). The aim of the present study was to clarify the clinical significance of ZEB1 in ICC and the associations between ZEB1 expression and EMT-related proteins. METHODS: We immunohistochemically examined the expression of EMT-related proteins, namely ZEB1, vimentin and E-cadherin, in ICC specimens from 102 patients. The clinicopathological and prognostic values of these markers were evaluated. RESULTS: ZEB1 and vimentin were expressed in 46.1% and 43.1% of tumours, respectively, and E-cadherin expression was lost in 44.1% of tumours. ZEB1 expression showed a significant inverse correlation with E-cadherin expression (p=0.004) and a positive correlation with vimentin expression (p=0.022). Altered expression of ZEB1 was associated with aggressive tumour characteristics, including advanced tumour stage (p=0.037), undifferentiated-type histology (p=0.017), lymph node metastasis (p=0.024) and portal vein invasion (p=0.037). Moreover, overall survival rates were significantly lower for patients with high ZEB1 expression than for patients with low ZEB1 expression (p=0.027). Kaplan-Meier analysis also identified E-cadherin expression (p=0.041) and vimentin expression (p=0.049) as prognostic indicators for overall survival. CONCLUSIONS: ZEB1 expression is associated with tumour progression and poor prognosis in patients with ICC through positive correlations with vimentin and negative correlations with E-cadherin. ZEB1 expression is associated with a poor prognosis and might be an attractive target for the treatment of ICC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
BACKGROUND/AIM: Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignant tumours, so the identification of molecular targets for ICC is an important issue. Zinc finger E-box binding homeobox 1 (ZEB1) is a key inducer of epithelial-mesenchymal transition (EMT). The aim of the present study was to clarify the clinical significance of ZEB1 in ICC and the associations between ZEB1 expression and EMT-related proteins. METHODS: We immunohistochemically examined the expression of EMT-related proteins, namely ZEB1, vimentin and E-cadherin, in ICC specimens from 102 patients. The clinicopathological and prognostic values of these markers were evaluated. RESULTS:ZEB1 and vimentin were expressed in 46.1% and 43.1% of tumours, respectively, and E-cadherin expression was lost in 44.1% of tumours. ZEB1 expression showed a significant inverse correlation with E-cadherin expression (p=0.004) and a positive correlation with vimentin expression (p=0.022). Altered expression of ZEB1 was associated with aggressive tumour characteristics, including advanced tumour stage (p=0.037), undifferentiated-type histology (p=0.017), lymph node metastasis (p=0.024) and portal vein invasion (p=0.037). Moreover, overall survival rates were significantly lower for patients with high ZEB1 expression than for patients with low ZEB1 expression (p=0.027). Kaplan-Meier analysis also identified E-cadherin expression (p=0.041) and vimentin expression (p=0.049) as prognostic indicators for overall survival. CONCLUSIONS:ZEB1 expression is associated with tumour progression and poor prognosis in patients with ICC through positive correlations with vimentin and negative correlations with E-cadherin. ZEB1 expression is associated with a poor prognosis and might be an attractive target for the treatment of ICC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Entities:
Keywords:
CHOLANGIOCARCINOMA; IMMUNOHISTOCHEMISTRY; LIVER CANCER