Brief Article
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World J Gastroenterol. Sep 21, 2011; 17(35): 4023-4030
Published online Sep 21, 2011. doi: 10.3748/wjg.v17.i35.4023
Clinicopathological significance of altered Notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma
Hyun Ah Yoon, Myung Hwan Noh, Byung Geun Kim, Ji Sun Han, Jin Seok Jang, Seok Ryeol Choi, Jin Sook Jeong, Jin Ho Chun
Hyun Ah Yoon, Myung Hwan Noh, Byung Geun Kim, Ji Sun Han, Jin Seok Jang, Seok Ryeol Choi, Department of Gastroenterology, Dong-A University Hospital, 3-1, Dong dae shin-dong, Seo-gu, Busan 602-715, South Korea Jin Sook Jeong, Department of Pathology, Dong-A University Hospital, 3-1, Dong dae shin-dong, Seo-gu, Busan 602-715, South Korea
Jin Ho Chun, Department of Preventive Medicine, Inje University Hospital, Gae gum 2-dong, Busanjingu, Busan 614-735, South Korea
Author contributions: Yoon HA, Noh MH and Jeong JS designed the study and collected the data; Kim BG, Han JS, Jang JS and Choi SR contributed to the analysis of the clinical data; Chun JH assisted in interpretation of statistical analysis; Jeong JS was involved in analysis and interpretation of histological data, and critical revision of the manuscript; Yoon HA wrote the manuscript; Noh MH was involved in study supervision and drafting the manuscript.
Correspondence to: Myung Hwan Noh, MD, PhD, Department of Gastroenterology, College of Medicine, Dong-A University, 3-1, Dong Dae Shin-dong, Seo-gu, Busan 602-715, South Korea.
Telephone: +82-51-2402862 Fax: +82-51-2425852
Received: November 12, 2010
Revised: January 11, 2011
Accepted: January 18, 2011
Published online: September 21, 2011

AIM: To investigate the role and clinicopathological significance of aberrant expression of Notch receptors and Delta-like ligand-4 (DLL4) in extrahepatic cholangiocarcinoma and gallbladder carcinoma.

METHODS: One hundred and ten patients had surgically resected extrahepatic cholangiocarcinoma (CC) and gallbladder carcinoma specimens examined by immunohistochemistry of available paraffin blocks. Immunohistochemistry was performed using anti-Notch receptors 1-4 and anti-DLL4 antibodies. We scored the immunopositivity of Notch receptors and DLL4 expression by percentage of positive tumor cells with cytoplasmic expression and intensity of immunostaining. Coexistent nuclear localization was evaluated. Clinicopathological parameters and survival data were compared with the expression of Notch receptors 1-4 and DLL4.

RESULTS: Notch receptor proteins showed in the cytoplasm with or without nuclear expression in cancer cells, as well as showing weak cytoplasmic expression in non-neoplastic cells. By semiquantitative evaluation, positive immunostaining of Notch receptor 1 was detected in 96 cases (87.3%), Notch receptor 2 in 97 (88.2%), Notch receptor 3 in 97 (88.2%), Notch receptor 4 in 103 (93.6), and DLL4 in 84 (76.4%). In addition, coexistent nuclear localization was noted [Notch receptor 1; 18 cases (18.8%), Notch receptor 2; 40 (41.2%), Notch receptor 3; 32 (33.0%), Notch receptor 4; 99 (96.1%), DLL4; 48 (57.1%)]. Notch receptor 1 expression was correlated with advanced tumor, node, metastasis (TNM) stage (P = 0.043), Notch receptor 3 with advanced T stage (P = 0.017), tendency to express in cases with nodal metastasis (P = 0.065) and advanced TNM stage (P = 0.052). DLL4 expression tended to be related to less histological differentiation (P = 0.095). Coexistent nuclear localization of Notch receptor 3 was related to no nodal metastasis (P = 0.027) and Notch receptor 4 with less histological differentiation (P = 0.036), while DLL4 tended to be related inversely with T stage (P = 0.053). Coexistent nuclear localization of DLL4 was related to poor survival (P = 0.002).

CONCLUSION: Aberrant expression of Notch receptors 1 and 3 play a role during cancer progression, and cytoplasmic nuclear coexistence of DLL4 expression correlates with poor survival in extrahepatic CC and gallbladder carcinoma.

Keywords: Notch receptors, Delta-like ligand-4, Cholangiocarcinoma, Gallbladder carcinoma, Immunohistochemistry