Expression of Notch pathway components (Numb, Itch, and Siah-1) in colorectal tumors: A clinicopathological study

BACKGROUND The role of the Notch pathway in carcinogenesis and tumor progression has been demonstrated in many organs, including the colon. Accordingly, studies aimed at developing therapies targeting this pathway in various cancers require the identification of several factors that may play a role in regulating Notch-1 expression. Although Numb, Itch, and seven in absentia homolog-1 (Siah-1) have been shown to contribute to the regulation of Notch signaling, their role in colorectal carcinogenesis and tumor progression has not been fully elucidated to date. AIM To evaluate Numb, Itch, and Siah-1 expression in colorectal tumors to clarify their relationship with Notch-1 expression and their role in carcinogenesis and tumor behavior. METHODS Expression of Notch-1, Numb, Itch, and Siah-1 was investigated in 50 colorectal carcinomas, 30 adenomas, and 20 healthy colonic tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR) analyses. RESULTS In contrast to Notch-1, which is expressed at higher levels in tumor tissues and adenomas, expression of Numb, Itch, and Siah-1 was stronger and more frequent in normal mucosa (P < 0.01). There was a positive correlation between Notch-1 expression and high histological grade, the presence of lymph node metastasis, and advanced-stage tumors, whereas expression of Numb, Itch, and Siah-1 was absent or reduced in tumors with these clinicopathological parameters (P < 0.05). In survival analysis, expression of Notch was related to poor prognosis but that of Numb, Itch, and Siah-1 correlated with improved survival (P < 0.05). Multivariate analysis revealed Notch-1 expression and loss of Numb expression to be independent prognostic parameters together with lymph node metastasis (P < 0.05). CONCLUSION Our findings support the role of Notch-1 in colorectal carcinoma and indicate that loss of Numb, Itch, and Siah-1 expression is associated with carcinogenesis. Our data also suggest that these three proteins might be involved in the Notch-1 pathway during colorectal carcinoma (CRC) progression and might play an essential role in approaches targeting Notch as novel molecular therapies for CRC.