Published online Jul 14, 2020. doi: 10.3748/wjg.v26.i26.3814
Peer-review started: February 26, 2020
First decision: March 18, 2020
Revised: May 18, 2020
Accepted: June 25, 2020
Article in press: June 25, 2020
Published online: July 14, 2020
The advances in immunohistochemical and molecular techniques in recent years, many studies have been carried out, aiming to determine new targets that can be useful in the treatment as well as predicting colorectal carcinoma (CRC) behavior. In this context, the role of Notch-1 in oncogenesis, tumor behavior, and survival have been investigated in recent studies with different results.
The contribution of Numb, Itch and Siah-1 in the Notch pathway is documented. On the other hand, the roles of Numb, Itch and Siah-1 expression in colorectal carcinogenesis and their relationship to tumor behavior, survival, Notch-1 expression have not been evaluated.
In this preliminary study, we aimed to evaluate the expression of Numb, Itch, and Siah-1 in colorectal tumors to clarify their relationship with Notch-1 expression and their role in carcinogenesis and tumor behavior.
We retrospectively investigated the expression of Notch, Numb, Itch and Siah-1 in 50 colorectal adenocarcinomas, 30 adenomas, and 10 healthy colon tissue by immunohistochemistry and quantitative real-time PCR analysis. Data were analyzed by the χ2 test, t-test and Spearman’s correlation test. Survival probability curves were calculated using the Kaplan-Meier method. A Cox proportional hazards regression model was applied for multivariate analysis. A P value < 0.05 was considered to be significant.
Notch-1 staining was more frequent in CRC than in adenomas and controls. However, the frequency of Numb, Itch, and Siah-1 staining was higher in controls and adenomas. While the expression of Notch-1 was more frequently observed in tumors with poor histological grade, lymph node metastasis, and an advanced stage, the expression of Numb, Itch, and Siah-1 was more frequent in tumors with well-differentiated morphology, without lymph node metastasis, and at an earlier stage. Although the survival of patients with Notch-1 expression was shorter than that among those without Notch-1 expression, Numb, Itch, and Siah-1 expression was related to better survival. Similarly, it was noted that the gene expression levels of Notch, Numb, Itch and Siah-1 were in line with the results of the immunohistochemical evaluation. The status of Notch-1, Numb, Itch, and Siah-1 expression and their expression levels, as well as lymph node metastasis and stage, were found to be significantly associated with survival. Cox regression analysis revealed that lymph node metastasis, upregulation of Notch, and downregulation of Numb were independent prognostic factors. The Notch-1 expression correlated inversely with the levels of Numb, Itch and Siah-1 expression.
Our findings support the role of Notch-1 in CRC and indicate that loss of Numb, Itch, and Siah-1 expression is associated with carcinogenesis. Our data also highlight that Numb, Itch, and Siah-1 might contribute to the Notch-1 signaling pathway during CRC progression. Therefore, these three proteins might be key in possible therapies targeting Notch-1 in the treatment of CRC.
In CRC, Numb, Itch and Siah-1 contribute to carcinogenesis and tumor behavior. In contrast to Notch-1, the relationship of Numb, Itch and Siah-1 expression with better prognostic parameters and improved survival can make them a potential therapeutic target. In this regard, further studies in large patient series and cell cultures can provide comprehensive information on the efficacy of the Notch pathway in therapy.