P-205 - mRNA level of the key components of the Notch signaling pathway in colorectal cancer

Date 04 July 2015
Event WorldGI 2015
Session Posters
Topics Colon and Rectal Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter O. Kowalczuk
Citation Annals of Oncology (2015) 26 (suppl_4): 1-100. 10.1093/annonc/mdv233
Authors O. Kowalczuk1, J. Zurawska2, J. Kisluk1
  • 1Medical University of Białystok, Białystok/PL
  • 2Medical University of Bialystok, Bialystok/PL

Abstract

Introduction

Notch signaling is up-regulated in different malignancies and seems to be involved in tumorigenesis. Their status in colorectal cancer (CRC) remains poorly investigated. We aimed to examine a transcriptional activity of the genes encoding key components of the Notch signaling in surgical CRC samples.

Methods

Specimens of tumors and corresponding normal colon mucosa tissues were collected intraoperationally from 65 CRC patients and used to extract RNA. mRNA for a receptor NOTCH1, ligands Jagged1, Jagged2, DLL1, DLL4 and downstream signaling target transcription factor HES1 was quantified by real-time PCR method and expressed as a fold-change (FC) between tumor and normal colon tissues.

Results

A significant increase in mRNA level in tumor compared to a matched unaffected colon tissue was observed for all analyzed genes (P < 0.001 in all cases). A strong correlation between the transcriptional activity of the particular genes was found, suggesting common patterns of their regulation (P < 0.001 in all cases). The most prominent differences in transcription were observed in the case of NOTCH1 and DLL4 genes (median log2(FC) 4.97 and 5.22; 25%-75% intervals 0.81-8.89 and 1.71-8.38 for NOTCH1 and DLL4, respectively). About 16-fold increase in HES1 mRNA level was also found (median log2(FC) 3.97; 25%-75% interval 1.07-6.04), while in the case of DLL1 and Jagged1 genes the activation was lower (median log2(FC) 3.03 and 2.97; 25%-75% intervals 0.07-5.80 and 0.41-6.58 for DLL1 and Jagged1, respectively). Jagged2 gene was found to be the least significantly upregulated gene in the analyzed tumors (median log2(FC) 1.88; 25%-75% interval (-)1.47-5.35).

No significant associations between mRNA level of the analyzed genes and patients' clinicopathological characteristics (sex, age, tumor histological type and localization, pathological stage, lymph node and distant metastases) were found with the exception of the NOTCH1 for which expression level depended on tumor histology and localization (P = 0.063 and P = 0.049, respectively).

Conclusion

Characteristic for CRC activation of the Notch signaling at least partially results from the transcriptional activation of the genes that encode the components of the pathway. This activation constitutes a common and probably early event in colorectal carcinogenesis. Similar molecular mechanisms may be involved in the regulation of the activity of Notch signaling genes. Although all the ligands for the pathway are over-represented in tumor tissue, DLL4 seems to play the most prominent role, while Jagged2 may be less frequently used for signaling.