Abstract
Colorectal cancer is a major health concern as it ranks third in incidence and second major cause of cancer-related deaths worldwide. A leading cause of treatment failure has been attributed to cancer stem cells that can invariably resist existing chemotherapeutic regimens. Notch signaling pathway has been involved in the maintenance of stem cells besides being crucial in cell fate decision and embryonic development. This pathway has also been implicated in several human malignancies including colorectal cancer. We investigated mRNA expression of four Notch receptors (Notch1–4), five ligands (Jag1, Jag2, Dll1, Dll3, and Dll4), and four target genes (Hes1, Hes5, Hey1, and Hey2) using highly specific TaqMan gene expression assays in colorectal adenomas and cancers. Upregulated expression of Notch receptors ranged between 29 and 73% in colorectal cancers and between 11 and 56% in adenomas. Expression of Notch3 and Notch4 receptors was significantly higher in colorectal cancers compared to normal and adenoma tissues. The Jagged and Delta-like ligands were overexpressed between 25 and 52% in colorectal cancers, while in adenomas, it ranged between 0 and 33%. Combining the data for upregulation of receptors and ligands suggests that 86% colorectal cancers and 56% adenomas exhibited overexpression of Notch pathway genes in our cohort. Notch target genes were upregulated between 24 and 33% in colorectal cancers and between 11 and 22% in adenomas. Collating upregulation of Notch receptors and ligands with the target genes showed concordance in 58% colorectal tumors. Additionally, we evaluated expression of Notch receptors, ligands, and target genes with prognosis using the TCGA mRNA expression dataset. Patients overexpressing Notch3, Notch4, and Hey1 had significantly poorer overall survival relative to those having lower levels of these genes. Taken together, Notch signaling components are aberrantly overexpressed in colorectal tumors, and development of therapeutics targeting the Notch pathway may prove to be beneficial in the management of colorectal cancers.
Highlights
Colorectal cancer (CRC) is the second most common cancer in women and ranks third in men worldwide [1]
We investigated the involvement of the Notch signaling pathway in colorectal adenomas and cancers arising in Saudi Arabian patients by examining the expression of Notch receptors, ligands, and target genes
In adenomas, ≥2-fold Notch3 expression was detected in 56% followed by Notch1 (44%), Notch4 (33%), and Notch2 (11%), while for ligand Jag1, mRNA was overexpressed in 33%, Jag2, Dll1, and Dll3 in 11%, whereas Dll4 was not expressed in adenomas
Summary
Colorectal cancer (CRC) is the second most common cancer in women and ranks third in men worldwide [1]. CRC is a group that includes cancers of the colon, rectum, and anus. For both sexes combined, CRC is the third most commonly diagnosed cancer representing 10.2% of the total cases and second leading cause of cancer-related death (9.2%) worldwide in 2018 [1]. In Saudi Arabia, it is the most common cancer in males (19.6%), while in female, it ranks. E cancer-related mortality in Saudi Arabia is highest for patients with CRC accounting for 15.2% of all deaths due to cancer [2]. Is resistance to therapy eventually leading to fatality has been mainly attributed to cancer stem cells (CSCs). Understating the mechanism about how these cells are able to resist existing treatments may lead to the development of new therapies targeting CSCs [4]
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