Notch Signaling Pathway in Cancer-Review with Bioinformatic Analysis

Abstract

Notch signaling is an evolutionarily conserved pathway regulating normal embryonic development and homeostasis in a wide variety of tissues. It is also critically involved in carcinogenesis, as well as cancer progression. Activation of the Notch pathway members can be either oncogenic or suppressive, depending on tissue context. The present study is a comprehensive overview, extended with a bioinformatics analysis of TCGA cohorts, including breast, bladder, cervical, colon, kidney, lung, ovary, prostate and rectum carcinomas. We performed global expression profiling of the Notch pathway core components and downstream targets. For this purpose, we implemented the Uniform Manifold Approximation and Projection algorithm to reduce the dimensions. Furthermore, we determined the optimal cutpoint using Evaluate Cutpoint software to established disease-free and overall survival with respect to particular Notch members. Our results demonstrated separation between tumors and their corresponding normal tissue, as well as between tumors in general. The differentiation of the Notch pathway, at its various stages, in terms of expression and survival resulted in distinct profiles of biological processes such as proliferation, adhesion, apoptosis and epithelial to mesenchymal transition. In conclusion, whether oncogenic or suppressive, Notch signaling is proven to be associated with various types of malignancies, and thus may be of interest as a potential therapeutic target.

Keywords: Notch signaling; carcinogenesis; global signaling.

Figure 1

Spatial profiling of BLCA, BRCA, CESC, COAD, KICH, KIRC, KIRP, LUAD, LUSC, OV, PRAD, READ and UCEC accompanied by normal tissue samples with respect to expression of Notch core components. Tumors are designated with a “c” ending, while normal tissues are designated with an “n” ending.

Figure 2

Heatmap reflecting the differential median expression of the Notch core components in the analyzed cancers and normal tissues: (A) ligands and receptors; (B) modulators.

Figure 3

Heatmap reflecting the differential median expression of the Notch core components in the analyzed cancers and normal tissues: (A) signal transductors; (B) transcription factors.

Figure 4

Spatial profiling of BLCA, BRCA, CESC, COAD, KICH, KIRC, KIRP, LUAD, LUSC, OV, PRAD, READ and UCEC, accompanied by normal tissue samples, with respect to expression of the Notch target genes. Tumors are designated with “c” endings, while normal tissues are designated with “n” endings.

Figure 5

Heatmap reflecting differential median gene expression of Notch target genes in the analyzed cancerous and normal tissues. Target genes are grouped into four biological processes: (A) Adhesion; (B) Apoptosis.

Figure 6

Heatmap reflecting differential median gene expression of Notch target genes in the analyzed cancerous and normal tissues. Target genes are grouped into four biological processes: (A) EMT; (B) Proliferation.