Notch signaling and the role of Notch/Skp2 axis in the tumorigenesis of Medulloblastoma

Abstract

Medulloblastoma is an embryonic neuroepithelial tumor originating from neural stem/ progenitor cells or Granular Precursor Cells (GPCs) in the embryonic layer of developing cerebellum. Medulloblastoma is the most common childhood malignant brain tumor with a higher incidence between 1 and 9 years of age and accounts for 25% of cancer-related deaths among children. In Medulloblastoma, studies have shown that important development pathways such as WNT, Sonic Hedgehog (SHH) and Notch are related to the tumorigenic process and these pathways may be acting in an interrelated way, as co-expression networks, for the development of Medulloblastoma. Notch signaling is critical for differentiation and proliferation and has a role in the initiation and progression of Medulloblastoma regulating downstream effectors, e.g. MYC. In the normal cerebellum, Notch2 is highly expressed in the proliferating cells of the external granular layer during the postnatal period and presents low expression when the GPCs leave the cell cycle and begin to differentiate. The Notch pathway regulates the transcription of several target genes. In 2005, researchers found that the Notch pathway activates the transcription of a cell cycle-related molecule called phase kinase-associated protein 2 (Skp2). The Skp2 overexpression was associated with late metastasis to the lymph nodes, leading to worse survival in colorectal cancer and Ma et al. demonstrated that the Skp2 overexpression was associated with a significant lower cell differentiation and patient survival in gastric cancer. Studies have described that the high expression of Skp2 is related to tumor metastasis in melanoma, oral squamous cell carcinoma, pancreatic cancer, prostate cancer and others. However, there are no studies investigating the Notch/Skp2 axis and its role in the tumorigenesis of Medulloblastoma. Skp2 is a member of the F-box family of substrate recognition subunits that participates in the ubiquitin E3 ligase SCF complex (Skp1-Culina1-F-Box) and this family of E3 ligases belongs to the Ubiquitin Proteasome System (UPS). There are three types of enzymes in the UPS: the ubiquitin activating enzyme (E1), the conjugating enzyme (E2), and the ubiquitin ligase (E3). In general, the specificity of the target protein is defined by E3, resulting in the its degradation, in an ATP-dependent way, by the 26S proteasome. Among many identified F-box proteins, Skp2 is one of the most well-characterized and studies show that it is involved in carcinogenesis by regulating many biological processes, especially the cell cycle, but also cell proliferation and differentiation, and apoptosis. This regulation is performed by the specific degradation process of several tumor suppressor proteins associated with cancer, such as p21 and p27. P27Kip1 and p21Cip1 are Cyclin-dependent kinase inhibitors (Cdks), and inhibit the progression of cells to the cell cycle S-phase. Skp2 is essential for the degradation of p27 and p21 to promote the entry into the S phase, consequently inducing cell proliferation. Finally, molecular and functional studies of pathways that are related to Medulloblastoma, such as the Notch pathway, and its interaction with the WNT and SHH pathways, and the cell cycle, may support improvement in prognosis/diagnosis and discovery of new therapeutic targets for the development of more effective treatments for patients with Medulloblastoma. (AU)