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The N-Myc Oncogene in Pediatric Tumors: Diagnostic, Prognostic and Biological Aspects
Published in John T. Kemshead, Pediatric Tumors: Immunological and Molecular Markers, 2020
Several observations suggest that N-myc may be involved in regulating cellular differentiation. Firstly, Thiele et al. have demonstrated that retinoic acid induced morphological differentiation of human neuroblastoma cells is preceded by a dramatic fall in N-myc mRNA expression.41 Secondly, it has been shown by in situ hybridization studies on neuroblastoma tissue sections, that primitive undifferentiated neuroblasts express higher levels of N-myc mRNA than the more differentiated cells of the tumor.42 Thirdly, analysis of mRNA extracted from developing mouse embryos has demonstrated that while c-myc expression is relatively generalized, expression of N-myc is restricted with respect to both tissue and embryonic stage.43 Finally, there is a highly significant correlation between the extent of N-myc amplification in human neuroblastoma and the stage of the disease; the highest levels of amplification being associated with the least differentiated and most advanced tumors.44,45 The clinical implications of this correlation will be considered further in the following section.
Oncogenes and Cancer
Published in Pimentel Enrique, Oncogenes, 2020
Amplification of some proto-oncogene sequences may be associated with the progression of certain tumors. In a patient with Philadelphia chromosome-positive CML, promyelocytic transformation of the disease was associated with 8- to 16-fold amplification of c-myc sequences, and subtle rearrangements of these sequences were detected in the neoplastic cells.140 Amplification of c-myc was detected in a subpopulation of human small cell lung carcinomas.141 A 3- to 30-fold amplification of c-myc and c-H-ras was detected in advanced stages of invasive squamous cell carcinomas of the human uterine cervix associated with the presence of papillomavirus genomes (HPV16 or HPV18).142 Since amplification of N-myc is not found in the tumor tissue of patients with stages 1 and 2 of neuroblastoma but is present in 50% of patients with stages 3 and 4 of the same tumor,126 this amplification could be associated with progression of neuroblastomas.
Wilms’ Tumor
Published in Victor A. Bernstam, Pocket Guide to GENE LEVEL DIAGNOSTICS in Clinical Practice, 2019
Likewise, the pattern of N-myc DNA probes allowed the diagnosis of intrarenal neuroblastoma; evaluation of N-myc gene amplification predicted a poor prognosis, subsequently confirmed by the clinical course.
Ten things you learned in your residency about retinoblastoma that have changed the 2023 Victor T. Curtin Lecture
Published in Ophthalmic Genetics, 2023
The Rb1 gene encoded by chromosome 13 is a tumor suppressor gene and loss of function predisposes you to retinoblastoma. There are many molecular mechanisms for derangement, including mutation, LOH (loss of heterozygosity), large deletions, translocations, and inversions, in addition to possible contributing factors from promoter abnormalities, and the autosomal dominant pattern of inheritance has repeatedly been found. Analysis of tumors demonstrates the mechanism of derangement in each allele (the “two hit hypothesis”). Over the years, however, rare patients were found where no Rb1 abnormality was identified. Finally, Gallie and colleagues identified another abnormality in patients with unilateral, unifocal retinoblastoma diagnosed at a younger age, and they believed that these patients had a more aggressive course (29). Rather than mutation or any abnormality of the Rb1 gene, they found amplification of N-MYC. N-MYC is a transcription factor dysregulated in many cancers, most notable neuroblastoma. It was known that N-MYC was altered in many retinoblastomas, but not that it alone could drive the development of retinoblastoma.
Synthesis and biological evaluation of thieno[3,2-c]pyrazol-3-amine derivatives as potent glycogen synthase kinase 3β inhibitors for Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ning Yan, Xiao-Long Shi, Long-Qian Tang, De-Feng Wang, Xun Li, Chao Liu, Zhao-Peng Liu
Compelling evidence indicated that GSK-3β plays a large part in synaptic plasticity and neurogenesis66,67. Differentiated SH-SY5Y cells express neurogenesis-related markers, including growth-associated protein 43 (GAP43), the N-myc gene as well as neuronal polarity marker microtubule-associated protein 2 (MAP-2). GAP43 is an intrinsic determinant of neuronal development and plasticity which regulates axon growth and regeneration68,69. N-myc is indispensable to normal neurogenesis in the expansion of progenitor cell populations70. MAP-2 regulates neuronal development, structural stability and synaptic plasticity through the formation of axonal and dendritic processes71,72. Inhibition of GSK-3β could induce neurogenesis and promote the expressions of the neurogenesis-related markers73. Firstly, we used SH-SY5Y cells to study the effect of 16b on neurite outgrowth, using retinoic acid (RA) as a positive control74. After incubating with 16b (10 μM) or RA (10 μM) for 72 h, the morphology of differentiated neuronal neurite outgrowth were obtained. As depicted in Figure 8(A), 16b exhibited a substantial ability in inducing SH-SY5Y cells neurite outgrowth compared with RA.
Exosomes from N-Myc amplified neuroblastoma cells induce migration and confer chemoresistance to non-N-Myc amplified cells: implications of intra-tumour heterogeneity
Published in Journal of Extracellular Vesicles, 2019
Pamali Fonseka, Michael Liem, Cemil Ozcitti, Christopher G. Adda, Ching-Seng Ang, Suresh Mathivanan
Neuroblastoma is the most common solid tumour in children that arises from the sympathetic nervous system and accounts for 15% of childhood cancer mortality [1]. Neuroblastoma is mostly present as a mass in pelvis, neck, abdomen and chest [2]. Neuroblastoma patients suffer from loss of weight, fever, anaemia and irritability. Due to its highly variable symptoms, the disease usually has metastasised to secondary locations by the time of diagnosis in most cases. Majority of the neuroblastoma deaths occur within two years of diagnosis due to the aggressiveness of the cancer [3]. About 20–30% of neuroblastoma patients are presented with the amplification of the oncogene N-Myc and is considered high-risk. Whilst N-Myc amplification status strongly correlates with higher tumour aggression and resistance to treatment, the role of N-Myc in the aggressiveness and progression of the disease is poorly understood [4]. As N-Myc is a transcription factor, it can be speculated that the N-Myc can modulate the secretion of key proteins that may play a pivotal role in tumorigenesis [5].