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Familial Neuroblastoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
At the molecular level, sporadic neuroblastoma is attributable to de novo germline or somatic single-nucleotide polymorphisms (SNP) that induce gain or loss of function in a number of genes, each with low relative risk, but acting together to increase the chances of disease occurrence. On the other hand, 59% of familial neuroblastoma cases are associated with autosomal-dominant inheritance of germline, gain-of-function mutations in the anaplastic lymphoma kinase (ALK) gene located on chromosome 2p23.2-1. A subset (∼10%) of familial cases are due to inheritance of germline, loss-of-function mutations in the paired-like homeobox 2B (PHOX2B) gene located on chromosome 4p13. In addition, neuroblastoma may constitute part of cancer predisposition syndromes. Nonetheless, genetic causes for about 15% of familial neuroblastoma cases remain unknown to date [1].
Habitual Abortion
Published in E. Nigel Harris, Thomas Exner, Graham R. V. Hughes, Ronald A. Asherson, Phospholipid-Binding Antibodies, 2020
Dwight D. Pridham, Christine L. Cook
Homeobox genes and oncogenes are gene sequences involved in the regulation and stimulation of growth and development in the embryo. These genes control the expression of groups of other genes, allowing regulation of pattern formation, as in segmentation of the developing embryo. Although well characterized in Drosophila and mice, such sequences have been documented in humans only recently.52 Su et al.53 have shown that mRNA for one of these homeobox genes (HU-2) is expressed from 8 to 10 weeks in the human embryo. Oncogenes, which probably act to stimulate proliferation, are also expressed during the same time period in human embryos. Deletional mutations in either of these gene systems theoretically should result in the demise of the early embryo.
Cell structure, function and adaptation
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
There is often a trade-off between a cell retaining the ability to proliferate and being able to exhibit differentiated functions necessary for the organism's wellbeing. In fetal development, differentiation occurs during morphogenesis to allow the formation of vital structures and organs. This involves cell migration, carefully regulated proliferation, cell differentiation to acquire new functional and structural characteristics, and, as mentioned below, selective and highly regulated deletion of some cells by a form of cell death described morphologically as apoptosis (Figure 2.7 and see Chapter 3). How this complex process is achieved in mammalian cells is only now beginning to be understood, having previously been extensively worked on in nematodes and fruit flies. The whole process is under very tight genetic control. The master genes that are identified are very similar in higher-order animals to those first identified in worms and flies; this indicates how conserved morphogenesis is in evolution. These genes are called homeobox genes and their primary purpose is to regulate the expression of groups of other genes and thus impose a discipline on the growing mass of cells. Mutations of these genes have been found, and these inevitably lead to developmental abnormalities. They have been implicated in some rare forms of childhood neoplasia. The main tumours of infancy are listed in Table 2.2.
FOXM1: a potential therapeutic target in human solid cancers
Published in Expert Opinion on Therapeutic Targets, 2020
Soheila Borhani, Andrei L. Gartel
Chan et al. [96] identified Homeobox protein DLX-1 as a novel target of FOXM1. The DLX homeobox family is a group of transcription factors, and aberrant expression of homeobox genes has been found in a variety of malignancies including ovarian cancer. The authors found that FOXM1 transcriptionally upregulated DLX1 via two binding sites located at +61 to +69 bp downstream and −675 to – 667 bp upstream of the DLX1 promoter. They also showed that DLX1 positively modulated the TGF-β/SMAD4 signaling pathway, thereby promoting ovarian cancer cell proliferation and cell migration/invasion. This result suggests how FOXM1 can induce TGF-β/SMAD4 pathway in OC. This study was performed using ovarian cancer cell lines A2780cp, A2780s, SKOV3, OVCA429, OVCA433, and ES2, as well as primary human ovarian cancer cells.
Incorporating molecular biomarkers into clinical practice for gastric cancer
Published in Expert Review of Anticancer Therapy, 2019
Shunsuke Nakamura, Mitsuro Kanda, Yasuhiro Kodera
Homeobox C10 (HOXC10) encodes a transcription factor that plays an important role in the morphogenesis of multicellular organism. The levels of HOXC10 are controlled during cell differentiation and proliferation, indicating that this protein contributes to oncogenesis. HOXC10 are expressed at high levels in normal human skeletal muscle, adipocytes, and kidneys and inappropriate regulation of HOX genes is associated with certain neoplasms [18]. We found that HOXC10 enhances the malignant phenotype of gastric cancer cells. Transcriptome analysis revealed that HOXC10 is highly expressed mainly in GC tissues compared with the corresponding noncancerous, adjacent gastric mucosa of patients with hepatic metastasis. The expression level of HOXC10 mRNA positively correlates with those of molecules that mediate the epithelial to-mesenchymal transition (EMT), such as fibroblast growth factor binding protein 1 (FGFBP1) and SRY-Box 10 (SOX10).
Caudal type homeoboxes as a driving force in Helicobacter pylori infection-induced gastric intestinal metaplasia
Published in Gut Microbes, 2020
Hong-Yan Chen, Yi Hu, Nong-Hua Lu, Yin Zhu
The homeobox (HOX) gene was first isolated from Drosophila, and encodes an evolutionarily conserved transcription factor that plays an important role in embryo growth, differentiation and development.33 The CDX proteins CDX1 and CDX2 belong to the ParaHox cluster of the HOX family, and they regulate the expression of intestine-specific proteins, including sucrase isomaltase,34 mucin2,35 KLF4,36 and LI-cadherin,37 to promote columnar morphogenesis and an intestinal cell phenotype. CDX1/2 show distinct expression patterns in the intestine. CDX1 expression is highest in the distal colon, whereas CDX2 expression is highest in the proximal colon; furthermore, the expression level of CDX1 was shown to gradually increase along the crypt-villus axis, and was more abundant in the crypts than in the villi, whereas CDX2 was found to be uniformly expressed along the crypt-villus axis, but was differentially phosphorylated.16 In addition, neither CDX1 nor CDX2 is expressed in normal gastric and esophageal tissues.16,38 Structurally, CDX1/2 have a high degree of homology along with overlapping functions in regulating intestinal homeostasis and colon configuration in adults.39,40 Several studies also showed that CDX1 and CDX2 exhibit transcriptional specificity in the intestine to regulate the expression of certain specific genes:41–43 intestinal alkaline phosphatase (an enterocyte differentiation marker gene regulated by CDX1) and the apical sodium-dependent bile acid transporter (involved in bile acid absorption and regulated by CDX1/2).