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Wnt signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Vertika Singh, Meghali Joshi, Kiran Singh, Rajender Singh
Altered expressions of Wnt signaling pathway genes have been found in testicular germ cell tumors (TGCTs) (65). Furthermore, genome-wide expression studies have shown that the Wnt signaling cascade is disrupted in carcinoma in situ (CIS) stage, a common precursor of TGCTs (66). This highlights the involvement of the Wnt signaling pathway in the development of GCTs. The expression of β-catenin has been shown in patients with gonadoblastoma (67). A study indicated that nuclear accumulation of β-catenin parallels with oct3/4 expression in the proliferation of immature germ cells in gonadoblastoma (68). Altered expression of genes such as Wnt5A and Fzd7 and some Wnt target genes such as JUN, FGF4, versican and connexion have been identified in patients with embryonic carcinoma. However, in seminomas, CDX1 and NRCAM show high expression (69). These studies highlight the significance of the Wnt signaling pathway in the transformation of the embryonic carcinomas into differentiated nonseminomas (70).
Micronutrients in Improvement of the Standard Therapy in Cancer
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Overexpression of miR-296-5p and reduced levels of its target protein CDX1 (Caudal-related homebox 1) were associated with increased proliferation, tumor growth, and reduced apoptosis in gastric cancer cells.39
Colorectal cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
The CDX1 and 2 homeotic genes have the characteristics of transcriptional regulatory proteins and are down-regulated in about 85% of CRCs. In cdx2+/-mice, multiple intestinal polyps are seen in the proximal colon (Chawengsaksophak et al., 1997). However, these polyps are not typical adenomas, and have similar histological characteristics to those seen in the Min mouse. These polyps occasionally contain true metaplasia and occasional large pedunculated tubulovillous colonic adenomas are seen. The fact that polyps are seen mostly in the proximal colon suggests that lowering levels of CDX2 would induce exaggerated cell growth leading to tumor formation, and expression would stimulate cell differentiation and growth arrest (Yagi et al., 1999). However, because the tumors display an unusual histological pattern, and human mutations have not been identified, the role of this gene in human carcinogenesis remains to be elucidated.
Neoadjuvant and adjuvant multimodality therapies in resectable esophagogastric adenocarcinoma
Published in Expert Opinion on Pharmacotherapy, 2021
David K. Lau, Avani Athauda, Ian Chau
A single patient classifier (SPC) of four genes was developed using exploratory, evaluation and validation patient data sets by Cheong and colleagues [68]. The included genes were felt to represent immune (GZMB, WARS), stem-like (SFRP4) and intestinal epithelial (CDX1) subsets of gastric cancer. Not only did this SPC demonstrate predictive value for adjuvant chemotherapy response, it also allowed prognostication into low-, medium- and high-risk groups. The prognostic performance of these groups was found to perform better than the TNM 8th edition staging system in terms of OS on subsequent analysis [69]. Furthermore, the utilization of this SPC along with MSI-H and EBV status from patients recruited to the CLASSIC study has demonstrated additional benefit of the combinatory use of these markers in identifying patients within MSS and EBV-negative groups who may not benefit from adjuvant chemotherapy [70]. However, the use of genetic signatures in routine clinical practice to influence treatment decisions remains problematic due to the associated expense as well as concerns with validation and reproducibility.
Expression of ADP receptor P2Y12, thromboxane A2 receptor and C-type lectin-like receptor 2 in cord blood-derived megakaryopoiesis
Published in Platelets, 2021
Catharina Gerhards, Stefanie Uhlig, Mani Etemad, Foteini Christodoulou, Karen Bieback, Harald Klüter, Peter Bugert
The molecular mechanisms of TBXA2R regulation have been extensively studied in human leukemia cell lines with phorbol 12-myristate 13-acetate (PMA) induced megakaryocytic differentiation [22,23]. A significant role for the transcription factors SP1, EGR1, NFE2, GATA1, ETS1, and WT1 was shown. By using in silico DNA sequence analysis binding sites for SP1, GATA1 and ETS1 were among the most frequent in the regulatory region of TBXA2R. These data confirmed the significance of the in silico TF binding site prediction by using the TFBIND prediction tool [11]. The significant differences in TF binding sites in the P2RY12, TBXA2R, and CLEC1B genes, probably, reflect the functional role of the TF in the differential regulation of gene expression. Binding sites for MZF1, an important regulator of early myelopoiesis [24], were more frequent in TBXA2R compared to P2RY12 and CLEC1B. Whereas binding sites for CDX1, SRY, and OCT1 sites were significantly more frequent in P2RY12 and CLEC1B compared to TBXA2R. CDX1 and OCT1 are known to be involved in the regulation of hematopoietic cell differentiation [25,26]. With regard to GATA1 as one of the most important TF in megakaryopoiesis [27], the CLEC1B gene showed the highest number of binding sites. This may reflect the strong induction of the gene in early megakaryopoiesis.
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
H. pylori induces chronic inflammation and IM through genetic and epigenetic changes that induce the activation of intracellular signaling pathways. Rau et al.62 investigated epigenetic changes in CDXs during the development of intestinal-type GC, revealing that the CDX1 promoter methylation level was reduced during H. pylori gastritis and IM; it reached the lowest level in dysplasia. When further developed into GC, the CDX1 promoter methylation level rose again. Moreover, NF-κB signaling activated CDX1 expression by directly binding to its unmethylated promoter, initiating gastric mucosal transdifferentiation. Their findings suggested that the CDX1 methylation pattern from low-grade to high-grade lesions may be a suitable predictive biomarker of GC, and CDX2 promoter methylation did not affect its transcription. In addition to the level of methylation that affects the expression of CDXs, CDX autoregulation also plays an important role in CDXs. CDX2 directly activates its own transcription by binding to its own promoter, and it maintains endogenous expression in IM lesions in human and mouse intestines.63 CDX1 can also automatically regulate its own expression, but does not directly bind to its own promoter; instead, the complex formed by the interaction of CDX1 and LEF1 (a nuclear effector of Wnt signaling) binds to the Lef/TCF response element on the CDX1 promoter to initiate transcription.64 Such autoregulation of CDXs may partially explain the irreversibility of GIM; thus, interference with the autoregulation of this IM loop may be an effective strategy for GC prevention. Ectopic expression of CDX1 conferred gastric epithelial cells with an intestinal phenotype via the induction of the stemness-associated reprogramming factors SALL4 and KLF5.65 Relatively few studies focus on the effect of H. pylori infection on CDX1 expression compared to those focused on CDX2 expression. Therefore, we further discuss research progress on the detailed regulatory mechanism of CDX2 by H. pylori.