RESUMO
A limited number of accessible and representative models of human trophoblast cells currently exist for the study of placentation. Current stem cell models involve either a transition through a naïve stem cell state or precise dynamic control of multiple growth factors and small-molecule cues. Here, we demonstrated that a simple five-day treatment of human induced pluripotent stem cells with two small molecules, retinoic acid (RA) and Wnt agonist CHIR 99021 (CHIR), resulted in rapid, synergistic upregulation of CDX2. Transcriptomic analysis of RA + CHIR-treated cells showed high similarity to primary trophectoderm cells. Multipotency was verified via further differentiation towards cells with syncytiotrophoblast or extravillous trophoblast features. RA + CHIR-treated cells were also assessed for the established criteria defining a trophoblast cell model, and they possess all the features necessary to be considered valid. Collectively, our data demonstrate a facile, scalable method for generating functional trophoblast-like cells in vitro to better understand the placenta.
Assuntos
Diferenciação Celular , Células-Tronco Pluripotentes Induzidas , Tretinoína , Trofoblastos , Humanos , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo , Trofoblastos/citologia , Tretinoína/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Piridinas/farmacologia , Feminino , Fator de Transcrição CDX2/metabolismo , Fator de Transcrição CDX2/genética , Pirimidinas/farmacologia , Gravidez , Modelos Biológicos , Células CultivadasRESUMO
Background: The etiopathogenesis of inflammatory bowel disease (IBD) is still unclear. Prior studies suggest genetic components that may influence the incidence and severity of the disease. Additionally, it was shown that low levels of serum vitamin D may have an impact on the clinical course of the disease due to its effect on the immunological system. Methods: We aimed to investigate the correlation between the incidence of vitamin D receptor (VDR) gene polymorphisms (rs11568820, rs10735810, rs1544410, rs7975232, and rs731236, commonly described as Cdx2, FokI, Bsm, ApaI, and TaqI, respectively) and vitamin D concentration with the clinical course of IBD (disease activity, extent of the intestinal lesions). Data were obtained from 62 patients with IBD (34 with Crohn's disease, 28 with ulcerative colitis), aged 3-18 years, and compared with controls (N = 47), aged 8-18 years. Results: Although there was no difference in the incidence of individual genotypes between the study groups (IBD, C) in all the polymorphisms examined, we described a significant increase in the chance of developing IBD for heterozygotes of Cdx2 (OR: 2.3, 95% CI 0.88-6.18, p = 0.04) and BsmI (OR: 2.07, 95% CI 0.89-4.82, p = 0.048) polymorphisms. The mean serum 25OHD level in patients with IBD was significantly higher compared with the controls (19.87 ng/mL vs. 16.07 ng/mL; p = 0.03); however, it was still below optimal (>30 ng/mL). Furthermore, a significant correlation was found between vitamin D level and TaqI in patients with IBD (p = 0.025) and patients with CD (p = 0.03), as well as with the BsmI polymorphism in patients with IBD (p = 0.04) and patients with CD (p = 0.04). A significant correlation was described between the degree of disease activity and genotypes for the FokI polymorphism in patients with UC (p = 0.027) and between the category of endoscopic lesions and genotypes for the Cdx2 polymorphism also in patients with UC (p = 0.046). Conclusions: The results suggest a potential correlation of VDR gene polymorphism with the chance of developing IBD, and the clinical course of the disease requires further studies in larger group of patients. Vitamin D supplementation should be recommended in both children with inflammatory bowel disease and in healthy peers.
Assuntos
Predisposição Genética para Doença , Doenças Inflamatórias Intestinais , Receptores de Calcitriol , Vitamina D , Humanos , Receptores de Calcitriol/genética , Criança , Adolescente , Masculino , Feminino , Vitamina D/sangue , Pré-Escolar , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/sangue , Polimorfismo de Nucleotídeo Único , Fator de Transcrição CDX2/genética , Genótipo , Estudos de Casos e Controles , Colite Ulcerativa/genética , Doença de Crohn/genética , Doença de Crohn/sangue , Polimorfismo GenéticoRESUMO
BACKGROUND/AIM: Caudal-type homeobox transcription factor 2 (CDX2) is a master regulator of intestinal development and maintenance of the intestinal epithelium. We previously revealed that CDX2Low colorectal cancers (CRCs) were associated with poor survival and differential response to adjuvant chemotherapy. MicroRNAs (miRNAs), a class of non-coding RNAs typically composed of fewer than 25 nucleotides, are known to regulate gene expression and signaling pathways. This study aimed to identify oncogenic miRNAs induced by CDX2 in CRC. MATERIALS AND METHODS: HCT116 cells were cultured and transfected with CDX2 siRNA. The expression levels of four oncogenic miRNAs (miR-9, miR-25, miR-106b and miR-221) were quantified by RT-qPCR. To understand whether CDX2 represented a key regulator of miR-221 expression in vivo, we analyzed the relationship between CDX2 and miR-221expression levels in the TCGA COAD database (n=454). RESULTS: The expression level of miR-221 was significantly up-regulated in CDX2 knockdown cells (n=2, p<0.05). In the TCGA database, we observed an inverse correlation between CDX2 and miR-221 expression levels, consistent with our in vitro data (r=-0.114, p=0.0149). Furthermore, the expression level of miR-221 was significantly elevated in patients with CDX2Low CRC (p<0.05). CONCLUSION: Knockdown of CDX2 induces microRNA-221 up-regulation in human CRC. Further research is warranted to elucidate the molecular mechanisms underlying miR-221 up-regulation in CDX2Low CRCs.
Assuntos
Fator de Transcrição CDX2 , Neoplasias do Colo , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Regulação para Cima , Humanos , MicroRNAs/genética , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/metabolismo , Células HCT116 , Técnicas de Silenciamento de GenesRESUMO
Objective: To investigate the immunophenotypic and molecular biological characteristics of patients with elevated serum alpha-fetoprotein (AFP) and enteroblastic differentiated gastric adenocarcinoma (GAED). Methods: The clinicopathological data of 13 patients with elevated serum AFP and GAED admitted to Shanxi Cancer Hospital from 2018 to 2020 were collected. Immunohistochemistry (IHC) and next-generation sequencing (NGS) were used to analyze the immune markers and molecular biological characteristics of the pathological tissues of the patients. Kaplan-Meier method and log rank test were used for survival analysis. Results: Among the 13 patients with GAED, 12 were male and 1 was female, aged 41-70 years, with a median age of 64 years. The lesions were mainly located in the gastric antrum (5 cases) and gastric body (4 cases). IHC results showed that the tumor embryonic protein (AFP, SALL4, GPC3), intestinal epithelial differentiation protein (CDX-2, CD10), and some original intestinal epithelial phenotype markers (OCT3/4, Claudin6) were expressed in the tumor tissues. Combined application of multiple markers can reduce the rate of missed diagnosis. Among the 13 patients, 12 had at least one mutation (1 mutation: 1 case, 2-5 mutations: 3 cases, 6-15 mutations: 8 cases), and 1 case was not detected. The gene with the highest mutation frequency was TP53 (10 cases), and other mutant genes included EPHB1 (3 cases), ATRX (2 cases), EPHA5 (2 cases), GATA3 (2 cases), LRP1B (2 cases) and MAP2K4 (2 cases) were also detected. Three of the 13 patients had structural variations, which were C14orf177-GNAS, AIM1-FGFR3, and EPHA6-ROS1 gene rearrangements. All 13 patients had copy number variation, and 11 patients had copy number variation of more than 2 genes. The common amplification genes were IRS2 (5 cases), PTEN (5 cases), GNAS (4 cases), CCNE1 (3 cases), CEBPA (3 cases), PCK1 (3 cases) and ERBB2 (2 cases). The common deletion genes were SOX2 (5 cases) and MYC (5 cases). Among the 13 patients, 4 died, and 2 of the dead patients had liver metastasis. There were 4 patients with disease-free survival and 5 patients with disease progression, including 3 cases of abdominal metastasis and 2 cases of liver metastasis. The 3-year survival rate of patients was 65.9 %, and the 3-year progression-free survival rate was 30.7 %. Gene LRP1B point mutation was associated with poor prognosis (Pï¼0.001). There was no significant improvement in the prognosis of patients treated with immunotherapy compared with those treated with chemotherapy alone (P=0.595), but the prognosis of patients treated with postoperative chemotherapy or postoperative chemotherapy plus immunotherapy was better than that of patients treated with surgery alone (Pï¼0.05). Conclusions: Elevated serum AFP with GAED is a highly invasive tumor with unique molecular characteristics, often accompanied by multiple molecular events. TP53 mutation is the most common type of gene mutation. In addition, some cases are accompanied by HER2 amplification and gene rearrangement.
Assuntos
Adenocarcinoma , Neoplasias Gástricas , alfa-Fetoproteínas , Humanos , Masculino , alfa-Fetoproteínas/metabolismo , Feminino , Pessoa de Meia-Idade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Idoso , Adulto , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/sangue , Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Diferenciação Celular , Mutação , Fator de Transcrição CDX2/metabolismo , Fator de Transcrição CDX2/genética , GlipicanasRESUMO
Abnormal trophoblast self-renewal and differentiation during early gestation is the major cause of miscarriage, yet the underlying regulatory mechanisms remain elusive. Here, we show that trophoblast specific deletion of Kat8, a MYST family histone acetyltransferase, leads to extraembryonic ectoderm abnormalities and embryonic lethality. Employing RNA-seq and CUT&Tag analyses on trophoblast stem cells (TSCs), we further discover that KAT8 regulates the transcriptional activation of the trophoblast stemness marker, CDX2, via acetylating H4K16. Remarkably, CDX2 overexpression partially rescues the defects arising from Kat8 knockout. Moreover, increasing H4K16ac via using deacetylase SIRT1 inhibitor, EX527, restores CDX2 levels and promoted placental development. Clinical analysis shows reduced KAT8, CDX2 and H4K16ac expression are associated with recurrent pregnancy loss (RPL). Trophoblast organoids derived from these patients exhibit impaired TSC self-renewal and growth, which are significantly ameliorated with EX527 treatment. These findings suggest the therapeutic potential of targeting the KAT8-H4K16ac-CDX2 axis for mitigating RPL, shedding light on early gestational abnormalities.
Assuntos
Fator de Transcrição CDX2 , Proliferação de Células , Autorrenovação Celular , Histona Acetiltransferases , Trofoblastos , Trofoblastos/metabolismo , Fator de Transcrição CDX2/metabolismo , Fator de Transcrição CDX2/genética , Animais , Feminino , Humanos , Camundongos , Gravidez , Autorrenovação Celular/genética , Histona Acetiltransferases/metabolismo , Histona Acetiltransferases/genética , Aborto Habitual/metabolismo , Aborto Habitual/genética , Camundongos Knockout , Histonas/metabolismo , Diferenciação Celular , Placentação/genéticaRESUMO
This study aimed to conduct an umbrella review of meta-analyses to synthesize the existing evidence regarding the relationship between vitamin D receptor (VDR) polymorphism and breast cancer (BC) risk. A comprehensive search was performed across multiple databases, including Embase, PubMed, Scopus, the Cochrane Database of Systematic Reviews, and the Web of Science. The investigation included 17 meta-analyses for the BsmI polymorphism, 6 for the Cdx2 polymorphism, and 6 for the Poly (A) polymorphism. Among the 119 datasets analyzed, only 6 (5 %) reported statistically significant outcomes (p < 0.05), comprising 2 comparisons for VDR BsmI polymorphism (3 %), 1 for VDR Cdx-2 polymorphism (4 %), and 3 for VDR Poly (A) polymorphism (14 %), across various genetic models. Notably, significant heterogeneity was observed in 82 comparisons, and publication bias was detected in 16 comparisons. Furthermore, a substantial proportion (86 %) of the included studies exhibited critically low methodological quality. In conclusion, our findings suggest that VDR polymorphism (BsmI, Cdx-2, and Poly (A)) is not strongly associated with BC risk in the general population.
Assuntos
Neoplasias da Mama , Predisposição Genética para Doença , Polimorfismo Genético , Receptores de Calcitriol , Feminino , Humanos , Neoplasias da Mama/genética , Fator de Transcrição CDX2/genética , Metanálise como Assunto , Estudos Observacionais como Assunto , Receptores de Calcitriol/genética , Fatores de RiscoRESUMO
Objective: To investigate the clinical and pathological characteristics of primary mucinous gland lesions of the fallopian tubes. Methods: The clinical data, pathomorphological characteristics and immunophenotype of 14 cases of primary mucinous gland lesions of the fallopian tube diagnosed at Obstetrics and Gynecology Hospital of Fudan University from 2015 to 2023 were analyzed retrospectively. In addition, a comprehensive review of relevant literature was conducted. Results: The age of 14 patients ranged from 53 to 83 years, with an average of 65 years. Among them, 13 cases exhibited unilateral involvement while one case showed bilateral presentation. Nine cases were mucinous metaplasia of the fallopian tube, four cases were invasive mucinous adenocarcinoma and one case was mucinous carcinoma in situ. Morphologically, mucinous metaplasia of the fallopian tube was focal, with or without inflammation. The cells of mucinous adenocarcinoma or mucinous carcinoma in situ exhibited characteristics indicative of gastrointestinal differentiation. Immunohistochemical analysis revealed diffuse positive expression of CK7, and negative expression of SATB2. CDX2 demonstrated positive staining in two cases. One case exhibited diffuse and strongly positive mutant expression of p53, whereas the remaining cases displayed wild-type expression. MUC6 showed diffuse or focally positive staining in mucinous gland lesions characterized by gastric differentiation. Some cases of mucinous adenocarcinoma of fallopian tube were subject to AB-PAS staining, resulting in red to purple cytoplasmic staining. Conclusions: Primary mucinous lesions of the fallopian tube are exceedingly uncommon. All cases of mucinous adenocarcinoma of fallopian tubes in this study exhibit the morphology and immunohistochemical characteristics of gastrointestinal differentiation. Mucinous metaplasia of the fallopian tube is a benign lesion of incidental finding, which is closely related to inflammation or gastric differentiation. Mucinous lesions of cervix, ovary and digestive tract are excluded in all patients, confirming the independent existence of mucinous lesions within fallopian tubes.
Assuntos
Adenocarcinoma Mucinoso , Neoplasias das Tubas Uterinas , Tubas Uterinas , Metaplasia , Proteína Supressora de Tumor p53 , Humanos , Feminino , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/metabolismo , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/metabolismo , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Tubas Uterinas/patologia , Idoso de 80 Anos ou mais , Proteína Supressora de Tumor p53/metabolismo , Metaplasia/patologia , Queratina-7/metabolismo , Fator de Transcrição CDX2/metabolismo , Fator de Transcrição CDX2/genética , Mucina-6/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Carcinoma in Situ/patologia , Imuno-HistoquímicaRESUMO
Background: Colorectal cancer (CRC) exhibits molecular and morphological diversity, involving genetic, epigenetic alterations, and disruptions in signaling pathways. This necessitates a comprehensive review synthesizing recent advancements in molecular mechanisms, established biomarkers, as well as emerging ones like CDX2 for enhanced CRC assessment. Material and Methods: This review analyzes the last decade's literature and current guidelines to study CRC's molecular intricacies. It extends the analysis beyond traditional biomarkers to include emerging ones like CDX2, examining their interaction with carcinogenic mechanisms and molecular pathways, alongside reviewing current testing methodologies. Results: A multi-biomarker strategy, incorporating both traditional and emerging biomarkers like CDX2, is crucial for optimizing CRC management. This strategy elucidates the complex interaction between biomarkers and the tumor's molecular pathways, significantly influencing prognostic evaluations, therapeutic decision-making, and paving the way for personalized medicine in CRC. Conclusions: This review proposes CDX2 as an emerging prognostic biomarker and emphasizes the necessity of thorough molecular profiling for individualized treatment strategies. By enhancing CRC treatment approaches and prognostic evaluation, this effort marks a step forward in precision oncology, leveraging an enriched understanding of tumor behavior.
Assuntos
Biomarcadores Tumorais , Fator de Transcrição CDX2 , Neoplasias Colorretais , Proteínas de Membrana , Instabilidade de Microssatélites , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/classificação , Fator de Transcrição CDX2/metabolismo , Fator de Transcrição CDX2/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas B-raf/genética , Prognóstico , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Reparo de Erro de Pareamento de DNA , Valor Preditivo dos Testes , Medicina de PrecisãoRESUMO
The control of eukaryotic gene expression is intimately connected to highly dynamic chromatin structures. Gene regulation relies on activator and repressor transcription factors (TFs) that induce local chromatin opening and closing. However, it is unclear how nucleus-wide chromatin organization responds dynamically to the activity of specific TFs. Here, we examined how two TFs with opposite effects on local chromatin accessibility modulate chromatin dynamics nucleus-wide. We combine high-resolution diffusion mapping and dense flow reconstruction and correlation in living cells to obtain an imaging-based, nanometer-scale analysis of local diffusion processes and long-range coordinated movements of both chromatin and TFs. We show that the expression of either an individual transcriptional activator (CDX2) or repressor (SIX6) with large numbers of binding sites increases chromatin mobility nucleus-wide, yet they induce opposite coherent chromatin motions at the micron scale. Hi-C analysis of higher-order chromatin structures shows that induction of the pioneer factor CDX2 leads both to changes in local chromatin interactions and the distribution of A and B compartments, thus relating the micromovement of chromatin with changes in compartmental structures. Given that inhibition of transcription initiation and elongation by RNA Pol II has a partial impact on the global chromatin dynamics induced by CDX2, we suggest that CDX2 overexpression alters chromatin structure dynamics both dependently and independently of transcription. Our biophysical analysis shows that sequence-specific TFs can influence chromatin structure on multiple architectural levels, arguing that local chromatin changes brought by TFs alter long-range chromatin mobility and its organization.
Assuntos
Cromatina , Fatores de Transcrição , Cromatina/metabolismo , Cromatina/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Humanos , Fator de Transcrição CDX2/metabolismo , Fator de Transcrição CDX2/genética , Regulação da Expressão Gênica , Núcleo Celular/metabolismo , Sítios de Ligação , Montagem e Desmontagem da CromatinaRESUMO
Embryos, originating from fertilized eggs, undergo continuous cell division and differentiation, accompanied by dramatic changes in transcription, translation, and metabolism. Chromatin regulators, including transcription factors (TFs), play indispensable roles in regulating these processes. Recently, the trophoblast regulator TFAP2C was identified as crucial in initiating early cell fate decisions. However, Tfap2c transcripts persist in both the inner cell mass and trophectoderm of blastocysts, prompting inquiry into Tfap2c's function in post-lineage establishment. In this study, we delineate the dynamics of TFAP2C during the mouse peri-implantation stage and elucidate its collaboration with the key lineage regulators CDX2 and NANOG. Importantly, we propose that de novo formation of H3K9me3 in the extraembryonic ectoderm during implantation antagonizes TFAP2C binding to crucial developmental genes, thereby maintaining its lineage identity. Together, these results highlight the plasticity of the chromatin environment in designating the genomic binding of highly adaptable lineage-specific TFs and regulating embryonic cell fates.
Assuntos
Fator de Transcrição CDX2 , Linhagem da Célula , Cromatina , Regulação da Expressão Gênica no Desenvolvimento , Fator de Transcrição AP-2 , Animais , Cromatina/metabolismo , Camundongos , Linhagem da Célula/genética , Fator de Transcrição AP-2/metabolismo , Fator de Transcrição AP-2/genética , Fator de Transcrição CDX2/metabolismo , Fator de Transcrição CDX2/genética , Proteína Homeobox Nanog/metabolismo , Proteína Homeobox Nanog/genética , Blastocisto/metabolismo , Blastocisto/citologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Feminino , Histonas/metabolismo , Diferenciação Celular/genética , Ectoderma/metabolismo , Ectoderma/citologia , Desenvolvimento Embrionário/genéticaRESUMO
Loss of Cdx2 in vivo leads to stunted development of the allantois, an extraembryonic mesoderm-derived structure critical for nutrient delivery and waste removal in the early embryo. Here, we investigate how CDX2 dose-dependently influences the gene regulatory network underlying extraembryonic mesoderm development. By engineering human induced pluripotent stem cells (hiPSCs) consisting of wild-type (WT), heterozygous (CDX2-Het), and homozygous null CDX2 (CDX2-KO) genotypes, differentiating these cells in a 2D gastruloid model, and subjecting these cells to single-nucleus RNA and ATAC sequencing, we identify several pathways that are dose-dependently regulated by CDX2 including VEGF and non-canonical WNT. snATAC-seq reveals that CDX2-Het cells retain a WT-like chromatin accessibility profile, suggesting accessibility alone is not sufficient to drive this variability in gene expression. Because the loss of CDX2 or TBXT phenocopy one another in vivo, we compared differentially expressed genes in our CDX2-KO to those from TBXT-KO hiPSCs differentiated in an analogous experiment. This comparison identifies several communally misregulated genes that are critical for cytoskeletal integrity and tissue permeability. Together, these results clarify how CDX2 dose-dependently regulates gene expression in the extraembryonic mesoderm and reveal pathways that may underlie the defects in vascular development and allantoic elongation seen in vivo.
Assuntos
Fator de Transcrição CDX2 , Dosagem de Genes , Redes Reguladoras de Genes , Células-Tronco Pluripotentes Induzidas , Humanos , Fator de Transcrição CDX2/genética , Diferenciação Celular/genética , Embrião de Mamíferos , MesodermaRESUMO
OBJECTIVE: Gastrointestinal metaplasia (GIM) has a close relationship with gastric cancer (GC), but it is unclear how to judge which GIM could develop into GC. This study aimed to assess the role of CDX2 and its association with Helicobacter pylori (H.pylori) genotypes in GIM. METHODS: CagA and vacA genes were identified via PCR in 466 H. pylori-positive gastric tissues, including gastritis (n=104), GIM diagnosed endoscopically (GIM-1; n=82), gastric cancer (GC; n=173), and paired adjacent GIM tumors resected surgically (GIM-2; n=107). GIM was subclassified per the HID- AB pH2.5-PAS as follows: type I (n=23), type II (n=43), and type III (n=16) in GIM-1; type I (n=8), type II (n=40), and type III (n=59) in GIM-2. CDX2 expression was evaluated immunohistochemically. RESULTS: In GIM-1, the infection rate of vacAm2 (55.8%) and vacAs1m2 (53.5%) was higher in subtype II than in others (P<0.05), while that of vacAm1 (49.2%) and vacAs1m1 (33.9%) was higher in subtype III than in others. The cagA+ rate was higher in subtypes I (75.0%) and III (64.4%) than in subtype II (40.0%; P<0.05) respectively. CDX2 was upregulated in subtype I than in subtypes II and III in GIM-1 and GIM-2. In GIM-2 and GC, CDX2 was downregulated in vacAm1, vacAs1m1, and cagA+ (P<0.05). The predominant genotype was vacAs1m2 in subtype II of GIM-1, CDX2 expression remaining unaltered; however, the predominant genotype was cagA+ vacAs1m1 in subtypes II and III of GIM-2, negatively correlated with CDX2 expression. CONCLUSION: These GIM subtypes (cagA+ vacAs1m1 H. pylori-positive GIM with negative CDX2 expression) resemble GC and should be evaluated similar to cancerous GIM.
Assuntos
Fator de Transcrição CDX2 , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Fator de Transcrição CDX2/genética , Genótipo , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Metaplasia/genética , Metaplasia/complicações , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMO
Cancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers exemplify such characteristics, with BRAFV600E predominantly occurring in proximal colon cancers along with increased DNA methylation phenotype. Using mouse colon organoids, here we show that proximal and distal colon stem cells have distinct transcriptional programs that regulate stemness and differentiation. We identify that the homeobox transcription factor, CDX2, which is silenced by DNA methylation in proximal colon cancers, is a key mediator of the differential transcriptional programs. Cdx2-mediated proximal colon-specific transcriptional program concurrently is tumor suppressive, and Cdx2 loss sufficiently creates permissive state for BRAFV600E-driven transformation. Human proximal colon cancers with CDX2 downregulation showed similar transcriptional program as in mouse proximal organoids with Cdx2 loss. Developmental transcription factors, such as CDX2, are thus critical in maintaining tissue-location specific transcriptional programs that create tissue-type origin specific dependencies for tumor development.
Assuntos
Neoplasias do Colo , Proteínas Proto-Oncogênicas B-raf , Humanos , Camundongos , Animais , Proteínas Proto-Oncogênicas B-raf/genética , Fator de Transcrição CDX2/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Proteínas de Ligação a DNA , Fatores de Transcrição/genética , Proteínas de Homeodomínio/genéticaRESUMO
In brief: Lineage specification plays a vital role in preimplantation development. TEAD4 is an essential transcription factor for trophectoderm lineage specification in mice but not in cattle. Abstract: Tead4, a critical transcription factor expressed during preimplantation development, is essential for the expression of trophectoderm-specific genes in mice. However, the functional mechanism of TEAD4 in mouse preimplantation development and its conservation across mammals remain unclear. Here, we report that Tead4 is a crucial transcription factor necessary for blastocyst formation in mice. Disruption of Tead4 through base editing results in developmental arrest at the morula stage. Additionally, RNA-seq analysis reveals dysregulation of 670 genes in Tead4 knockout embryos. As anticipated, Tead4 knockout led to a decrease in trophectoderm genes Cdx2 and Gata3. Intriguingly, we observed a reduction in Krt8, suggesting that Tead4 influences the integrity of the trophectoderm epithelium in mice. More importantly, we noted a dramatic decrease in nuclear Yap in outside cells for Tead4-deficient morula, indicating that Tead4 directly regulates Hippo signaling. In contrast, bovine embryos with TEAD4 depletion could still develop to blastocysts with normal expression of CDX2, GATA3, and SOX2, albeit with a decrease in total cell number and ICM cell number. In conclusion, we propose that Tead4 regulates mouse blastocyst formation via Krt8 and Yap, both of which are critical regulators of mouse preimplantation development.
Assuntos
Proteínas de Ligação a DNA , Fatores de Transcrição , Animais , Bovinos , Camundongos , Blastocisto/metabolismo , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Desenvolvimento Embrionário/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Via de Sinalização Hippo , Mamíferos/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Hypoxia-induced apoptosis and oxidative stress in spermatogenic cells are considered to be important factors leading to male infertility. It was reported that CDX2 expression was downregulated in hypoxia-stimulated spermatogenic cells. However, the effects of CDX2 on hypoxia-induced apoptosis and oxidative stress in spermatogenic cells are still unknown. This study aimed to explore the roles of CDX2 in hypoxia-induced injury of spermatogenic cells, as well as its mechanism of action. Spermatogenic cells were cultured under 1% oxygen for 48 h to established hypoxia damage model. Reactive oxygen species (ROS) generation was determined using 2',7'-dichlorofluorescein diacetate assay. Apoptosis was assessed using flow cytometry. Enzyme-linked immunosorbent assay was used to evaluate oxidative stress markers, including malondialdehyde (MDA) content and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidases (GSH-Px). Protein levels were detected using western blotting. Hypoxia exposure induced increase in ROS generation, apoptosis rate, and oxidative stress in spermatogenic cells. ROS scavenger inhibited hypoxia-induced apoptosis, oxidative stress, and Wnt/ß-catenin pathway activation. Hypoxia exposure induced CDX2 downregulation. CDX2 overexpression suppressed hypoxia-induced ROS generation, apoptosis rate, oxidative stress, and Wnt/ß-catenin pathway activation. Moreover, CDX2 knockdown restores the inhibitory effects of si-ß-catenin or NAC on hypoxia-induced activation of the Wnt/ß-catenin pathway, apoptosis, and oxidative stress. In conclusion, our study suggests that CDX2 overexpression alleviates hypoxia-induced apoptosis and oxidative stress by suppression of ROS-mediated Wnt/ß-catenin pathway in spermatogenic cells.
Assuntos
Apoptose , Fator de Transcrição CDX2 , Hipóxia Celular , Estresse Oxidativo , Espécies Reativas de Oxigênio , Via de Sinalização Wnt , Estresse Oxidativo/efeitos dos fármacos , Masculino , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Fator de Transcrição CDX2/metabolismo , Fator de Transcrição CDX2/genética , Camundongos , beta Catenina/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genéticaRESUMO
The relationship between the expression of the SATB2 and CDX2 proteins and common molecular changes and clinical prognosis in colorectal cancer (CRC) still needs further clarification. We collected 1180 cases of CRC and explored the association between the expression of SATB2 and CDX2 and clinicopathological characteristics, molecular alterations, and overall survival of CRC using whole-slide immunohistochemistry. Our results showed that negative expression of SATB2 and CDX2 was more common in MMR-protein-deficient CRC than in MMR-protein-proficient CRC (15.8% vs. 6.0%, P = 0.001; 14.5% vs. 4.0%, P = 0.000, respectively). Negative expression of SATB2 and CDX2 was more common in BRAF-mutant CRC than in BRAF wild-type CRC (17.2% vs. 6.1%, P = 0.003; 13.8% vs. 4. 2%; P = 0.004, respectively). There was no relationship between SATB2 and/or CDX2 negative expression and KRAS, NRAS, and PIK3CA mutations. The lack of expression of SATB2 and CDX2 was associated with poor histopathological features of CRC. In multivariate analysis, negative expression of SATB2 (P = 0.030), negative expression of CDX2 (P = 0.043) and late clinical stage (P = 0.000) were associated with decreased overall survival of CRC. In conclusion, the lack of SATB2 and CDX2 expression in CRC was associated with MMR protein deficiency and BRAF mutation, but not with KRAS, NRAS and PIK3CA mutation. SATB2 and CDX2 are prognostic biomarkers in patients with CRC.
Assuntos
Adenocarcinoma , Neoplasias Encefálicas , Neoplasias Colorretais , Proteínas de Ligação à Região de Interação com a Matriz , Síndromes Neoplásicas Hereditárias , Deficiência de Proteína , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Reparo de Erro de Pareamento de DNA/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenocarcinoma/genética , Neoplasias Colorretais/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Mutação , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismoRESUMO
BACKGROUND AND AIMS: Psoriasis is a chronic, non-contagious autoimmune condition marked by dry, itchy,erythematous and scaly plaques. From modest, localized plaques to total body coverage, the severity of psoriasis varies. Plaque, guttate, inverted, pustular, and erythrodermic psoriasis are the five primary kinds. About 90% of cases are of plaque psoriasis, commonly known as psoriasis vulgaris. Study aims to determine the impact of an rs2228570 (FokI) variant and an rs11568820 (CDX2) variant on serum vitamin D levels (SVD) in patients with psoriasis, and the correlation between the two variants and disease severity. METHODS: A case-control study consisting of 95 psoriasis vulgaris patients and 84 healthy controls. The clinical investigation, molecular genetics analysis, and biochemical analysis were done for both groups. RESULTS: SVD levels were significantly decreased in psoriasis patients group. FokI genotypes analysis, we found no significant variance between groups. CDX2 G/G genotype is more prevalent in patients than controls. Moderate psoriasis vulgaris patients with CDX2 G/G genotypes have higher SVD levels than CDX2 G/A, and CDX2 A/A p = 0.003. CONCLUSION: The study found a difference in vitamin D levels between patients and healthy subjects, as well as a difference in vitamin D levels with different FoKI and CDX2 genotypes.
Assuntos
Psoríase , Vitamina D , Humanos , Alelos , Projetos Piloto , Estudos de Casos e Controles , Receptores de Calcitriol/genética , Predisposição Genética para Doença , Psoríase/genética , Fator de Transcrição CDX2/genéticaRESUMO
Adjuvant chemotherapy following surgical intervention remains the primary treatment option for patients with localized colorectal cancer (CRC). However, a significant proportion of patients will have an unfavorable outcome after current forms of chemotherapy. While reflecting the increasing complexity of CRC, the clinical application of molecular biomarkers provides information that can be utilized to guide therapeutic strategies. Among these, caudal-related homeobox transcription factor 2 (CDX2) emerges as a biomarker of both prognosis and relapse after therapy. CDX2 is a key transcription factor that controls intestinal fate. Although rarely mutated in CRC, loss of CDX2 expression has been reported mostly in right-sided, microsatellite-unstable tumors and is associated with aggressive carcinomas. The pathological assessment of CDX2 by immunohistochemistry can thus identify patients with high-risk CRC, but the evaluation of CDX2 expression remains challenging in a substantial proportion of patients. In this review, we discuss the roles of CDX2 in homeostasis and CRC and the alterations that lead to protein expression loss. Furthermore, we review the clinical significance of CDX2 assessment, with a particular focus on its current use as a biomarker for pathological evaluation and clinical decision-making. Finally, we attempt to clarify the molecular implications of CDX2 deficiency, ultimately providing insights for a more precise evaluation of CDX2 protein expression.
Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais , Humanos , Prognóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Recidiva Local de Neoplasia , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , BiologiaRESUMO
Anorectal malformations (ARMs) constitute a group of congenital defects of the gastrointestinal and urogenital systems. They affect males and females, with an estimated worldwide prevalence of 1 in 5000 live births. These malformations are clinically heterogeneous and can be part of a syndromic presentation (syndromic ARM) or as a nonsyndromic entity (nonsyndromic ARM). Despite the well-recognized heritability of nonsyndromic ARM, the genetic etiology in most patients is unknown. In this study, we describe three siblings with diverse congenital anomalies of the genitourinary system, anemia, delayed milestones, and skeletal anomalies. Genome sequencing identified a novel, paternally inherited heterozygous Caudal type Homeobox 2 (CDX2) variant (c.722A > G (p.Glu241Gly)), that was present in all three affected siblings. The variant identified in this family is absent from population databases and predicted to be damaging by most in silico pathogenicity tools. So far, only two other reports implicate variants in CDX2 with ARMs. Remarkably, the individuals described in these studies had similar clinical phenotypes and genetic alterations in CDX2 CDX2 encodes a transcription factor and is considered the master regulator of gastrointestinal development. This variant maps to the homeobox domain of the encoded protein, which is critical for interaction with DNA targets. Our finding provides a potential molecular diagnosis for this family's condition and supports the role of CDX2 in anorectal anomalies. It also highlights the clinical heterogeneity and variable penetrance of ARM predisposition variants, another well-documented phenomenon. Finally, it underscores the diagnostic utility of genomic profiling of ARMs to identify the genetic etiology of these defects.
Assuntos
Malformações Anorretais , Anus Imperfurado , Deformidades Congênitas dos Membros , Masculino , Feminino , Humanos , Canal Anal/anormalidades , Malformações Anorretais/genética , Anus Imperfurado/genética , Sistema Urogenital , Fator de Transcrição CDX2/genéticaRESUMO
Barrett's oesophagus (BO) is a pathological condition in which the squamous epithelium of the distal oesophagus is replaced by an intestinal-like columnar epithelium originating from the gastric cardia. Several somatic mutations contribute to the intestinal-like metaplasia. Once these have occurred in a single cell, it will be unable to expand further unless the altered cell can colonise the surrounding squamous epithelium of the oesophagus. The mechanisms by which this happens are still unknown. Here we have established an in vitro system for examining the competitive behaviour of two epithelia. We find that when an oesophageal epithelium model (Het1A cells) is confronted by an intestinal epithelium model (Caco-2 cells), the intestinal cells expand into the oesophageal domain. In this case the boundary involves overgrowth by the Caco-2 cells and the formation of isolated colonies. Two key transcription factors, normally involved in intestinal development, HNF4α and CDX2, are both expressed in BO. We examined the competitive ability of Het1A cells stably expressing HNF4α or CDX2 and placed in confrontation with unmodified Het1A cells. The key result is that stable expression of HNF4α, but not CDX2, increased the ability of the cells to migrate and push into the unmodified Het1A domain. In this situation the boundary between the cell types is a sharp one, as is normally seen in BO. The experiments were conducted using a variety of extracellular substrates, which all tended to increase the cell migration compared to uncoated plastic. These data provide evidence that HNF4α expression could have a potential role in the competitive spread of BO into the oesophagus as HNF4α increases the ability of cells to invade into the adjacent stratified squamous epithelium, thus enabling a single mutant cell eventually to generate a macroscopic patch of metaplasia.