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Bisphenol A (BPA) is a well-documented endocrine-disrupting chemical widely used in plastic products. In addition to its endocrine-disrupting effects, BPA exhibits immunotoxicity. Many countries have banned BPA because of its adverse effects on human health. In recent years, many chemicals such as bisphenol B (BPB), bisphenol E (BPE), bisphenol S (BPS), and bisphenol fluorene (BHPF) have been used to replace BPA. Because these replacement chemicals have chemical structures similar to that of BPA, they may also harm human health. However, their immunotoxicity and the molecular mechanisms underlying their toxicity remain largely unknown. The aim of this study was to investigate the immunotoxicity of BPA and its replacement chemicals, as well as the underlying mechanisms by exposing primary human lymphocytes to BPA and its replacement chemicals. Our results showed that exposure to BPA and its replacement chemicals altered the interleukin (IL) and cytokine production, such as IL-1b, IL-5, IL-6, IL-8, interferon alfa-2b (IFN-a2B), and tumor necrosis factor alpha (TNF-α), in the lymphocytes. Among these, BPA and BHPF caused a greater inhibition. Using comparative transcriptomic analysis, we further investigated the biological processes and signaling pathways altered by BHPF exposure. Our data highlighted alterations in the immune response, T cell function, and cytokine-cytokine receptor interactions in human lymphocytes through the deregulation of gene clusters. In addition, the results of ingenuity pathway analysis demonstrated the inhibition of T lymphocyte function, including differentiation, movement, and infiltration. Our results, for the first time, delineate the mechanisms underlying the immunotoxicity of BHPF in human lymphocytes.
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Compuestos de Bencidrilo , Linfocitos , Fenoles , Sulfonas , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Fenoles/toxicidad , Sulfonas/toxicidad , Compuestos de Bencidrilo/toxicidad , Citocinas/metabolismo , Células Cultivadas , Disruptores Endocrinos/toxicidadRESUMEN
The tumor microenvironment (TME) consists of tumor cells, non-tumor cells, extracellular matrix, and signaling molecules, which can contribute to tumor initiation, progression, and therapy resistance. In response to starvation, hypoxia, and drug treatments, tumor cells undergo a variety of deleterious endogenous stresses, such as hypoxia, DNA damage, and oxidative stress. In this context, to survive the difficult situation, tumor cells evolve multiple conserved adaptive responses, including metabolic reprogramming, DNA damage checkpoints, homologous recombination, up-regulated antioxidant pathways, and activated unfolded protein responses. In the last decades, the protein O-GlcNAcylation has emerged as a crucial causative link between glucose metabolism and tumor progression. Here, we discuss the relevant pathways that regulate the above responses. These pathways are adaptive adjustments induced by endogenous stresses in cells. In addition, we systematically discuss the role of O-GlcNAcylation-regulated stress-induced adaptive response pathways (SARPs) in TME remodeling, tumor progression, and treatment resistance. We also emphasize targeting O-GlcNAcylation through compounds that modulate OGT or OGA activity to inhibit tumor progression. It seems that targeting O-GlcNAcylated proteins to intervene in TME may be a novel approach to improve tumor prognosis.
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Acetilglucosamina , Neoplasias , Transducción de Señal , Microambiente Tumoral , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/genética , Acetilglucosamina/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , N-Acetilglucosaminiltransferasas/genética , Animales , Estrés Oxidativo , Estrés Fisiológico , GlicosilaciónRESUMEN
Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. It is characterized by a rapid progression, poor prognosis, and early pulmonary metastasis. Over the past 30 years, approximately 85% of patients with osteosarcoma have experienced metastasis. The five-year survival of patients with lung metastasis during the early stages of treatment is less than 20%. The tumor microenvironment (TME) not only provides conditions for tumor cell growth but also releases a variety of substances that can promote the metastasis of tumor cells to other tissues and organs. Currently, there is limited research on the role of the TME in osteosarcoma metastasis. Therefore, to explore methods for regulating osteosarcoma metastasis, further investigations must be conducted from the perspective of the TME. This will help to identify new potential biomarkers for predicting osteosarcoma metastasis and assist in the discovery of new drugs that target regulatory mechanisms for clinical diagnosis and treatment. This paper reviews the research progress on the mechanism of osteosarcoma metastasis based on TME theory, which will provide guidance for the clinical treatment of osteosarcoma.
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Neoplasias Óseas , Neoplasias Pulmonares , Osteosarcoma , Adolescente , Niño , Humanos , Microambiente Tumoral , Osteosarcoma/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Óseas/tratamiento farmacológico , PronósticoRESUMEN
The slow-evolving invertebrate amphioxus has an irreplaceable role in advancing our understanding of the vertebrate origin and innovations. Here we resolve the nearly complete chromosomal genomes of three amphioxus species, one of which best recapitulates the 17 chordate ancestor linkage groups. We reconstruct the fusions, retention, or rearrangements between descendants of whole-genome duplications, which gave rise to the extant microchromosomes likely existed in the vertebrate ancestor. Similar to vertebrates, the amphioxus genome gradually establishes its three-dimensional chromatin architecture at the onset of zygotic activation and forms two topologically associated domains at the Hox gene cluster. We find that all three amphioxus species have ZW sex chromosomes with little sequence differentiation, and their putative sex-determining regions are nonhomologous to each other. Our results illuminate the unappreciated interspecific diversity and developmental dynamics of amphioxus genomes and provide high-quality references for understanding the mechanisms of chordate functional genome evolution.
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Anfioxos , Animales , Cromatina , Cromosomas Sexuales , Reordenamiento Génico , Familia de MultigenesRESUMEN
OBJECTIVE: DNA damage response (DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation (DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor (ICI) therapy in gastrointestinal (GI) cancer. METHODS: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts. RESULTS: The DRIA signature includes three genes (CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients (81.8% vs. 8.8%; P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve (AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein-Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer. CONCLUSIONS: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pan-cancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.
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Adenocarcinoma , Infecciones por Virus de Epstein-Barr , Neoplasias Gastrointestinales , Melanoma , Neoplasias Pancreáticas , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Herpesvirus Humano 4 , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Reparación del ADNRESUMEN
Vertebrate evolution was accompanied by two rounds of whole-genome duplication followed by functional divergence in terms of regulatory circuits and gene expression patterns. As a basal and slow-evolving chordate species, amphioxus is an ideal paradigm for exploring the origin and evolution of vertebrates. Single-cell sequencing has been widely used to construct the developmental cell atlas of several representative species of vertebrates (human, mouse, zebrafish, and frog) and tunicates (sea squirts). Here, we perform single-nucleus RNA sequencing (snRNA-seq) and single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) for different stages of amphioxus (covering embryogenesis and adult tissues). With the datasets generated, we constructed a developmental tree for amphioxus cell fate commitment and lineage specification and characterize the underlying key regulators and genetic regulatory networks. The data are publicly available on the online platform AmphioxusAtlas.
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Anfioxos , Animales , Cromatina/genética , Expresión Génica , Genoma , Anfioxos/genética , Ratones , Pez Cebra/genéticaRESUMEN
The incidence rate of breast cancer is the highest in the world, and major problem in the clinical treatment is the therapy resistance of breast cancer stem cells (CSCs). Thus, new therapeutic approaches targeting breast CSCs are needed. Our previous study demonstrated cancer-derived sialylated IgG (SIA-IgG) is highly expressed in cancer cells with stem/progenitor features. Furthermore, a high frequency of SIA-IgG in breast cancer tissue predicted metastasis and correlated with poor prognosis factors, and depletion of IgG in breast cancer leads to lower malignancy of cancer cells, suggesting SIA-IgG could be a potential therapeutic target in breast cancer. In this study, we first investigated the relationship of SIA-IgG expression with the clinicopathological characteristics and clinical prognosis of breast carcinoma patients, and the data confirmed that the expression of SIA-IgG confers poor prognosis in breast cancer. Successively, by using a monoclonal antibody specifically against SIA-IgG, we targeted SIA-IgG on the surface of MDA-MB-231 cells and detected their functional changes, and the results suggested SIA-IgG to be a promising antibody therapeutic target in breast cancer. In addition, we explored the mechanism of action at the molecular level of SIA-IgG on breast cancer cell, the findings suggest that SIA-IgG promotes proliferation, metastasis, and invasion of breast cancer cells through the Wnt/ß-catenin signaling pathway. Developing therapeutic antibody needs effective therapeutic target, and the antibody should better be a monoclonal antibody with high affinity and high specificity. This study provides a potential prognostic marker and a novel therapeutic target for breast cancer.
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Neoplasias de la Mama , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Inmunoglobulina G , Pronóstico , Vía de Señalización WntRESUMEN
The karyotype of most birds has remained considerably stable during more than 100 million years' evolution, except for some groups, such as parrots. The evolutionary processes and underlying genetic mechanism of chromosomal rearrangements in parrots, however, are poorly understood. Here, using chromosome-level assemblies of four parrot genomes, we uncover frequent chromosome fusions and fissions, with most of them occurring independently among lineages. The increased activities of chromosomal rearrangements in parrots are likely associated with parrot-specific loss of two genes, ALC1 and PARP3, that have known functions in the repair of double-strand breaks and maintenance of genome stability. We further find that the fusion of the ZW sex chromosomes and chromosome 11 has created a pair of neo-sex chromosomes in the ancestor of parrots, and the chromosome 25 has been further added to the sex chromosomes in monk parakeet. Together, the combination of our genomic and cytogenetic analyses characterizes the complex evolutionary history of chromosomal rearrangements and sex chromosomes in parrots.
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Evolución Molecular , Loros/genética , Cromosomas Sexuales/genética , Animales , Pintura Cromosómica , Roturas del ADN de Doble Cadena , ADN Helicasas/genética , Femenino , Reordenamiento Génico , Inestabilidad Genómica , Cariotipo , Cariotipificación , Filogenia , Poli(ADP-Ribosa) Polimerasas/genética , SinteníaRESUMEN
Stroke is a public health threat that requires urgent attention in China. Nutrients have individual significant impacts on the prevalence of stroke. However, little research has been conducted on the impact of dietary knowledge on stroke and whether the impact is potentially heterogeneous under the effect of socioeconomic status. This study used the 2015 Chinese Health and Nutrition Survey to explore the impact of dietary knowledge and socioeconomic factors on populations suffering from stroke. Results indicated that risk of stroke decreased significantly with increasing dietary knowledge score. Additionally, the impact of dietary knowledge scores on the prevalence of stroke has obvious heterogeneity. First, dietary knowledge scores significantly influenced low-income groups and individuals with low educational levels. Second, the risk of stroke in females is more affected by dietary knowledge. Third, for people living in different areas, dietary knowledge determines whether rural populations suffer from stroke.
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Goldfish have been subjected to over 1,000 y of intensive domestication and selective breeding. In this report, we describe a high-quality goldfish genome (2n = 100), anchoring 95.75% of contigs into 50 pseudochromosomes. Comparative genomics enabled us to disentangle the two subgenomes that resulted from an ancient hybridization event. Resequencing 185 representative goldfish variants and 16 wild crucian carp revealed the origin of goldfish and identified genomic regions that have been shaped by selective sweeps linked to its domestication. Our comprehensive collection of goldfish varieties enabled us to associate genetic variations with a number of well-known anatomical features, including features that distinguish traditional goldfish clades. Additionally, we identified a tyrosine-protein kinase receptor as a candidate causal gene for the first well-known case of Mendelian inheritance in goldfish-the transparent mutant. The goldfish genome and diversity data offer unique resources to make goldfish a promising model for functional genomics, as well as domestication.
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Domesticación , Evolución Molecular , Carpa Dorada/genética , Selección Artificial/genética , Animales , Mapeo Contig , Conjuntos de Datos como Asunto , Femenino , Proteínas de Peces/genética , Variación Genética , Genoma/genética , Genómica , Hibridación Genética , Masculino , Modelos Animales , Filogenia , Proteínas Tirosina Quinasas/genéticaRESUMEN
The emergence of adaptive immunity in jawed vertebrates depended on the appearance of variable immune receptors, BCRs and TCRs, which exhibit variable-J-constant (VJ-C)-type Ig superfamily folds. Hitherto, however, the structures of IgV-J-IgC-type molecules had never been characterized in invertebrates, leaving the origin of BCR/TCR-type molecules unknown. Using x-ray crystallography, the structure of a VJ-C2 molecule, named AmpIgVJ-C2, was determined in amphioxus (Branchiostoma floridae). The first domain shows typical V folding, including the hydrophobic core, CDR analogs, and eight conserved residues. The second domain is a C2-type Ig superfamily domain, as defined by its short length and the absence of ß-strand D- and C1-typical motifs. AmpIgVJ-C2 molecules form homodimers, using "three-layer packing dimerization," as described for TCRs and BCRs. The AmpIgVJ-C2 V domain harbors a diglycine motif in ß-strand G and forms a ß-bulge structure participating in V-V intermolecular interaction. By immunohistochemistry, AmpIgVJ-C2 molecules were primarily found in mucosal tissues, whereas PCR and sequence analysis indicated considerable genetic variation at the single-gene level; these findings would be consistent with an immune function and a basic ability to adapt to binding different immune targets. Our results show a BCR/TCR-ancestral like molecule in amphioxus and help us to understand the evolution of the adaptive immune system.
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Dominios de Inmunoglobulinas/genética , Región Variable de Inmunoglobulina/química , Anfioxos/inmunología , Receptores Inmunológicos/química , Receptores Inmunológicos/genética , Inmunidad Adaptativa/fisiología , Animales , Evolución Molecular , Anfioxos/genéticaRESUMEN
Autoimmune diabetes is a disorder of immune homeostasis that leads to targeted insulin-secreting islet ß cell destruction characterized by insulitis. Human amylin (hA) is an important neuroendocrine hormone co-secreted with insulin by pancreatic ß cells. Here, we report hA immune-modulatory action through inducing regulatory T cells. We ex vivo-treated human peripheral blood mononuclear cells (hPBMCs) with hA for 24 h and counted CD4+Foxp3+ regulatory T cells (Treg) using flow cytometry. Diabetic status was monitored and splenic Treg were measured in non-obese diabetic (NOD) male mice. NOD mice were intraperitoneally injected once daily with hA (n = 25) or solvent for control (n = 25) for 7 months continuously. Spleen tissues were collected at the end of intervention and processed for flow cytometry and Western blot. We found a 2.9-fold (p < 0.05) increase of CD4+Foxp3+ Treg in hPBMCs treated with 10 nmol/L hA compared with negative control. Incidence of diabetes in hA-treated NOD mice decreased 44% (p = 0.045) in the 6th month and 57% (p = 0.0002) in the 7th month. Meanwhile, the hA treatment induced a 1.5-fold increase of CD4+Foxp3+ Treg from mouse splenocytes (p = 0.0013). Expression of transforming growth factor-ß (TGF-ß) and toll-like receptor-4 (TLR-4) were upregulated in hA-treated mice. Human amylin might protect against autoimmune diabetes via the induction of CD4+Foxp3+ Treg, which suggests a novel approach to improve autoimmune conditions.
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Diabetes Mellitus Tipo 1/inmunología , Células Secretoras de Insulina/patología , Polipéptido Amiloide de los Islotes Pancreáticos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos CD4/metabolismo , Células Cultivadas , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunomodulación , Masculino , Ratones , Ratones Endogámicos NOD , Receptor Toll-Like 4/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Vertebrates diverged from other chordates ~500 Myr ago and experienced successful innovations and adaptations, but the genomic basis underlying vertebrate origins are not fully understood. Here we suggest, through comparison with multiple lancelet (amphioxus) genomes, that ancient vertebrates experienced high rates of protein evolution, genome rearrangement and domain shuffling and that these rates greatly slowed down after the divergence of jawed and jawless vertebrates. Compared with lancelets, modern vertebrates retain, at least relatively, less protein diversity, fewer nucleotide polymorphisms, domain combinations and conserved non-coding elements (CNE). Modern vertebrates also lost substantial transposable element (TE) diversity, whereas lancelets preserve high TE diversity that includes even the long-sought RAG transposon. Lancelets also exhibit rapid gene turnover, pervasive transcription, fastest exon shuffling in metazoans and substantial TE methylation not observed in other invertebrates. These new lancelet genome sequences provide new insights into the chordate ancestral state and the vertebrate evolution.
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Evolución Molecular , Genoma , Anfioxos/genética , Adaptación Fisiológica , Animales , Elementos Transponibles de ADN , Exones , Anfioxos/clasificación , Anfioxos/fisiología , Vertebrados/clasificación , Vertebrados/genéticaRESUMEN
BACKGROUND: In a previous study, we showed that the cephalochordate amphioxus Branchiostoma floridae has localized maternal transcripts of conserved germ cell markers Vasa and Nanos in its early embryos. These results provided strong evidence to support a preformation mechanism for primordial germ cell (PGC) development in B. floridae. RESULTS: In this study, we further characterize the expression of B. floridae homologs of Piwi and Tudor, which play important roles in germline development in diverse metazoan animals. We show that maternal mRNA of one of the identified Piwi-like homologs, Bf-Piwil1, also colocalizes with Vasa in the vegetal germ plasm and has zygotic expression in both the putative PGCs and the tail bud, suggesting it may function in both germline and somatic stem cells. More interestingly, one Tudor family gene, Bf-Tdrd7, is only expressed maternally and colocalizes with Vasa in germ plasm, suggesting that it may function exclusively in germ cell specification. To evaluate the conservation of the preformation mechanism among amphioxus species, we further analyze Vasa, Nanos, Piwil1, and Tdrd7 expression in two Asian amphioxus species, B. belcheri and B. japonicum. Their maternal transcripts all localize in similar patterns to those seen in B. floridae. In addition, we labeled putative PGCs with Vasa antibody to trace their dynamic distribution in developing larvae. CONCLUSIONS: We identify additional germ plasm components in amphioxus and demonstrate the molecular distinction between the putative germline stem cells and somatic stem cells. Moreover, our results suggest that preformation may be a conserved mechanism for PGC specification among Branchiostoma species. Our Vasa antibody staining results suggest that after the late neurula stage, amphioxus PGCs probably proliferate with the tail bud cells during posterior elongation and are deposited near the forming myomere boundaries. Subsequently, these PGCs would concentrate at the ventral tip of the myoseptal walls to form the gonad anlagen.
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CD27 and its ligand, CD70, are major costimulatory molecules whose interaction can regulate the expansion and differentiation of effector and memory T-cell populations. Their abnormal expression can disturb the immune response and lead to an increased risk of cancer. This study aims to evaluate the associations between single nucleotide polymorphisms (SNPs) in CD27/CD70 gene and breast cancer susceptibility. Five tagSNPs and one coding polymorphism in CD27, as well as three tagSNPs in CD70, were genotyped in a case-control study of 610 breast cancer patients and 617 healthy controls. In CD27, rs3136550 CT and rs2267966 AT genotypes were associated with a decreased risk of breast cancer (P = 0.03, OR = 0.76; P = 0.02, OR = 0.75, respectively). In CD70, AG and GG genotypes in rs1862511 and CC genotype in rs2059154 also showed significant associations with a decreased risk of breast cancer (P = 2.00 × 10(-3), OR = 0.69; P = 0.03, OR = 0.62; P = 2.00 × 10(-3), OR = 0.53; respectively). Significant associations were also found in the dominant and recessive models for rs2059154 and dominant model for rs1862511. In haplotype analysis, CCGAG haplotype in CD27 and TAA haplotype in CD70 conferred an increased risk of breast cancer (P = 5.60 × 10(-3); P = 7.75 × 10(-5), respectively), but TGC, TAC and TGA haplotypes in CD70 were associated with a decreased risk of breast cancer (P = 0.01; P = 5.2 × 10(-3); P = 2.00 × 10(-3), respectively). The associations of CCGAG, TAA, TAC and TGA haplotypes remained significant after correcting P value for multiple testing. Significant associations were shown between the SNPs of CD27 and lymph node metastasis, and ER and PR statuses. These results indicate that CD27 and CD70 gene polymorphisms may affect the risk of breast cancer and show that some SNPs are associated with breast cancer characteristics in a northern Chinese population.
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Pueblo Asiatico/genética , Neoplasias de la Mama/genética , Ligando CD27/genética , Polimorfismo de Nucleótido Simple , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Adulto , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Estudios de Casos y Controles , China/epidemiología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , RiesgoRESUMEN
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule that plays a pivotal role in downregulating T-cell mediated immune responses. To determine the role of CTLA-4 in tumor immunity, and to validate previous results as well, we investigated four tag single nucleotide polymorphisms (SNPs) of CTLA-4 in a relatively large Chinese Han cohort from northeastern China. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 581 patients and 566 age-matched controls. Our data indicated that compared with the common genotype and allele of each SNP, the -1722 CC genotype and C allele showed an increased risk of breast cancer (P = 0.030, odds ratio (OR) = 1.457, 95% confidence internal (CI) 1.036-2.051; P = 0.024, OR = 1.214, 95% CI 1.026-1.436, respectively). The -1661 GG genotype and G allele were also associated with an increased risk of breast cancer (P = 0.018, OR = 1.396, 95% CI 1.058-1.843; P = 0.013, OR = 1.353, 95% CI 1.066-1.717, respectively). In the haplotype analysis, the CAAA haplotype showed a higher frequency in cases (P = 0.004), and this association remained significant after correcting the P value for multiple testing. Associations were shown between the SNPs of CTLA-4 and lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR) and P53 statuses. These results indicate that some SNPs in the CTLA-4 gene may affect the risk of breast cancer and show that some SNPs are associated with breast cancer characteristics in Han women in northeastern China.
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Neoplasias de la Mama/genética , Antígeno CTLA-4/genética , Estudios de Asociación Genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Neoplasias de la Mama/patología , China , Femenino , Genotipo , Haplotipos , Humanos , Ganglios Linfáticos/patología , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Riesgo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Inducible costimulator (ICOS), a costimulatory molecular of the CD28 family, provides positive signal to enhance T cell proliferation. Its abnormal expression can disturb the immune response and entail an increased risk of cancer. To investigate whether single nucleotide polymorphisms (SNPs) in the ICOS gene are associated with sporadic breast cancer susceptibility and progression in Chinese women, a case-control study was conducted. METHODS: In the study cohort, we genotyped five SNPs (rs11889031, rs10932029, rs4675374, rs10183087 and rs10932037) in ICOS gene among 609 breast cancer patients and 665 age-matched healthy controls. Furthermore, the positive results were replicated in an independent validation cohort of 619 patients and 682 age-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the genotypes. RESULTS: In rs10932029, compared with TT genotype and T allele, the CT genotype and C allele showed a significantly increased risk of breast cancer (P = 0.030, OR = 1.467, 95% CI 1.037-2.077; P = 0.017, OR = 1.481, 95% CI 1.070-2.049, respectively), and the associations were also significant in the validation cohort (P = 0.002, OR = 1.693, 95% CI 1.211-2.357; P = 0.003, OR = 1.607, 95% CI 1.171-2.204, respectively). Haplotype analysis showed that CTCAC haplotype containing rs10932029 T allele had a lower frequency in cases than in controls (P = 0.015), whereas haplotype CCCAC containing rs10932029 C allele was more common in cases than in controls (P = 0.013). In the analysis of clinicopathologic features, rs11889031 CT genotype and T allele were associated with progesterone receptor (PR) status and lymph node metastasis, which were further supported by our validation cohort. Moreover, some haplotypes were associated with estrogen receptor (ER) and PR statuses. CONCLUSIONS: These results indicate that ICOS gene polymorphisms may affect the risk of breast cancer and show that some SNPs are associated with breast cancer characteristics in a northern Chinese population.
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Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Polimorfismo de Nucleótido Simple , Adulto , Alelos , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Persona de Mediana EdadRESUMEN
To study the anti-tumor activity of Scurrula parasitica polysaccharides (SP). Water extraction and ethanol precipitation were used to isolate SP from S. parasitica leaf. S180, K562 and HL-60 cell lines proliferation inhibition by SP were detected by MTT assay. The expressions of Ki-67, Cyclin D1, Bax and Bcl-2 protein in the sarcoma S180 tissues were detected by immunohistochemistry technique to approach the anti-tumor mechanism of SP+ SP could not inhibit cancer cell proliferation. SP ip could inhibit the growth of sarcoma S180 in mice, 100 mg x kg(-1) x d(-1). SP ip was the optimal dose on inhibiting S180 growth, with the tumor inhibition rate of 54%. The expression of Ki-67, Cyclin D1, Bax and Bcl-2 protein in the sarcoma S180 tissues were detected by immunohistochemistry technique to approach the anti-tumor mechanism of SP. The result showed that SP could down-regulate the expression of Ki-67, CyclinD1 and Bcl-2 protein, and up-regulate the expression of Bax protein. It indicted that inhibiting cancer cell proliferation and promoting cancer cell apoptosis in vivo maybe one of the anti-cancer mechanisms of SP.
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Medicamentos Herbarios Chinos/uso terapéutico , Loranthaceae/química , Plantas Medicinales/química , Polisacáridos/uso terapéutico , Sarcoma 180/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina D1/metabolismo , Medicamentos Herbarios Chinos/química , Femenino , Células HL-60 , Humanos , Inmunohistoquímica , Células K562 , Masculino , Ratones , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Sarcoma 180/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Bone morphogenetic proteins (BMPs) are responsible for regulating embryo development and tissue homeostasis beyond osteogenesis. However, the precise biological roles of BMP3 and BMP3b remain obscure to a certain extent. In the present study, we cloned an orthologous gene (AmphiBMP3/3b) from amphioxus (Branchiostoma japonicum) and found its exon/intron organization is highly conserved. Further, in situ hybridization revealed that the gene was strongly expressed in the dorsal neural plate of the embryos. The gene also appeared in Hatschek's left diverticulum, neural tube, preoral ciliated pit and gill slit of larvae, and adult tissues including ovary, neural tube and notochordal sheath. Additionally, real-time quantitative polymerase chain reaction (RTqPCR) analysis revealed that the expression displayed two peaks at gastrula and juvenile stages. These results indicated that AmphiBMP3/3b, a sole orthologue of vertebrate BMP3 and BMP3b, might antagonize ventralizing BMP2 orthologous signaling in embryonic development, play a role in the evolutionary precursors of adenohypophysis, as well as act in female ovary physiology in adult.
Asunto(s)
Proteína Morfogenética Ósea 3/genética , Cordados no Vertebrados/genética , Regulación del Desarrollo de la Expresión Génica , Factor 10 de Diferenciación de Crecimiento/genética , Animales , Cordados no Vertebrados/embriología , Clonación Molecular , Perfilación de la Expresión Génica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Especificidad de la EspecieRESUMEN
Green fluorescent protein (GFP) has been widely used as a molecular marker in modern biological research. Before the recent report of one GFP gene in Branchiostoma floridae, GFP family members were cloned only from other two groups of species: Cnidaria and Copepoda. Here we describe the complete GFP gene repertoire of B. floridae which includes 13 functional genes and 2 pseudogenes, representing the largest GFP family found so far. Coupling with nine other GFP sequences from another two species of genus Branchiostoma and the sequences from Cnidaria and Copepoda, we made a deep-level phylogenetic analysis for GFP genes in cephalochordates and found: 1) GFP genes have experienced a divergent evolution in cephalochordates; 2) all amphioxus GFP genes form four main clades on the tree which had diverged before the radiation of the last common ancestor of all extant cephalochordates; 3) GFP genes in amphioxus shared a common ancestor with that in Copepoda rather than being derived from horizontal gene transfer, which indicates that our ancestor was derived from a fluorescent organism and lost this ability after its separation from Cephalochordata, and also makes GFP a rare gene which has a rather unusual evolutionary path. In addition, we also provided evidence indicating that GFP genes have evolved divergent functions by specializing their expression profile, and different fluorescent spectra by changing their emission peaks. These findings spark two interesting issues: what are GFP in vivo functions in cephalochordates and why they are lost in other examined deuterostomes?