Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 427
Filtrar
1.
Front Immunol ; 12: 715559, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539647

RESUMO

The involvement of gut microbiota in T-cell trafficking into tumor tissue of colorectal cancer (CRC) remains to be further elucidated. The current study aimed to evaluate the expression of major cytotoxic T-cell trafficking chemokines (CTTCs) and chemokine-associated microbiota profiles in both tumor and adjacent normal tissues during CRC progression. We analyzed the expression of chemokine C-X-C motif ligands 9, 10, and 11 (CXCL9, CXCL10, and CXCL11), and C-C motif ligand 5 (CCL5), characterized gut mucosa-associated microbiota (MAM), and investigated their correlations in CRC patients. Our results showed that the expression of CXCL9, CXCL10, and CXCL11 was significantly higher in tumor than in adjacent normal tissues in 136 CRC patients. Notably, the high expression of CXCL9 in tumor tissues was associated with enhanced CD8+ T-cell infiltration and improved survival. Moreover, the MAM in tumor tissues showed reduction of microbial diversity and increase of oral bacteria. Microbial network analysis identified differences in microbial composition and structure between tumor and adjacent normal tissues. In addition, stronger associations between oral bacteria and other gut microbes were observed. Furthermore, the correlation analysis between the defined MAM and individual CTTCs showed that the CTTCs' correlated operational taxonomic units (OTUs) in tumor and adjacent normal tissues rarely overlap with each other. Notably, all the enriched OTUs were positively correlated with the CTTCs in either tumor or adjacent normal tissues. Our findings demonstrated stronger interactions between oral bacteria and gut microbes, and a shifted correlation pattern between MAM and major CTTCs in tumor tissues, underlining possible mechanisms of gut microbiota-host interaction in CRC.

2.
Stem Cell Res Ther ; 12(1): 474, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425902

RESUMO

Endometrial stem/progenitor cells have been proved to exist in periodically regenerated female endometrium and can be divided into three categories: endometrial epithelial stem/progenitor cells, CD140b+CD146+ or SUSD2+ endometrial mesenchymal stem cells (eMSCs), and side population cells (SPs). Endometrial stem/progenitor cells in the menstruation blood are defined as menstrual stem cells (MenSCs). Due to their abundant sources, excellent proliferation, and autotransplantation capabilities, MenSCs are ideal candidates for cell-based therapy in regenerative medicine, inflammation, and immune-related diseases. Endometrial stem/progenitor cells also participate in the occurrence and development of endometriosis by entering the pelvic cavity from retrograde menstruation and becoming overreactive under certain conditions to form new glands and stroma through clonal expansion. Additionally, the limited bone marrow mesenchymal stem cells (BMDSCs) in blood circulation can be recruited and infiltrated into the lesion sites, leading to the establishment of deep invasive endometriosis. On the other hand, cell derived from endometriosis may also enter the blood circulation to form circulating endometrial cells (CECs) with stem cell-like properties, and to migrate and implant into distant tissues. In this manuscript, by reviewing the available literature, we outlined the characteristics of endometrial stem/progenitor cells and summarized their roles in immunoregulation, regenerative medicine, and endometriosis, through which to provide some novel therapeutic strategies for reproductive and cancerous diseases.

3.
Nat Commun ; 12(1): 4230, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244494

RESUMO

Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXß2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXß2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXß2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXß2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.


Assuntos
Processamento Alternativo , Carcinoma Epitelial do Ovário/genética , Proteínas da Matriz Extracelular/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/terapia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas da Matriz Extracelular/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Integrina alfaXbeta2/genética , Integrina alfaXbeta2/metabolismo , Estimativa de Kaplan-Meier , Camundongos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Ovário/patologia , Ovário/cirurgia , Fosforilação/genética , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA-Seq , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
BMC Cancer ; 21(1): 423, 2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33863293

RESUMO

BACKGROUND: Glia maturation factor-γ (GMFG) is reported to inhibit the actin nucleation through binding to the actin-related protein-2/3 complex (Arp2/3). Considering the main function of GMFG in actin remodeling, which is vital for immune response, angiogenesis, cell division and motility, GMFG is supposed to have important roles in tumor development, while up to now, only two studies described the role of GMFG in cancers. By investigating the clinical values of GMFG using The Cancer Genome Atlas (TCGA) data and the functional mechanisms of GMFG through analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments, this study was aimed to better understand the impact of GMFG in pan-cancers and to draw more attentions for the future research of GMFG. METHODS: RNA-seq and clinical data of cancer patients were collected from TCGA and analyzed by the Kaplan-Meier methods. GO and KEGG analyses were conducted using the online tools from the Database for Annotation, Visualization and Integrated Discovery (DAVID). RESULTS: Compared to the corresponding normal samples, GMFG was significantly upregulated in glioblastoma (GBM), kidney clear cell carcinoma (KIRC), lower grade glioma (LGG), acute myeloid leukemia (LAML), and pancreatic cancer (PAAD), testicular cancer (TGCT), but was downregulated in kidney chromophobe (KICH), lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) (P < 0.05 for all). High expression of GMFG predicted worse OS in GBM (HR = 1.5, P = 0.017), LGG (HR = 2.2, P < 0.001), LUSC (HR = 1.4, P = 0.022) and ocular melanomas (UVM) (HR = 7, P < 0.001), as well as worse DFS in LGG (HR = 1.8, P < 0.001) and prostate cancer (PRAD) (HR = 1.9, P = 0.004). In contrast, high expression of GMFG was associated with better OS in skin cutaneous melanoma (SKCM) (HR = 0.59, P < 0.001) and thymoma (THYM) (HR = 0.098, P = 0.031), as well as better DFS in bile duct cancer (CHOL) (HR = 0.2, P = 0.003). GMFG was mainly involved in the immune response, protein binding and cytokine-cytokine receptor interaction pathways, and was positively associated with multiple immunomodulators in most cancers. CONCLUSION: Our study preliminarily identified that GMFG may cause different survivals for different cancers through modulating tumor progression, immune response status and tissue-specific tumor microenvironment (TME).


Assuntos
Biomarcadores Tumorais , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Fator de Maturação da Glia/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Imunomodulação/genética , Estimativa de Kaplan-Meier , Estadiamento de Neoplasias , Especificidade de Órgãos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/imunologia , Prognóstico , Transcriptoma , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
5.
Plant Dis ; 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33881919

RESUMO

In the main wheat production area of China (The Huang Huai Plain, HHP), both Fusarium graminearum and F. asiaticum, the causal agents of Fusarium head blight (FHB), are present. We investigated whether the relative prevalence of F. graminearum and F. asiaticum is related to cropping systems and/or climate factors. A total of 1844 Fusarium isolates were obtained from 103 fields of two cropping systems: maize-wheat and rice-wheat rotations. To maximize the differences in climatic conditions, isolates were sampled from the north and south HHP region. Based on the phylogenetic analysis of EF-1α and Tri101sequences, 1207 of the 1844 isolates belonged to F. graminearum, and the remaining 637 isolates belonged to F. asiaticum. The former was predominant in the northern region: 1022 of the 1078 Fusarium isolates in the north were F. graminearum. The latter was predominant in the southern region: 581 of the 766 Fusarium isolates belonging to F. asiaticum. Analysis based on generalised linear modelling, the relative prevalence of the two species was associated more with climatic conditions than with the cropping system. Fusarium graminearum was associated with drier conditions, cooler conditions during the winter but warmer conditions in the infection and grain-colonization period, and with the maize-wheat rotation. The opposite was true for F. asiaticum. Except 15-ADON, the trichothecene chemotype composition of F. asiaticum differed between the two cropping systems. The 3-ADON was more prevalent in the maize-wheat rotation; whereas NIV more prevalent in the rice-wheat rotation. The results also suggested that environmental conditions in the overwintering period appeared to be more important than that in the infection and grain-colonization and pre-anthesis sporulation periods in affecting the relative prevalence of F. graminearum and F. asiaticum. More research is needed to study the effect of overwintering conditions on subsequent epidemic in the following spring.

7.
Alcohol Clin Exp Res ; 45(2): 307-317, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33283290

RESUMO

BACKGROUND: Aldehyde dehydrogenase-2 (ALDH2) plays an important role in the alcohol detoxification and acetaldehyde metabolism. Published studies have demonstrated some inconsistent associations between ALDH2 rs671 G>A polymorphism and head and neck cancer (HNC) risk. METHODS: A meta-analysis was performed to provide pooled data on the association between the ALDH2 rs671 G>A polymorphism and HNC risk. Electronic databases were searched to identify relevant studies. Odds ratios and 95% confidence intervals (CIs) were used to examine the pooled effect size of each genetic model. In addition, heterogeneity test, accumulative analysis, sensitivity analysis, and publication bias were conducted to test the statistical power. RESULTS: Thirteen publications (14 independent case-control studies) involving 10,939 subjects were selected. The stratified analysis indicated that both light/moderated drinking (e.g., GA vs. GG: OR = 1.47, 95% CI = 1.16 to 1.86, p < 0.01, I2  = 81.1%) and heavy drinking would increase HNC risk with rs671 G>A mutation (e.g., GA vs. GG: OR = 2.30, 95% CI = 1.11 to 4.77, p = 0.03, I2  = 81.9%). CONCLUSIONS: In summary, this meta-analysis suggested that the ALDH2 rs671 G>A polymorphism may play an important synergistic effect in the pathogenesis of HNC development in East Asians.

8.
PeerJ ; 8: e10255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33282553

RESUMO

Background: Ovarian cancer is one of the leading causes of cancer-related death in women. The incidence of ovarian cancer is insidious, and the recurrence rate is high. The survival rate of ovarian cancer has not significantly improved over the past decade. Recently, immune checkpoint inhibitors such as those targeting CTLA-4, PD-1, or PD-L1 have been used to treat ovarian cancer. Therefore, a full analysis of the immune biomarkers associated with this malignancy is necessary. Methods: In this study, we used data from The Cancer Genome Atlas (TCGA) database to analyze the infiltration patterns of specific immune cell types in tumor samples. Data from the Gene Expression Omnibus (GEO) database was used for external validation. According to the invasion patterns of immune cells, we divided the ovarian cancer microenvironment into two clusters: A and B. These tumor microenvironment (TME) subtypes were associated with genomic and clinicopathological characteristics. Subsequently, a random forest classification model was established. Differential genomic features, functional enrichment, and DNA methylation were analyzed between the two clusters. The characteristics of immune cell infiltration and the expression of immune-related cytokines or markers were analyzed. Somatic mutation analysis was also performed between clusters A and B. Finally, multivariate Cox analysis was used to analyze independent prognostic factors. Results: The ovarian cancer TME cluster A was characterized by less infiltration of immune cells and sparse distribution and low expression of immunomodulators. In contrast, cytotoxic T cells and immunosuppressive cells were significantly increased in the ovarian cancer TME cluster B. Additionally, immune-related cytokines or markers, including IFN-γ and TNF-ß, were also expressed in large quantities. In total, 35 differentially methylated and expressed genes (DMEGs) were identified. Functional enrichment analyses revealed that the DMEGs in cluster B participated in important biological processes and immune-related pathways. The mutation load in cluster B was insignificantly higher than that of cluster A (p = 0.076). Multivariate Cox analysis showed that TME was an independent prognostic factor for ovarian cancer (hazard ratio: 1.33, 95% confidence interval: 1.01-1.75, p = 0.041). Conclusion: This study described and classified basic information about the immune invasion pattern of ovarian cancer and integrated biomarkers related to different immunophenotypes to reveal interactions between ovarian cancer and the immune system.

9.
Zhongguo Zhong Yao Za Zhi ; 45(21): 5273-5279, 2020 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-33350245

RESUMO

This paper aimed to investigate the protective effect and mechanism of the Tibetan medicine Ershiwuwei Songshi Pills on α-naphthalene isothiocyanate(ANIT)-induced cholestatic liver injury in rats based on the farnesol X receptor(FXR) signaling pathway. SD rats were randomly divided into blank group, model group, ursodeoxycholic acid(UDCA) group, Tibetan medicine Ershiwuwei Songshi Pills low, medium and high dose groups(0.09, 0.18, 0.36 g·kg~(-1)). A prophylactic dosing regimen was used in the experiment. From the 1 st to 4 th days, the UDCA group and the Tibetan medicine Ershiwuwei Songshi Pills suspension groups received prophylactic gavage administration; on the 5 th day, the blank control group was given an equal volume of olive oil blank reagent, and the remaining groups were given ANIT modeling reagent. Administration was continued on day 5 to 6 in each administration group. Forty-eight hours after modeling on the 7 th day, blood was collected from the femoral artery of rats. Serum alkaline phosphatase(ALP), alanine aminotransferase(ALT), aspartate aminotransferase(AST), direct bilirubin(DBIL), total bilirubin(TBIL), and total bile acid(TBA) levels were detected, and liver histopathological changes were observed. The relative expression changes of FXR, SHP, CYP7 A1, MRP2, MRP3, NTCP, BSEP mRNA in liver tissues were detected by Real-time fluorescence quantitative method, and the expression changes of FXR, SHP, UGT2 B4 protein in liver tissues were detected by Western blot. The results showed that the Tibetan medicine Ershiwuwei Songshi Pills significantly reduced the levels of ALT, ALP, DBIL, TBIL and TBA in the serum of the ANIT mo-del rats(P<0.01, P<0.05), significantly up-regulated the mRNA expressions of SHP and NTCP(P<0.01, P<0.05), significantly down-regulated the mRNA expression of CYP7 A1 and MRP3(P<0.01, P<0.05); and significantly up-regulated the protein expressions of FXR and SHP(P<0.01, P<0.05). The Tibetan medicine Ershiwuwei Songshi Pills have an obvious protective effect on ANIT-induced cholestatic liver injury in rats, and its mechanism may be related to the bile acid metabolism mediated by the FXR signaling pathway.


Assuntos
Colestase , Medicina Tradicional Tibetana , Animais , Colestase/tratamento farmacológico , Colestase/genética , Fígado , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
10.
Front Oncol ; 10: 593017, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194756

RESUMO

Ovarian cancer is one of the most malignant gynecological cancers around the world. In spite of multiple treatment options, the five-year survival rate is still very low. Several metabolism alterations are described as a hallmark in cancers, but alterations of lipid metabolism in ovarian cancer have been paid less attention. To explore new markers/targets for accurate diagnosis, prognosis, and therapeutic treatments based on metabolic enzyme inhibitors, here, we reviewed available literature and summarized several key metabolic enzymes in lipid metabolism of ovarian cancer. In this review, the rate limiting enzymes associated with fatty acid synthesis (FASN, ACC, ACLY, SCD), the lipid degradation related enzymes (MAGL, CPT, 5-LO, COX2), and the receptors related to lipid uptake (FABP4, CD36, LDLR), which promote the development of ovarian cancer, were analyzed and evaluated. We also focused on the review of application of current metabolic enzyme inhibitors for the treatment of ovarian cancer through which the potential therapeutic agents may be developed for ovarian cancer therapy.

11.
J Nutr ; 150(9): 2442-2450, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32692347

RESUMO

BACKGROUND: Soy is commonly consumed in east Asian countries and is suggested to reduce colorectal cancer (CRC) risk. However, results from epidemiologic studies are inconsistent, despite the anti-inflammatory and antiproliferative properties of soy isoflavones and soy protein. OBJECTIVE: We evaluated the association between soy isoflavones and soy protein and CRC risk using 4 prospective cohort studies from China and Japan. METHODS: Data were pooled from the Shanghai Women's Health Study (SWHS), Shanghai Men's Health Study (SMHS), Japan Public Health Center-based Prospective Study Cohort 1 (JPHC1), and Cohort 2 (JPHC2). Cox proportional hazards models estimated HRs and corresponding 95% CIs for the association of soy protein and isoflavone intake with CRC risk. The study included 205,060 individuals, among whom 2971 were diagnosed with incident CRC over an average follow-up of 12.7 y. RESULTS: No statistically significant associations with CRC risk were observed for soy protein or isoflavone intake. No association was observed among ever smokers consuming higher isoflavones (HRisoflavones: 0.83; 95% CI: 0.68, 1.00) and soy protein (HRsoy protein: 0.81; 95% CI: 0.39, 1.10). However, risk reductions were observed among premenopausal women with a body mass index [BMI (kg/m2)] <23.0 at baseline for higher isoflavone (HRisoflavones: 0.58, 95% CI: 0.34, 0.98). CONCLUSIONS: No evidence for an overall reduction in CRC risk by increasing soy food intake (i.e., protein or isoflavones) was observed. However, the association between soy and CRC risk may vary by BMI, smoking, and menopausal status among women. Future investigations are needed to further understand the biologic mechanisms observed.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Alimentos de Soja , Idoso , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
12.
Biochem Biophys Res Commun ; 527(2): 574-580, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32423805

RESUMO

Adipogenesis, a differentiation process that transitions preadipocytes to adipocytes, is key to understanding the biology of fat accumulation and obesity. During this process, there many crucial transcription factors, such as PPARγ and the C/EBP family. Here we show a transcription factor in preadipocytes --- Sox5, that has a function in porcine adipogenesis. In our porcine subcutaneous-derived preadipocyte differentiation model, we found Sox5 expression displayed a significant upregulation after initial induction and decreased afterwards, which resembles the PPARγ expression pattern. siRNA knockdown of Sox5 in porcine preadipocytes significantly promoted cell growth and accelerated cell cycle progression. After inducing differentiation, knockdown of Sox5 notably down-regulated the expression of adipogenic marker genes: PPARγ, aP2, FAS and impaired lipid accumulation. Mechanistically, the deletion of Sox5 down-regulated the BMP R-Smads signal pathway, a crucial signal pathway for controlling preadipocyte fate commitment and adipogenesis. After using BMP4 recombinant protein to activate the BMP R-Smads signal, Sox5 function was partially rescued. In conclusion, our findings uncovered a function of Sox5 in porcine adipogenesis and reveal an interaction between Sox5 and BMP signaling.


Assuntos
Adipogenia , Proteínas Morfogenéticas Ósseas/metabolismo , Fatores de Transcrição SOXD/genética , Transdução de Sinais , Proteínas Smad/metabolismo , Suínos/fisiologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Células Cultivadas , Regulação para Baixo , Interferência de RNA , Fatores de Transcrição SOXD/metabolismo , Proteínas Smad/genética , Suínos/genética , Regulação para Cima
13.
Cell Death Dis ; 11(2): 137, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080166

RESUMO

Chemoresistance is one of the major reasons leading to ovarian cancer high mortality and poor survival. Studies have shown that the alteration of cellular autophagy is associated with cancer cell chemoresistance. Here, we investigated whether the ovarian cancer chemoresistance is associated with the autophagy induced by the inhibitor of DNA binding 1 (ID1). By using gene overexpression or silencing, luciferase assay and human specimens, we show that ID1 induces high autophagy and confers cancer cell chemoresistance. The mechanistic study demonstrates that ID1 first activates the NF-κB signaling through facilitating the nuclear translocation of NF-κB p65, which strengthens the expression and secretion of IL-6 from cancer cells to subsequently activate the signal transducer and activator of transcription 3 (STAT3) through the protein phosphorylation at Y705. We further identified that STAT3 functions to promote the transcription of the activating transcription factor 6 (ATF6), which induces endoplasmic reticulum stress to promote cellular autophagy, granting cancer cell resistance to both cisplatin and paclitaxel treatment. Moreover, we found a significant correlation between the expression of ID1 and ATF6 in 1104 high grade serous ovarian cancer tissues, and that patients with the high expression of ID1 or ATF6 were resistant to platinum treatment and had the poor overall survival and progression-free survival. Thus, we have uncovered a mechanism in which ID1 confers cancer cell chemoresistance largely through the STAT3/ATF6-induced autophagy. The involved molecules, including ID1, STAT3, and ATF6, may have a potential to be targeted in combination with chemotherapeutic agents to improve ovarian cancer survival.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Antineoplásicos/farmacologia , Autofagia , Resistencia a Medicamentos Antineoplásicos , Proteína 1 Inibidora de Diferenciação/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Fator 6 Ativador da Transcrição/genética , Animais , Linhagem Celular Tumoral , Cisplatino/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Fosforilação , Transdução de Sinais
14.
Mol Ther Nucleic Acids ; 19: 865-876, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-31982773

RESUMO

Accumulating evidence indicates that cryptochrome circadian regulatory (CRY) proteins have emerged as crucial regulators of osteogenic differentiation. However, the associated mechanisms are quite elusive. In this study, we show that knockdown of CRY2 downregulated the expression of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN) to facilitate osteoblast differentiation. Further study identified that CRY2 was directly targeted by microRNA (miR)-7-5p, which was highly induced during osteoblast differentiation. The expression of Runx2, ALP, collagen type I alpha 1 (Col1a1), and OCN was upregulated by overexpression of miR-7-5p and induction of osteoblast differentiation. Moreover, signal transducer and activator of transcription 3 (STAT3) transcriptionally activated miR-7-5p to significantly enhance the expression of above osteogenic marker genes and mineral formation. However, overexpression of CRY2 abolished the osteogenic differentiation induced by miR-7-5p overexpression. Silencing of CRY2 unraveled the binding of CRY2 with the circadian locomotor output cycles kaput (CLOCK)/brain and muscle ARNT-like 1 (BMAL1) complex to release CLOCK/BMAL1, which facilitated the binding of CLOCK/BMAL1 to the promoter region of the P300 E-box to stimulate the transcription of P300. P300 subsequently promoted the acetylation of histone 3 and the formation of a transcriptional complex with Runx2 to enhance osteogenesis. Taken together, our study revealed that CRY2 is repressed by STAT3/miR-7-5p to promote osteogenic differentiation through CLOCK/BMAL1/P300 signaling. The involved molecules may be potentially targeted for treatment of osteoporosis.

15.
Int J Cancer ; 146(3): 839-849, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31001807

RESUMO

Specific organochlorines (OCs) have been associated with non-Hodgkin lymphoma (NHL) with varying degrees of evidence. These associations have not been evaluated in Asia, where the high exposure and historical environmental contamination of certain OC pesticides (e.g., dichlorodiphenyltrichloroethane [DDT], hexachlorocyclohexane [HCH]) are different from Western populations. We evaluated NHL risk and prediagnostic blood levels of OC pesticides/metabolites and polychlorinated biphenyl congeners in a case-control study of 167 NHL cases and 167 controls nested within three prospective cohorts in Shanghai and Singapore. Conditional logistic regression was used to analyze lipid-adjusted OC levels and NHL risk. Median levels of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), the primary DDT metabolite, and ß-HCH were up to 12 and 65 times higher, respectively, in samples from the Asian cohorts compared to several cohorts in the United States and Norway. An increased risk of NHL was observed among those with higher ß-HCH levels both overall (3rd vs. 1st tertile OR = 1.8, 95%CI = 1.0-3.2; ptrend = 0.049) and after excluding cases diagnosed within 2 years of blood collection (3rd vs. 1st tertile OR = 2.0, 95%CI = 1.1-3.9; ptrend = 0.03), and the association was highly consistent across the three cohorts. No significant associations were observed for other OCs, including p,p'-DDE. Our findings provide support for an association between ß-HCH blood levels and NHL risk. This is a concern because substantial quantities of persistent, toxic residues of HCH are present in the environment worldwide. Although there is some evidence that DDT is associated with NHL, our findings for p,p'-DDE do not support an association.


Assuntos
Poluentes Ambientais/sangue , Hidrocarbonetos Clorados/sangue , Linfoma não Hodgkin/epidemiologia , Praguicidas/sangue , Idoso , Estudos de Casos e Controles , China/epidemiologia , Poluentes Ambientais/efeitos adversos , Feminino , Seguimentos , Humanos , Hidrocarbonetos Clorados/efeitos adversos , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/etiologia , Masculino , Pessoa de Meia-Idade , Praguicidas/efeitos adversos , Estudos Prospectivos , Fatores de Risco , Singapura/epidemiologia
16.
Int J Cancer ; 146(10): 2728-2735, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351006

RESUMO

Ghrelin is a hormone produced in the oxyntic glands of the stomach. Previous work by our group has suggested that serum ghrelin concentrations are inversely associated with gastric and esophageal cancer risk. We measured ghrelin concentrations in the Linxian General Population Nutrition Intervention Trial (NIT), and the Shanghai Women's Health Study (SWHS). In NIT, we analyzed serum samples from 298 esophageal squamous cell carcinoma (ESCC) cases, 518 gastric cardia adenocarcinoma (GCA) cases, 258 gastric noncardia adenocarcinoma (GNCA) cases and 770 subcohort controls (case-cohort). In SWHS, we measured ghrelin in plasma samples from 249 GNCA cases and 498 matched controls (nested case-control). Ghrelin was measured using radioimmunoassay. In NIT and SWHS, low ghrelin concentrations were associated with an increased risk of developing GNCA and GCA. The hazard ratio (HR Q1:Q4 ) for GNCA in NIT was 1.35 (95% CI: 0.89-2.05; p-trend = 0.02); the odds ratio in SWHS was 1.66 (95% CI: 1.02-2.70; p-trend = 0.06). Low ghrelin was associated with a twofold increase of GCA (HR Q1:Q4 = 2.00, 95% CI: 1.45-2.77; p-trend<0.001). In contrast, a lower risk of ESCC (NIT ESCC HR Q1:Q4 = 0.65, 95% CI: 0.45-0.92; p-trend = 0.02) was found in NIT. Low baseline ghrelin concentrations were associated with an increased risk for GNCA and GCA in the NIT and the SWHS. In contrast, low ghrelin concentrations at baseline were associated with a reduced risk of developing ESCC in the NIT. Ghrelin may be an early marker of future cancer risk for developing upper gastrointestinal cancer in regions of high incidence.


Assuntos
Carcinoma/sangue , Neoplasias Esofágicas/sangue , Grelina/sangue , Neoplasias Gástricas/sangue , Adulto , Idoso , Carcinoma/epidemiologia , China/epidemiologia , Estudos de Coortes , Neoplasias Esofágicas/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Neoplasias Gástricas/epidemiologia
17.
Int J Epidemiol ; 49(1): 56-68, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377785

RESUMO

BACKGROUND: Lifetime use of bituminous ('smoky') coal is associated with nearly a 100-fold higher risk of lung cancer mortality compared with anthracite ('smokeless') coal use in rural Xuanwei, China, among women. Risk of mortality from ischaemic heart disease (IHD) and stroke for these coal types has not been evaluated. METHODS: A cohort of 16 323 non-smoking women in Xuanwei, who were lifetime users of either smoky or smokeless coal, were followed up from 1976 to 2011. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) to evaluate lifetime use of coal types and stoves in the home in relation to risk of IHD and stroke mortality. RESULTS: Among lifetime users of smokeless coal, higher average exposure intensity (≥4 tons/year vs <2.5 tons/year, HR = 7.9, 95% CI = 3.5-17.8; Ptrend =<0.0001) and cumulative exposure (>64 ton-years vs ≤28 ton-years, HR = 6.5, 95% CI = 1.5-28.3; Ptrend =0.003) during follow-up and over their lifetime was associated with increased IHD mortality, and ventilated stove use dramatically reduced this risk (HR = 0.2, 95% CI 0.1-0.5). Higher cumulative exposure to smoky coal during follow-up showed positive associations with IHD mortality, but the evidence for other metrics was less consistent compared with associations with smokeless coal use. CONCLUSIONS: Higher use of smokeless coal, which is burned throughout China and is generally regarded to be a cleaner fuel type, is associated with IHD mortality. Use of cleaner fuels or stove interventions may be effective in reducing the increasing burden of IHD in developing regions that currently rely on smokeless coal for cooking and heating.


Assuntos
Poluição do Ar em Ambientes Fechados/efeitos adversos , Carvão Mineral/efeitos adversos , Culinária , Calefação/efeitos adversos , Isquemia Miocárdica/mortalidade , Acidente Vascular Cerebral/mortalidade , Adulto , China/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Isquemia Miocárdica/etiologia , Modelos de Riscos Proporcionais , População Rural , Acidente Vascular Cerebral/etiologia
18.
Math Biosci Eng ; 17(1): 92-104, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31731341

RESUMO

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with stronger invasive capacity. For the operation strategies of early staged (stage I and stage II) TNBC patients, BCS plus radiotherapy (BCS+RT), mastectomy only (MRM only) or MRM plus radiotherapy (MRM+RT) is feasible, but no clear conclusion has been made on the choice of these treatments. Methods: The early staged TNBC patients (stage I and stage II) from the Surveillance, Epidemiology and End Results (SEER) program database between 1973 and 2014 were included in the study. Survival curves, univariate and multivariate cox proportional hazards models and propensity score weighting were applied to evaluate the prognostic impact among BCS+RT, MRM only and MRM+RT for patients. Results: Both overall and cancer-specific survival analysis showed that BCS+RT had better prognostic effect than MRM and MRM+RT in the cohort of early-staged triple-negative breast cancer patients (overall survival, P < 0.001; cancer-specific survival, P < 0.001). By taking all the risk factors into a multivariate cox proportional model, MRM and MRM+RT remained to have detrimental effect on the prognosis compared with BCS+RT as shown by either overall (HR = 1.742, CI = 1.387-2.188, P < 0.001; HR = 1.449, CI = 1.038-2.204, P = 0.029) or cancer-specific survival (HR = 1.876, CI = 1.415-2.489, P < 0.001; HR = 1.701, CI = 1.168-2.478, P = 0.006). After we performed propensity score weighting and integrated the weights for each covariate in the multivariate cox proportional model. BCS+RT remained to be prognostic beneficial compared to the other treatment options (P < 0.001). Conclusion: BCS+RT demonstrated better prognosis than MRM only and MRM+RT treatments for early-staged TNBC patients.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Mastectomia Segmentar/métodos , Mastectomia/métodos , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/cirurgia , Adulto , Idoso , Neoplasias da Mama/radioterapia , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Pontuação de Propensão , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Fatores de Risco , Programa de SEER , Neoplasias de Mama Triplo Negativas/radioterapia , Estados Unidos
19.
Oncogenesis ; 8(10): 59, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597912

RESUMO

Chemoresistance has been the biggest obstacle in ovarian cancer treatment, and STAT3 may play an important role in chemoresistance of multiple cancers, but the underlying mechanism of STAT3 in ovarian cancer chemoresistance has long been truly illusive, particularly in association with p53 and RAS signaling. In this study, by using wild type, constitutive active, and dominant negative STAT3 constructs, wild-type p53, and RAS-mutant V12, we performed a series of in vitro and in vivo experiments by gene overexpression, drug treatment, and animal assays. We found that phosphorylation of STAT3 Y705 but not S727 promoted cancer cell EMT and metastasis through the Slug-mediated regulation of E-cadherin and Vimentin. The phosphorylation of STAT3 at Y705 also activated the MAPK and PI3K/AKT signaling to inhibit the ERS-mediated autophagy through down-regulation of pPERK, pelf2α, ATF6α, and IRE1α, which led to increased cisplatin resistance. Induction of wild type p53 in STAT3-DN-transfected cells further diminished the chemoresistance and tumor growth through the upregulation of the MAPK- and PI3K/AKT-mediated ERS and autophagy. Introduction of STAT3-DN deprived the RASV12-induced ERS, autophagy, oncogenicity, and cisplatin resistance, whereas introduction of p53 in STAT3-DN/RASV12 expressing cells induced additional tumor retardation and cisplatin sensitivity. Thus, our data provide strong evidence that the crosstalk between STAT3 and p53/RAS signaling controls ovarian cancer cell metastasis and cisplatin resistance via the Slug/MAPK/PI3K/AKT-mediated regulation of EMT and autophagy.

20.
Mol Ther ; 27(9): 1653-1664, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31278033

RESUMO

Accounting for more than 70% of ovarian cancer cases, epithelial ovarian malignancy has a low 5-year survival rate. MicroRNAs may be targeted in the clinical treatment of the disease. In this study, we first found that miR-1251-5p was significantly upregulated in human ovarian cancer cell lines and tissues with the cancer progression and stages. Overexpression or inhibition of miR-1251-5p promoted or impeded cell proliferation and cell cycle progression. Subsequently, TBCC, one of the tubulin-binding cofactors (TBCs), was identified as a target of miR-1251-5p to be negatively associated with cell cycle and autophagy. Exogenous overexpression of TBCC inhibited the expressions of CDK4 and LC3BII, but it promoted the expressions of α/ß-tubulin and p62 to suppress cell growth and autophagy, particularly under the starving condition; whereas the introduction of miR-1251-5p in TBCC-overexpressing cells rescued the suppressive effects of TBCC on cell cycle and autophagy through the inverse regulation of the above proteins. Finally, miR-1251-5p was proven to enhance xenograft tumor growth through the downregulation of TBCC but upregulation of Ki67 and LC3B in xenograft tumor tissues. Collectively, these results suggest that miR-1251-5p functions as an oncogene to suppress TBCC and α/ß-tubulin expression. Thus, the miR-1251-5p/TBCC/α/ß-tubulin axis may be targeted for ovarian cancer treatment.


Assuntos
Autofagia/genética , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Chaperonas Moleculares/genética , Neoplasias Ovarianas/genética , Regiões 3' não Traduzidas , Animais , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Camundongos , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Interferência de RNA , Recidiva
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...