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BACKGROUND: Split kidney function (SKF) is critical for treatment decision in pediatric patients with hydronephrosis and is commonly measured using renal scintigraphy (RS). Non-contrast-enhanced magnetic resonance urography (NCE-MRU) is increasingly used in clinical practice. This study aimed to investigate the feasibility of using NCE-MRU as an alternative to estimate SKF in pediatric patients with hydronephrosis, compared to RS. METHODS: Seventy-five pediatric patients with hydronephrosis were included in this retrospective study. All patients underwent NCE-MRU and RS within 2 weeks. Kidney parenchyma volume (KPV) and texture analysis parameters were obtained from T2-weighted (T2WI) in NCE-MRU. The calculated split KPV (SKPV) percent and texture analysis parameters percent of left kidney were compared with the RS-determined SKF. RESULTS: SKPV showed a significant positive correlation with SKF (r = 0.88, p < 0.001), while inhomogeneity was negatively correlated with SKF (r = - 0.68, p < 0.001). The uncorrected and corrected prediction models of SKF were established using simple and multiple linear regression. Bland-Altman plots demonstrated good agreement of both predictive models. The residual sum of squares of the corrected prediction model was lower than that of the uncorrected model (0.283 vs. 0.314) but not statistically significant (p = 0.662). Subgroup analysis based on different MR machines showed correlation coefficients of 0.85, 0.95, and 0.94 between SKF and SKPV for three different scanners, respectively (p < 0.05 for all). CONCLUSIONS: NCE-MRU can be used as an alternative method for estimating SKF in pediatric patients with hydronephrosis when comparing with RS. Specifically, SKPV proves to be a simple and universally applicable indicator for predicting SKF.
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Hidronefrose , Urografia , Criança , Humanos , Estudos Retrospectivos , Urografia/métodos , Hidronefrose/diagnóstico por imagem , Rim/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Cintilografia , Espectroscopia de Ressonância MagnéticaRESUMO
PIWI-interacting RNAs (piRNAs), an emergent type of non-coding RNAs during oncogenesis, play critical roles in regulating tumor microenvironment. Systematic analysis of piRNAs' roles in modulating immune pathways is important for tumor immunotherapy. In this study, in-depth analysis of piRNAs was performed to develop an integrated computational algorithm, the immunology piRNA (ImmPI) pipeline, for uncovering the global expression landscape of piRNAs and identifying their regulatory roles in immune pathways. The immunology piRNAs show a tendency towards overexpression patterns in immune cells, causing perturbations in tumors, being significantly associated with infiltration of immune cells, and having prognostic value. The ImmPI score can contribute to prioritizing tumor-related piRNAs and distinguish two subtypes of SKCM (immune-cold and hot phenotypes), as characterized by different prognoses, immunogenicity and antitumor immunity. Finally, we developed an interactive web resource (ImmPI portal: http://www.hbpding.com/ImmPi) for the biomedical research community, with several useful modules to browse, visualize, and download the results of immunology piRNAs analysis. Overall, our work provides a comprehensive landscape of piRNAs across multiple cancer types and sheds light on their regulatory and functional roles in tumor immunity. These findings pave the way for future research and development of piRNA-based immunotherapies for cancer treatment.
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Altered promoter activity has been generally observed in diverse biological processes, including tumorigenesis. Accumulating evidence suggests that employing a quantitative trait locus mapping approach is effective in comprehending the genetic basis of promoter activity. By utilizing genotype data from The Cancer Genome Atlas and calculating corresponding promoter activity values using proActiv, we systematically evaluated the impact of genetic variants on promoter activity and identified >1.0 million promoter activity quantitative trait loci (paQTLs) as both cis- and trans-acting. Additionally, leveraging data from the genome-wide association study (GWAS) catalog, we discovered >1.3 million paQTLs that overlap with known GWAS linkage disequilibrium regions. Remarkably, â¼9324 paQTLs exhibited significant associations with patient prognosis. Moreover, investigating the impact of promoter activity on >1000 imputed antitumor therapy responses among pan-cancer patients revealed >43 000 million significant associations. Furthermore, â¼25 000 significant associations were identified between promoter activity and immune cell abundance. Finally, a user-friendly data portal, Pancan-paQTL (https://www.hbpding.com/PancanPaQTL/), was constructed for users to browse, search and download data of interest. Pancan-paQTL serves as a comprehensive multidimensional database, enabling functional and clinical investigations into genetic variants associated with promoter activity, drug responses and immune infiltration across multiple cancer types.
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Large-scale multidimensional cancer genomic and pharmacological profiles have been created by several large consortium projects, including NCI-60, GDSC and DepMap, providing novel opportunities for data mining and further understanding of intrinsic therapeutic response mechanisms. However, it is increasingly challenging for experimental biologists, especially those without a bioinformatic background, to integrate, explore, and analyse these tremendous pharmacogenomics. To address this gap, IMOPAC, an interactive and easy-to-use web-based tool, was introduced to provide rapid visualizations and customizable functionalities on the basis of these three publicly available databases, which may reduce pharmacogenomic profiles from cell lines into readily understandable genetic, epigenetic, transcriptionomic, proteomic, metabolomic, and pharmacological events. The user-friendly query interface together with customized data storage enables users to interactively investigate and visualize multiomics alterations across genes and pathways and to link these alterations with drug responses across cell lines from diverse cancer types. The analyses in our portal include pancancer expression, drug-omics/pathway correlation, cancer subtypes, omics-omics (cis-/trans-regulation) correlation, fusion query analysis, and drug response prediction analysis. The comprehensive multiomics and pharmacogenomic analyses with simple clicking through IMOPAC will significantly benefit cancer precision medicine, contribute to the discoveries of potential biological mechanisms and facilitate pharmacogenomics mining in the identification of clinically actionable biomarkers for both basic researchers and clinical practitioners. IMOPAC is freely available at http://www.hbpding.com/IMOPAC.
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High response rates in B-cell malignancies have been achieved with chimeric antigen receptor (CAR) T-cell therapy. Emerging reports indicate a risk of active tuberculosis (TB) with novel immunotherapy for tumors. However, studies of TB in patients post CAR T-cell therapy are limited. In this case series study, we describe five patients with active TB post CD19/CD22 target CAR T-cell therapy alone or following autologous stem cell transplantation (ASCT). One of the patients developed active TB within the first 30 days post CAR T-cell therapy, and fever was the dominant presenting symptom; extrapulmonary manifestations of active TB were common in the other four patients and manifested after the first 30 days of CAR T-cell therapy. Four of the five patients improved with anti-TB treatment, but one patient with isoniazid resistance died of central nervous system TB infection. Our study provides the first series report of active TB following CD19/CD22 target CAR T-cell therapy.
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Transplante de Células-Tronco Hematopoéticas , Tuberculose , Humanos , Imunoterapia Adotiva/efeitos adversos , Estudos Retrospectivos , Transplante Autólogo , Antígenos CD19 , Linfócitos TRESUMO
CONTEXT: Although the incidence of papillary thyroid carcinoma (PTC) is significantly higher in females than in males, the prognosis of male PTC is more unfavorable. However, the cause of higher malignancy of PTC in male patients remains unclear. OBJECTIVE: We conducted our analysis on microarrays datasets, tissue samples from PTC patients and the RNAseq datasets from TCGA with survival data. METHODS: We searched all publicly available microarray datasets and performed a genome-wide meta-analysis comparing PTC and normal samples. Gene Ontology analysis was then conducted. The candidate genes were tested by quantitative real-time polymerase chain reaction. The analysis of prognostic value of genes was performed with datasets from The Cancer Genome Atlas. RESULTS: After meta-analyses, 150 significantly differentially expressed genes (DEGs) were specifically found in male subjects. Gene Ontology analysis of these 150 genes revealed that the viral process was activated. Seven genes involved in the viral process in male patients showed a significantly differential expression between PTC and normal tissue. Survival analysis exhibited that the 7 genes, used in combination, were prognostically valuable and, of them, PSMB1 possessed a conspicuous prognostic value, especially in males. CONCLUSION: In this study, we searched all publicly available microarray datasets and conducted a comprehensive analysis to understand the male propensity for higher malignancy. We found that markers of viral infection showed significantly differential expression only in male patients compared with their female counterparts and had a sex-sensitive prognostic value in PTC.
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Câncer Papilífero da Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Viroses/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Conjuntos de Dados como Assunto , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Caracteres Sexuais , Câncer Papilífero da Tireoide/epidemiologia , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética , Transcriptoma , Viroses/diagnósticoRESUMO
The authors would like to correct Fig. 1, Fig. 3 and Fig. 5G, as errors were introduced in the preparation of these figures for publication. The authors declare that these corrections do not change the results or conclusions of this paper. We sincerely apologize for having this error in the article, and apologize for any inconvenience caused. The authors have provided corrected version of Fig. 1, Fig. 3 and Fig. 5G here.
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The Hippo pathway is an evolutionarily conserved regulator of organ size and tumorigenesis that negatively regulates cell growth and survival. Whether the Hippo pathway regulates cell metabolism is unknown. Here, we report that in the nucleus of hepatocytes, Yes-associated protein(YAP)-the terminal effector of the Hippo pathway-directly interacts with sterol regulatory element binding proteins (SREBP-1c and SREBP-2) on the promoters of the fatty acid synthase (FAS) and 30-hydroxylmethyl glutaryl coenzyme A reductase (HMGCR), thereby stimulating their transcription and promoting hepatocyte lipogenesis and cholesterol synthesis. In diet-induced diabetic mice, either Lats1 overexpression or YAP knockdown protects against hepatic steatosis and hyperlipidaemia through suppression of the interaction between YAP and SREBP-1c/SREBP-2. These results suggest that YAP is a nuclear co-factor of SREBPs and that the Hippo pathway negatively affects hepatocyte lipogenesis by inhibiting the function of YAP-SREBP complexes.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fígado Gorduroso/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular/genética , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Dieta Hiperlipídica/efeitos adversos , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Fígado Gorduroso/genética , Hepatócitos/metabolismo , Via de Sinalização Hippo , Lipogênese/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Ligação Proteica , Transdução de Sinais/genética , Proteínas de Sinalização YAPRESUMO
Chemoresistance is a major unmet clinical obstacle in ovarian cancer treatment. Epigenetics plays a pivotal role in regulating the malignant phenotype, and has the potential in developing therapeutically valuable targets that improve the dismal outcome of this disease. Here we show that a series of transcription factors, including C/EBPß, GCM1, and GATA1, could act as potential modulators of histone methylation in tumor cells. Of note, C/EBPß, an independent prognostic factor for patients with ovarian cancer, mediates an important mechanism through which epigenetic enzyme modifies groups of functionally related genes in a context-dependent manner. By recruiting the methyltransferase DOT1L, C/EBPß can maintain an open chromatin state by H3K79 methylation of multiple drug-resistance genes, thereby augmenting the chemoresistance of tumor cells. Therefore, we propose a new path against cancer epigenetics in which identifying and targeting the key regulators of epigenetics such as C/EBPß may provide more precise therapeutic options in ovarian cancer.
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Biomarcadores Tumorais/genética , Proteína beta Intensificadora de Ligação a CCAAT/genética , Cromatina/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Histonas/genética , Neoplasias Ovarianas/genética , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Linhagem Celular Tumoral , Cromatina/química , Cisplatino/farmacologia , Proteínas de Ligação a DNA , Bases de Dados Factuais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Histona-Lisina N-Metiltransferase , Histonas/metabolismo , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Cultura Primária de Células , Prognóstico , Análise de Sobrevida , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Novel molecular-targeted treatments show great prospects for radioiodine-refractory and surgically inoperable thyroid carcinomas. While aberrations in protein-coding genes are a focus in molecular thyroid cancer medicine, the impact of oncogenes on the expression of long noncoding RNAs (lncRNAs) has been largely uncharacterized. We aimed to identify the expression patterns of lncRNAs and mRNAs in high-throughput molecular profiles of 18 papillary thyroid cancer (PTC) patients. We identified 452 mRNAs and 240 unannotated lncRNAs that were differentially expressed in PTC. Significantly enriched GO terms and pathways were identified, many of which were linked to cancer. By integrating the predicted lncRNA target genes with differentially expressed mRNAs, we identified 20 candidate lncRNAs in 45 PTC patients. Five lncRNAs (CTD-3193O13.11, RP5-1024C24.1, AC007255.8, HOXD-AS1, and RP11-402L6.1) were verified to be differentially expressed in PTC and to exhibit specific topological characteristics in the lncRNA-mRNA co-expression network. LncRNA CTD-3193O13.11 was determined to comprise a node of co-regulation with the other lncRNAs in PTC tumorigenesis. LncRNA RP5-1024C24.1, AC007255.8, and HOXD-AS1 expression was significantly related to clinical stage, lncRNA RP11-402L6.1 expression was associated with lymph node metastasis, lncRNA CTD-3193O13.11 expression was proportional to tumor size, and lncRNA AC007255.8 expression was proportional to patient age. Therefore, our study provides a genome-wide screening and analysis of lncRNA expression in PTC, which brings novel insights into the roles of lncRNAs in PTC progression.
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RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Humanos , MicroRNAs/metabolismo , Neoplasias da Glândula Tireoide/genéticaRESUMO
BACKGROUND: Epigenetics has been known to play a critical role in regulating the malignant phenotype. This study was designed to examine the expression of DOT1L (histone 3 lysine 79 methyltransferase) and H3K79 methylation in normal ovarian tissues and ovarian tumors and to explore the function of DOT1L and its underline mechanisms in ovarian cancer. METHODS: The expression of DOT1L and H3K79 methylation in 250 ovarian tumor samples and 24 normal ovarian samples was assessed by immunohistochemistry. The effects of DOT1L on cell proliferation in vitro were evaluated using CCK8, colony formation and flow cytometry. The DOT1L-targeted genes were determined using chromatin immune-precipitation coupled with high-throughput sequencing (ChIP-seq) and ChIP-PCR. Gene expression levels were measured by real-time PCR and immunoblotting. The effects of DOT1L on tumor growth in vivo were evaluated using an orthotopic ovarian tumor model. RESULTS: DOT1L expression and H3K79 methylation was significantly increased in malignant ovarian tumors. High DOT1L expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, histologic grade, and lymphatic metastasis. DOT1L was an independent prognostic factor for the overall survival (OS) and progression-free survival (PFS) of ovarian cancer, and higher DOT1L expression was associated with poorer OS and PFS. Furthermore, DOT1L regulates the transcription of G1 phase genes CDK6 and CCND3 through H3K79 dimethylation; therefore, blocking DOT1L could result in G1 arrest and thereby impede the cell proliferation in vitro and tumor growth in vivo. CONCLUSIONS: Our findings first demonstrate that DOT1L over-expression has important clinical significance in ovarian cancer and also clarify that it drives cell cycle progression through transcriptional regulation of CDK6 and CCND3 through H3K79 methylation, suggesting that DOT1L might be potential target for prognostic assessment and therapeutic intervention in ovarian cancer.
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Epigênese Genética , Regulação da Expressão Gênica , Metiltransferases/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Intervalo Livre de Doença , Feminino , Fase G1 , Histona-Lisina N-Metiltransferase , Histonas/metabolismo , Humanos , Metástase Linfática , Metiltransferases/uso terapêutico , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/mortalidade , Prognóstico , Taxa de Sobrevida , Análise Serial de TecidosRESUMO
BACKGROUND/AIMS: Epithelial ovarian cancer (OC) is the leading cause of death in patients with gynecologic malignancy. Malignant ascites, a shared symptom of advanced OC patients, plays an important role in the peritoneal metastasis cascade of OC. Since leptin existed in great amount in malignant ascites, we speculated that it might be involved in the modulation of tumor cells malignant behavior. METHOD: Here, we demonstrated that blocking of leptin could significantly suppress ovarian malignant ascitesinduced metastatic aggravation of OC cells. Furthermore, our results suggested that leptin was highly expressed in OC and correlated with poor outcome of OC patients. Recombinant leptin notably promoted the migration, invasion and proliferation of OC cells. RESULT: Mechanistically, we found that leptin induced epithelial-mesenchymal transition (EMT) program in OC cells through the activation of the PI3K/Akt/mTOR pathway. Pharmacological inhibition of the PI3K/Akt/mTOR pathway partly impaired leptin-induced malignant transformation of OC cells. More importantly, our in vivo xenograft experiment showed that blocking of leptin could dramatically inhibit OC cells peritoneal dissemination. CONCLUSION: Collectively, this study emphasized the importance of leptin in OC progression and illustrated a novel mechanism that the PI3K/Akt/mTOR pathway was involved in leptin-induced EMT. Our findings provide new insights into leptin exertion on OC metastasis and identify the potential of leptin neutralizing as a novel strategy against OC peritoneal dissemination.
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Antineoplásicos/farmacologia , Leptina/antagonistas & inibidores , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Carcinoma Epitelial do Ovário , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Leptina/genética , Leptina/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Epithelial-mesenchymal transition (EMT) plays a critical role in promoting tumor invasion and metastasis. However, the key cofactors that modulate the signal transduction to induce EMT have note been fully explored to date. The present study reports that sine oculis homeobox homolog 1 (SIX1) is able to promote EMT of cervical cancer by coordinating with transforming growth factor (TGF)ß-SMAD signals. The expression of SIX1 was negatively correlated with the expression of the epithelial marker E-cadherin in two independent groups of cervical cancer specimens. SIX1 could promote the transition of mesenchymal phenotype in the presence of active TGFß signals in vitro and in vivo. TGFß-SMAD signals were required for the SIX1-mediated promotion of EMT and metastatic capacity of cervical cancer cells. Together, SIX1 and TGFß cooperated to induce more remarkable changes in the transition of phenotype than each of them alone, and coordinated to promote cell motility and tumor metastasis in cervical cancer. These results suggest that the coordination of SIX1 and TGFß signals may be crucial in the EMT program, and that SIX1/TGFß may be considered a valuable marker for evaluating the metastatic potential of cervical cancer cells, or a therapeutic target in the treatment of cervical cancer.
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The purpose of this study was to identify risk factors in patients with surgically treated node-positive IB1-IIB cervical cancer and to establish a risk model for disease-free survival (DFS) and overall survival (OS). A total of 170 patients who underwent radical hysterectomy and bilateral pelvic lymphadenectomy as primary treatment for node-positive International Federation of Gynaecology and Obstetrics (FIGO) stage IB1-IIB cervical cancer from January 2002 to December 2008 were retrospectively analyzed. Five published risk models were evaluated in this population. The variables, including common iliac lymph node metastasis and parametrial invasion, were independent predictors of outcome in a multivariate analysis using a Cox regression model. Three distinct prognostic groups (low, intermediate, and high risk) were defined using these variables. Five-year DFS rates for the low-, intermediate-, and high-risk groups were 73.7%, 60.0%, and 25.0%, respectively (P<0.001), and 5-year OS rates were 81.9%, 42.8%, and 25.0%, respectively (P<0.001). The risk model derived in this study provides a novel means for assessing prognosis of patients with node-positive stage IB1-IIB cervical cancer. Future study will focus on external validation of the model and refinement of the risk scoring systems by adding new biologic markers.
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The Cancer Genome Atlas network has revealed that the 'mesenchymal' epithelial ovarian cancer (EOC) subtype represents the poorest outcome, indicating a crucial role of stromal cancer-associated fibroblasts (CAFs) in disease progression. The cooperative role of CAFs in EOC metastasis has long been recognized, but the mechanisms of stromal CAFs activation are still obscure. Therefore, we carried out an integrative analysis to identify the regulator genes that are responsible for CAFs activation in microdissected tumor stroma profiles. Here, we determined that myristoylated alanine-rich C-kinase substrate (MARCKS) was highly expressed in ovarian stroma, and was required for the differentiation and tumor promoting function of CAFs. Suppression of MARCKS resulted in the loss of CAF features, and diminished role of CAFs in supporting tumor cell growth in 3D organotypic cultures and in murine xenograft model. Mechanistically, we found that MARCKS maintained CAF activation through suppression of cellular senescence and activation of the AKT/Twist1 signaling. Moreover, high MARCKS expression was associated with poor patient survival in EOC. Collectively, our findings identify the potential of MARCKS inhibition as a novel stroma-oriented therapy in EOC.
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Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Substrato Quinase C Rico em Alanina Miristoilada/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Animais , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Humanos , Camundongos , Substrato Quinase C Rico em Alanina Miristoilada/genética , Metástase Neoplásica , Neoplasias Ovarianas/genética , Transdução de SinaisRESUMO
Lymphatic vessels are one of the major routes for the dissemination of cancer cells. Malignant tumors release growth factors such as VEGF-C to induce lymphangiogenesis, thereby promoting lymph node metastasis. Here, we report that sine oculis homeobox homolog 1 (SIX1), expressed in tumor cells, can promote tumor lymphangiogenesis and lymph node metastasis by coordinating with TGFß to increase the expression of VEGF-C. Lymphangiogenesis and lymph node metastasis in cervical cancer were closely correlated with higher expression of SIX1 in tumor cells. By enhancing VEGF-C expression in tumor cells, SIX1 could augment the promoting effect of tumor cells on the migration and tube formation of lymphatic endothelial cells (LEC) in vitro and lymphangiogenesis in vivo. SIX1 enhanced TGFß-induced activation of SMAD2/3 and coordinated with the SMAD pathway to modulate VEGF-C expression. Together, SIX1 and TGFß induced much higher expression of VEGF-C in tumor cells than each of them alone. Despite its effect in promoting VEGF-C expression, TGFß could inhibit lymphangiogenesis by directly inhibiting tube formation by LECs. However, the increased production of VEGF-C not only directly promoted migration and tube formation of LECs but also thwarted the inhibitory effect of TGFß on LECs. That is, tumor cells that expressed high levels of SIX1 could promote lymphangiogenesis and counteract the negative effects of TGFß on lymphangiogenesis by increasing the expression of VEGF-C. These findings provide new insights into tumor lymphangiogenesis and the various roles of TGFß signaling in tumor regulation. Our results also suggest that SIX1/TGFß might be a potential therapeutic target for preventing lymph node metastasis of tumor.
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Proteínas de Homeodomínio/fisiologia , Linfangiogênese/fisiologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , RNA Interferente Pequeno , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/fisiopatologiaRESUMO
Malignant proliferation is the fundamental trait of tumor cells. The initiation of DNA replication represents a key process for cell proliferation, and has a marked impact on tumorigenesis and progression. Here we report that Sine oculis homeobox homolog 1 (SIX1) functions as a master regulator in DNA replication of cervical cancer cells. The expression of SIX1 was induced by the E7 oncoprotein of human papillomaviruses in cervical intraepithelial neoplasia and cervical cancer. The increase of SIX1 expression resulted in the upregulation of multiple genes related to the initiation of DNA replication, including the genes coding for the proteins in minichromosome maintenance complex (MCM2, MCM3, MCM6), DNA polymerase α-primase complex (POLA1, PRIM1, PRIM2), clamp loader (RFC3, RFC4, RFC5), DNA polymerase δ complex (POLD3) and DNA polymerase ε complex (POLE2). In line with this, the increase of SIX1 expression enhanced DNA synthesis, accelerated G1 to S phase progression, and promoted the proliferation of cervical cancer cells and the growth of cervical cancer. Consistently, knockdown of SIX1 could hamper DNA synthesis, slow down G1 to S phase progression, and suppress tumor cell proliferation and tumor growth. Importantly, SIX1 could more efficiently promote anchorage-independent cell growth. These results suggest that the increase of SIX1 expression could promote tumorigenesis, progression and invasive growth of cervical cancer by promoting DNA replication, and that targeting SIX1 may have significant therapeutic value in cervical cancer treatment.
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Replicação do DNA , Proteínas de Homeodomínio/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Animais , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos NOD , Neoplasias Experimentais , Proteínas E7 de Papillomavirus/metabolismo , Neoplasias do Colo do Útero/virologiaRESUMO
Sine oculis homeobox homolog 1 (SIX1) has been supposed to be correlated with the metastasis and poor prognosis of several malignancies. However, the effect of SIX1 on the metastatic phenotype of tumor cells and the underlying mechanisms were still unclear to date. Here we report that SIX1 can promote α5ß1-mediated metastatic capability of cervical cancer cells. SIX1 promoted the expression of α5ß1 integrin to enhance the adhesion capacity of tumor cells in vitro and tumor cell arrest in circulation in vivo. Moreover, higher expression of SIX1 in tumor cells resulted in the increased production of active MMP-2 and MMP-9, up-regulation of anti-apoptotic genes (BCL-XL and BCL2) and down-regulation of pro-apoptotic genes (BIM and BAX), thus promoting the invasive migration and anoikis-resistance of tumor cells. Importantly, blocking α5ß1 abrogated the regulatory effect of SIX1 on the expression of these genes, and also abolished the promotional effect of SIX1 on invasive capability of tumor cells. Furthermore, knock-down of α5 could abolish the promoting effect of SIX1 on the development of metastatic lesions in both experimental and spontaneous metastasis model. Therefore, by up-regulating α5ß1 expression, SIX1 not only promoted the adhesion capacity, but also augmented ECM-α5ß1-mediated regulation of gene expression to enhance the metastatic potential of cervical cancer cells. These results suggest that SIX1/α5ß1 might be considered as valuable marker for metastatic potential of cervical cancer cells, or a therapeutic target in cervical cancer treatment.