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1.
Cancer Sci ; 114(1): 91-104, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36056599

RESUMO

Cell division cycle associated 7 (CDCA7) is a copy number amplification gene that contributes to the metastasis and invasion of tumors, including esophageal squamous cell carcinoma (ESCC). This present study aimed at clarifying whether high expression of CDCA7 promotes the metastasis and invasion of ESCC cell lines and exploring the underlying mechanisms implicated in epithelial-mesenchymal transition (EMT) of ESCC. The role of CDCA7 in the regulation of ESCC metastasis and invasion was evaluated using ESCC cell lines. Expression of EMT-related markers including E-cadherin, N-cadherin, Vimentin, Snail, and Slug, transforming growth factor ß (TGF-ß) signaling pathway including Smad2/3, p-Smad2/3, Smad4, and Smad7 were detected in CDCA7 knockdown and overexpressed cell lines. Dual-luciferase reporter assay and rescue assay were used to explore the underlying mechanisms that CDCA7 contributed to the metastasis and invasion of ESCC. High CDCA7 expression significantly promoted the metastasis and invasion of ESCC cell lines both in vivo and in vitro. Additionally, the expression of CDCA7 positively correlated with the expression of N-cadherin, Vimentin, Snail, Slug, TGF-ß signaling pathway and negatively correlated with the expression of E-cadherin. Furthermore, CDCA7 transcriptionally regulated the expression of Smad4 and Smad7. Knockdown of CDCA7 inhibited the TGF-ß signaling pathway and therefore inhibited EMT. Our data indicated that CDCA7 was heavily involved in EMT by regulating the expression of Smad4 and Smad7 in TGF-ß signaling pathway. CDCA7 might be a new therapeutic target in the suppression of metastasis and invasion of ESCC.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Fator de Crescimento Transformador beta/metabolismo , Vimentina/genética , Vimentina/metabolismo , Neoplasias Esofágicas/patologia , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Caderinas/genética , Caderinas/metabolismo , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteínas Nucleares/genética , Proteína Smad7/genética , Proteína Smad7/metabolismo
2.
Neoplasma ; 70(6): 733-746, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38014700

RESUMO

F-box and WD repeat domain containing 7 (FBXW7) is an aboriginal and high-frequency mutant gene associated with esophageal squamous cell carcinoma (ESCC). This study was designed to determine the clinical value and molecular mechanisms of FBXW7 in the development of ESCC. The clinical significance of FBXW7 was analyzed in ESCC from TCGA data. The effects of FBXW7 on proliferation, colony formation, migration and invasion, angiogenesis, and apoptosis were tested in ESCC cells. PCR-array, sphere formation assay, and quantitative real-time polymerase chain reaction (qPCR) were used to explore the mechanism of FBXW7. FBXW7 was a significantly mutated gene in ESCC. It was an independent and potential predictor for survival in ESCC patients. In addition, FBXW7 overexpression significantly inhibited ESCC cell proliferation, migration, invasion, angiogenesis, and promoted cell apoptosis. PCR array revealed that FBXW7 overexpression leads to a significant change of gene expressions associated with angiogenesis, cell senescence, and DNA damage and repair. Sphere formation assay and qPCR showed FBXW7 was associated with ESCC stem cell formation. Our results suggest that FBXW7 may act as a tumor suppressor by repressing cancer stem cell formation and regulating tumor angiogenesis, cell senescence, DNA damage, and repair in ESCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética
3.
Cent Eur J Immunol ; 48(2): 111-125, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37692032

RESUMO

Introduction: At present, cancer remains a persistent public health challenge facing the whole world. Studies have found that PTPN21 is associated with the development of cancer. However, the prognostic potential of PTPN21 in pan-cancer remains unclear. In this work, we aimed to analyze the expression and prognostic value of PTPN21 in pan-cancer and to further study the relationship between PTPN21 and immune infiltration. Material and methods: TCGA and GEO data were used for expression and survival analysis. Genetic alterations in PTPN21 from TCGA cancer were studied in cBioPortal. TIMER2 was used to evaluate the correlation between PTPN21 expression and immune infiltration. The R packages "ggplot2" and "clusterProfiler" were used for GO and KEGG analysis. Results: PTPN21 was found to be a valuable diagnostic biomarker in multiple cancers, including bladder urothelial carcinoma (BLCA), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and lung squamous cell carcinoma (LUSC). In addition, we observed that PTPN21 expression was associated with a variety of tumor mutations. Our results indicated a correlation between PTPN21 expression and immune infiltration. Enrichment analysis showed that PTPN21 was mainly involved in the regulation of neuroactive ligand-receptor interaction. Conclusions: Our study showed that PTPN21 expression is associated with clinical prognosis, mutation, and immune infiltration of tumors. PTPN21 may be a potential biomarker for many cancers, especially in KIRC.

4.
Int J Med Sci ; 17(13): 2013-2023, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32788880

RESUMO

Non-muscle myosin heavy chain 9 (MYH9) is one novel low frequency mutated gene identified in esophageal squamous cell carcinoma (ESCC) using next-generation sequencing. However, its clinical relevance, potential function and mechanisms remain elusive. Methods: Genomic sequencing datas from 104 esophageal squamous cell carcinoma (ESCC) cases were screened a series of low frequency mutant genes. MYH9 was selected to further analyze its clinical significance, function and PCR-array was performed to explore its potential mechanism. Results: MHY9 is a low frequency mutant gene with a mutation frequency of 2.88% in ESCC. Immunohistochemical analysis showed that MYH9 expression was significantly higher in ESCC tumor tissues, and the expression levels were associated with lymph node metastasis of ESCC patients. Moreover, we found that MYH9 knock-down led to inhibition of cell migration and invasion. PCR-array showed MYH9 knockdown led to a significant change of genes expression associated with angiogenesis and epithelial-to-mesenchymal transition (EMT). This observation is further confirmed in TCGA database of LUSC (lung squamous cell carcinoma), CESC (cervical squamous cell carcinomas) and HNSC (head and neck squamous cell carcinoma). Conclusions: Collectively, our study identifies a novel role and mechanism of MYH9, highlights a significance of MYH9 as a metastatic biomarker, and offers potential therapeutic targets for ESCC patients harboring MYH9 mutations.


Assuntos
Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Cadeias Pesadas de Miosina/genética , Neovascularização Patológica/genética , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Esofágicas/irrigação sanguínea , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/irrigação sanguínea , Carcinoma de Células Escamosas do Esôfago/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mutação , Cadeias Pesadas de Miosina/metabolismo , Neovascularização Patológica/patologia , Prognóstico
5.
Am J Hum Genet ; 98(2): 256-74, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26833333

RESUMO

Comprehensive identification of somatic structural variations (SVs) and understanding their mutational mechanisms in cancer might contribute to understanding biological differences and help to identify new therapeutic targets. Unfortunately, characterization of complex SVs across the whole genome and the mutational mechanisms underlying esophageal squamous cell carcinoma (ESCC) is largely unclear. To define a comprehensive catalog of somatic SVs, affected target genes, and their underlying mechanisms in ESCC, we re-analyzed whole-genome sequencing (WGS) data from 31 ESCCs using Meerkat algorithm to predict somatic SVs and Patchwork to determine copy-number changes. We found deletions and translocations with NHEJ and alt-EJ signature as the dominant SV types, and 16% of deletions were complex deletions. SVs frequently led to disruption of cancer-associated genes (e.g., CDKN2A and NOTCH1) with different mutational mechanisms. Moreover, chromothripsis, kataegis, and breakage-fusion-bridge (BFB) were identified as contributing to locally mis-arranged chromosomes that occurred in 55% of ESCCs. These genomic catastrophes led to amplification of oncogene through chromothripsis-derived double-minute chromosome formation (e.g., FGFR1 and LETM2) or BFB-affected chromosomes (e.g., CCND1, EGFR, ERBB2, MMPs, and MYC), with approximately 30% of ESCCs harboring BFB-derived CCND1 amplification. Furthermore, analyses of copy-number alterations reveal high frequency of whole-genome duplication (WGD) and recurrent focal amplification of CDCA7 that might act as a potential oncogene in ESCC. Our findings reveal molecular defects such as chromothripsis and BFB in malignant transformation of ESCCs and demonstrate diverse models of SVs-derived target genes in ESCCs. These genome-wide SV profiles and their underlying mechanisms provide preventive, diagnostic, and therapeutic implications for ESCCs.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Estudos de Associação Genética/métodos , Variação Genética , Linhagem Celular , Ciclina D1/genética , Variações do Número de Cópias de DNA , Receptores ErbB/genética , Carcinoma de Células Escamosas do Esôfago , Deleção de Genes , Rearranjo Gênico , Genes p16 , Genoma Humano , Genômica , Humanos , Hibridização in Situ Fluorescente , Receptor ErbB-2/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Notch1/genética , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Translocação Genética
6.
Am J Hum Genet ; 96(4): 597-611, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25839328

RESUMO

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.


Assuntos
Carcinoma de Células Escamosas/genética , Citidina Desaminase/genética , Neoplasias Esofágicas/genética , Predisposição Genética para Doença/genética , Genoma Humano/genética , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética , Desaminase APOBEC-1 , Análise de Variância , Sequência de Bases , Proteína de Ligação a CREB/genética , Linhagem Celular Tumoral , China , Classe I de Fosfatidilinositol 3-Quinases , Variações do Número de Cópias de DNA/genética , Carcinoma de Células Escamosas do Esôfago , Técnicas de Silenciamento de Genes , Humanos , Immunoblotting , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Proteínas com Domínio LIM/genética , Ligases , Dados de Sequência Molecular , Receptores Patched , Receptor Patched-1 , Complexo Repressor Polycomb 1/genética , Proteínas do Grupo Polycomb/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Superfície Celular/genética , Análise de Sequência de DNA , Sais de Tetrazólio , Tiazóis , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Ubiquitina-Proteína Ligases/genética
9.
Eur J Nucl Med Mol Imaging ; 41(7): 1343-53, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24562650

RESUMO

OBJECTIVE: The aim of this prospective study is to evaluate the combined use of fluorine-18 fluorodeoxyglucose ((18) F-FDG) and fluorine-18 sodium fluoride ((18) F-NaF) PET/CT in the skeletal assessment of patients with multiple myeloma (MM) and to compare the efficacy of these two PET tracers regarding detection of myeloma-indicative osseous lesions. PATIENTS AND METHODS: The study includes 60 patients with multiple myeloma (MM) diagnosed according to standard criteria. All patients underwent dynamic (dPET/CT) scanning of the pelvis as well as whole body PET/CT studies with both tracers. The interval between the two exams was one day. Sites of focal increased (18) F-FDG uptake were considered as highly suspicious of myelomatous involvement. The lesions detected on the (18) F-NaF PET/CT scans were then correlated with those detected on (18) F-FDG PET/CT, which served as a reference. Moreover, the (18) F-FDG PET/CT results were also correlated with the low-dose CT findings. The evaluation of dPET/CT studies was based on qualitative evaluation, SUV calculation, and quantitative analysis based on a 2-tissue compartment model and a non-compartmental approach. RESULTS: Whole body (18) F-FDG PET/CT revealed approximately 343 focal lesions while (18) F-NaF PET/CT revealed 135 MM-indicative lesions (39 % correlation). CT demonstrated 150 lesions that correlated with those in (18) F-FDG PET/CT (44 % correlation). Six patients demonstrated a diffuse pattern of disease with (18) F-FDG, while 15 of them had a mixed (diffuse and focal) pattern of skeletal (18) F-FDG uptake. A high number of degenerative, traumatic and arthritic disease lesions were detected with (18) F-NaF PET/CT. In three patients with multiple focal (18) F-FDG-uptake, (18) F-NaF PET/CT failed to demonstrate any bone lesion. The dPET/CT scanning of the pelvic area with (18) F-FDG and (18) F-NaF revealed 77 and 24 MM-indicative lesions, respectively. Kinetic analysis of (18) F-FDG revealed the following mean values: SUVaver = 5.1, k1 = 0.37 (1/min), k3 = 0.10 (1/min), VB = 0.06, influx = 0.04 (1/min), FD = 1.28; the respective values for (18) F-NaF were SUVaverage = 10.7, k1 = 0.25 (1/min), k3 = 0.34 (1/min), VB = 0.02, influx = 0.10 (1/min), FD = 1.37. Apart from the correlation between VB of (18) F-FDG and k1 of (18) F-NaF (r = 0.54), no other significant correlation was observed between the two tracers' kinetic parameters. We found a significant correlation between FD and SUVaverage (r = 0.93), FD and SUVmax (r = 0.80), FD and influx ( r = 0.85), as well as between influx and SUVaverage (r = 0.74) for (18) F-FDG. In (18) F-NaF we observed the most significant correlations between FD and SUVaverage (r = 0.97), FD and SUVmax (r = 0.87), and between influx and k1 (r = 0.72). CONCLUSION: The combined use of (18) F-FDG PET/CT and (18) F-NaF PET/CT provides different molecular information regarding the biological processes that take place in a MM osseous lesion. (18) F-FDG PET/CT proved to be a more specific biomarker than (18) F-NaF PET/CT in multiple myeloma skeletal assessment.


Assuntos
Fluordesoxiglucose F18/farmacocinética , Mieloma Múltiplo/diagnóstico , Tomografia por Emissão de Pósitrons , Fluoreto de Sódio/farmacocinética , Tomografia Computadorizada por Raios X , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/metabolismo , Pelve/diagnóstico por imagem , Traçadores Radioativos , Imagem Corporal Total
10.
Med Sci Monit ; 20: 1942-9, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25317537

RESUMO

BACKGROUND: The aim of the current study was to measure and compare the effect of various biomaterials for the healing of osteoporotic bone defects in the rat femur using 18F-sodium fluoride dPET-CT. MATERIAL AND METHODS: Osteoporosis was induced by ovariectomy and a calcium-restricted diet. After 3 months, rats were operated on to create a 4-mm wedge-shaped defect in the distal metaphyseal femur. Bone substitution materials of calcium phosphate cement (CPC), composites of collagen and silica, and iron foams with interconnecting pores were inserted. Strontium or bisphosphonate, which are well known for having positive effects in osteoporosis treatment, were added into the materials. Eighteen weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with 18F-Sodium Fluoride. Standardized uptake values (SUVs) and a 2-tissue compartmental learning-machine model (K1-k4, vessel density [VB], influx [ki]) were used for quantitative analysis. RESULTS: k3, reflecting the formation of fluoroapatite, revealed a statistically significant increase at the biomaterial-bone interface due to the Sr release from strontium-modified calcium phosphate cement (SrCPC) compared to CPC, which demonstrated enhanced new bone formation. In addition, k3 as measured in the porous scaffold silica/collagen xerogel (Sc-B30), showed a significant increase based on Wilcoxon rank-sum test (p<0.05) as compared with monolithic silica/collagen xerogel (B30) in the defect region. Furthermore, ki, reflecting the net plasma clearance of tracer to bone mineral measured in the iron foam with coating of the bisphosphonate zoledronic acid (Fe-BP), was enhanced as compared with plain iron foam (Fe) in the defect region. CONCLUSIONS: k3 was the most significant parameter for the characterization of healing processes and revealed the best differentiation between the 2 different biomaterials. PET scanning using 18F-sodium fluoride seems to be a sensitive and useful method for evaluation of bone healing after replacement with these biomaterials.


Assuntos
Materiais Biocompatíveis , Osteoporose/patologia , Fluoreto de Sódio/administração & dosagem , Animais , Modelos Animais de Doenças , Feminino , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley , Tomografia Computadorizada por Raios X
11.
Environ Technol ; : 1-12, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35793158

RESUMO

In this paper, the hydrophilic UiO-66-NH2 nanomaterial was synthesized by the solvent-thermal method and characterized. Then, UiO-66-NH2 was introduced into the casting membrane solution of cellulose acetate (CA) forward osmosis (FO) membrane, and CA/UiO-66-NH2 forward osmosis membrane was prepared by the phase inversion method. The optimum preparation conditions of CA/UiO-66-NH2 mixed matrix membranes were determined as follows: the content of UiO-66-NH2 was 0.4 wt%, the coagulation bath temperature was 35°C, the mixing temperature was 50°C and the heat treatment temperature was 50°C. FTIR, SEM, water contact angle and AFM were carried out on CA/UiO-66-NH2 forward osmosis membrane prepared under the best preparation conditions. Compared to the CA forward osmosis membrane, the permeability and selectivity of the CA/UiO-66-NH2 membrane were improved. The water flux and reverse salt flux of the CA/UiO-66-NH2 forward osmosis membrane reached 52.32 L/(m2·h) and 2.43 g/(m2·h), respectively. The permeability selectivity of CA membranes and CA/UiO-66-NH2 membranes did not change much during 180 min, indicating that the two membranes had good long-term stability. This study shows a potential advantage of UiO-66-NH2 as additives for improvement in the desalination performance of forward osmosis membranes.

12.
Membranes (Basel) ; 12(2)2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35207046

RESUMO

Forward osmosis membranes have a wide range of applications in the field of water treatment. However, the application of seawater desalination is restricted, so the research of forward osmosis membranes for seawater desalination poses new challenges. In this study, zeolitic imidazolate framework-8 (ZIF-8) was synthesized by a mechanical stirring method, and its crystal structure, surface morphology, functional group characteristics, thermochemical stability, pore size distribution and specific surface area were analyzed. The cellulose acetate (CA)/ZIF-8 mixed matrix forward osmosis membrane was prepared by using the synthesized ZIF-8 as a modified additive. The effects of the additive ZIF-8 content, coagulation bath temperature, mixing temperature and heat treatment temperature on the properties of the CA/ZIF-8 forward osmosis membrane were systematically studied, and the causes were analyzed to determine the best membrane preparation parameters. The structure of the CA membrane and CA/ZIF-8 mixed matrix forward osmosis membranes prepared under the optimal conditions were characterized by Fourier Transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), contact angle and Atomic force microscope (AFM). Finally, the properties of the HTI membrane (Membrane manufactured by Hydration Technology Innovations Inc.), CA forward osmosis membrane and CA/ZIF-8 mixed matrix forward osmosis membrane were compared under laboratory conditions. For the CA membrane, the water flux and reverse salt flux reached 48.85 L·m-2·h-1 and 3.4 g·m-2·h-1, respectively. The reverse salt flux and water flux of the CA/ZIF-8 membrane are 2.84 g·m-2·h-1 and 50.14 L·m-2·h-1, respectively. ZIF-8 has a promising application in seawater desalination.

13.
Cell Death Discov ; 8(1): 182, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35396552

RESUMO

Family with sequence similarity 84, member B (FAM84B) is a significant copy number amplification gene in the 8q24.21 locus identified by our previous WGS study in esophageal squamous cell carcinoma (ESCC). However, its clinical relevance and potential mechanisms have been elusive. Here, we performed the association analyses between FAM84BAmp and clinicopathological features using 507 ESCC samples. The results indicated that, compared with the FAM84Bnon-Amp patients, the FAM84BAmp patients showed a more aggressive and a worse prognosis. A significant correlation was discovered between the expression level of FAM84B and FAM84BAmp in the ESCC cohort. Furthermore, we found that the forced expression change of FAM84B can influence ESCC cell proliferation and cell-cycle status, which is probably mediated by NPM1. A direct interaction between FAM84B and the C-terminal (189-294aa) of NPM1 was identified, which increased the NPM1 nuclear expression. Over-expression of NPM1 could inhibit the CDKN2A protein expression, which might affect the ESCC cell cycle. Our results indicate FAM84B CNA may be a potential diagnostic and therapeutic biomarker in ESCC, meanwhile, reveal a novel mechanism of FAM84B that promotes tumorigenesis via interacting with NPM1 and suppressing CDKN2A.

14.
Nat Commun ; 13(1): 6296, 2022 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-36272974

RESUMO

Esophageal squamous cell carcinoma (ESCC) demonstrates high genome instability. Here, we analyze 528 whole genomes to investigate structural variations' mechanisms and biological functions. SVs show multi-mode distributions in size, indicating distinct mutational processes. We develop a tool and define five types of complex rearrangements with templated insertions. We highlight a type of fold-back inversion, which is associated with poor outcomes. Distinct rearrangement signatures demonstrate variable genomic metrics such as replicating time, spatial proximity, and chromatin accessibility. Specifically, fold-back inversion tends to occur near the centrosome; TD-c2 (Tandem duplication-cluster2) is significantly enriched in chromatin-accessibility and early-replication region compared to other signatures. Analyses of TD-c2 signature reveal 9 TD hotspots, of which we identify a hotspot consisting of a super-enhancer of PTHLH. We confirm the oncogenic effect of the PTHLH gene and its interaction with enhancers through functional experiments. Finally, extrachromosomal circular DNAs (ecDNAs) are present in 14% of ESCCs and have strong selective advantages to driver genes.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Cromatina/genética , China , DNA Circular
15.
Front Oncol ; 11: 734655, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34737951

RESUMO

BACKGROUND: CDCA7 is a copy number amplified gene identified not only in esophageal squamous cell carcinoma (ESCC) but also in various cancer types. Its clinical relevance and underlying mechanisms in ESCC have remained unknown. METHODS: Tissue microarray data was used to analyze its expression in 179 ESCC samples. The effects of CDCA7 on proliferation, colony formation, and cell cycle were tested in ESCC cells. Real-time PCR and Western blot were used to detect the expression of its target genes. Correlation of CDCA7 with its target genes in ESCC and various SCC types was analyzed using GSE53625 and TCGA data. The mechanism of CDCA7 was studied by chromatin immunoprecipitation (ChIP), luciferase reporter assays, and rescue assay. RESULTS: The overexpression of CDCA7 promoted proliferation, colony formation, and cell cycle in ESCC cells. CDCA7 affected the expression of cyclins in different cell phases. GSE53625 and TCGA data showed CCNA2 expression was positively correlated with CDCA7. The knockdown of CCNA2 reversed the malignant phenotype induced by CDCA7 overexpression. Furthermore, CDCA7 was found to directly bind to CCNA2, thus promoting its expression. CONCLUSIONS: Our results reveal a novel mechanism of CDCA7 that it may act as an oncogene by directly upregulating CCNA2 to facilitate tumor progression in ESCC.

16.
Int J Gynecol Pathol ; 29(1): 55-62, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19952936

RESUMO

It can sometimes be difficult to distinguish between the 2 main types of uterine mesenchymal neoplasms; uterine smooth muscle tumors (SMTs) and endometrial stromal sarcomas (ESSs), particularly when the ESSs show smooth muscle differentiation or the SMTs are highly cellular. The aim of this study was to investigate myocardin expression in normal uterus myometrium, in SMTs, and in ESSs and to determine whether myocardin can be used as a useful diagnostic tool in the classification of problematic uterine mesenchymal tumors. Immunohistochemical staining was performed in each group. Besides myocardin, all cases were also stained for other smooth muscle markers (h-caldesmon, desmin, smooth muscle actin) and for CD10. All tested markers were analyzed in 21 conventional leiomyomas (LMs), 21 highly cellular leiomyomas (HCLs), 12 leiomyosarcomas (LMSs), 3 endometrial stromal nodules (ESNs), 11 ESSs, and 15 normal uterus myometrium. Myocardin was expressed in all normal uterine myometrium and in SMTs (even in the regions with epithelioid features) moderately or strongly, at least topically, whereas in endometrium, in ESNs and in ESSs, except in the regions of smooth muscle differentiation, it was negative. All ESNs, 11 of 11 ESSs and 14 of 15 endometrium were negative for h-caldesmon, but all SMTs and normal uterine myometrium were positive for h-caldesmon except for 2 LMSs, 2 HCLs, and for the regions with epithelioid features in 2 LMs. Desmin was stained in all normal uterine myometrium and in SMTs (except those of the regions with epithelioid features), but it was negative in 1 HCL and 1 LMS. One of 3 ESNs and 2 of 11 ESSs were expressed in desmin. Smooth muscle actin was negative in all ESNs, 2 LMSs, and 2 HCLs, and positive in all myometriums, LMs (except for the regions with epithelioid features), 1 ESSs, and 1 proliferative phase endometrium. Eight of 11 ESSs and all ESNs were positive for CD10, as was 1 HCL, and 2 LMSs. All uterine myometrium, 3 ESSs, and 3 endometriums were negative for CD10. Our study indicates that the myocardin is expressed in normal and neoplastic uterine smooth muscle cells sensitively and that the evaluation of myocardin expression is useful in distinguishing SMTs from ESSs.


Assuntos
Neoplasias do Endométrio/classificação , Proteínas Nucleares/biossíntese , Sarcoma do Estroma Endometrial/classificação , Tumor de Músculo Liso/classificação , Transativadores/biossíntese , Neoplasias Uterinas/classificação , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Sarcoma do Estroma Endometrial/metabolismo , Sarcoma do Estroma Endometrial/patologia , Tumor de Músculo Liso/metabolismo , Tumor de Músculo Liso/patologia , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Útero/metabolismo
17.
Urol Int ; 85(3): 296-303, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20881356

RESUMO

AIMS: To detect microsatellite loci alterations by fluorescent multiplex PCR in urine sediment cell of urothelial carcinoma, and to determine if they can be used as genetic markers for diagnosis of urothelial carcinoma. MATERIALS AND METHODS: Microsatellite alteration analysis was conducted using fluorescent multiplex PCR with samples from 64 cases of urothelial carcinomas of the bladder. Three microsatellites spanning the 3p14 and two additional microsatellites in 9q33 and 9p22 were analyzed. Microsatellite alterations (microsatellite instability and/or loss of heterozygosity) in urine sediment cells of urothelial carcinoma patients matched for peripheral blood and tumor tissue were all analyzed. RESULTS: The frequency of microsatellite alterations in urothelial carcinoma was chromosome 3p (D3S1234: 14.6% (7/48), D3S1300: 16.7% (8/48), D3S1313: 8.35% (4/48)); 9q (D9S242: 33.3% (16/48)), and 9p (D9S162: 27.1% (13/48)). Microsatellite alterations happened in 62.5% (40/64) of the patients when combined with all five markers. Our study showed a significant correlation between the microsatellite alteration of the five-locus panel and recurrence (p = 0.010) and smoking habit (p = 0.006). CONCLUSIONS: The results suggest that these microsatellite loci alterations may have an important role in the recurrence of urothelial carcinomas. Further studies are needed to better determine the effect of microsatellite loci alterations on prognosis.


Assuntos
Repetições de Microssatélites , Microscopia de Fluorescência/métodos , Reação em Cadeia da Polimerase/métodos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Urina/química , Urotélio/patologia , Idoso , Alelos , Feminino , Seguimentos , Humanos , Perda de Heterozigosidade , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Prognóstico , Análise de Sequência de DNA , Fatores Sexuais , Fumar/efeitos adversos
18.
Breast Cancer ; 27(3): 464-476, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31919642

RESUMO

BACKGROUND: Splicing factor 3b subunit 1 (SF3B1) was frequently reported to be significantly mutated in breast cancer. However, the status of SF3B1 expression, its function and molecular consequence in breast cancer remained unreported. METHODS: Immunohistochemistry was used to assess SF3B1expression in 110 breast cancer samples. SF3B1 knock­down in ZR-75-30 and MDA-MB-231 cells was performed by shRNA transfection. The expression of SF3B1 in cells was detected by quantitative real­time PCR and western blot. Cell proliferation ability was determined by MTT and colony formation assay. Migration and invasion were determined by transwell assay. Flow cytometry was performed to investigate cell cycle and apoptosis. RNA-sequencing was performed to examine differentially expressed genes and affected alternative splicing events. RESULTS: SF3B1 is overexpressed in breast cancer tissues compared with normal tissues. Overexpression of SF3B1 is associated with lymph node metastasis. SF3B1 knockdown in MDA-MB-231 and ZR-75-30 breast cancer cells significantly induced the suppression of proliferation, migration, invasion and also enhancement of apoptosis. RNA-sequencing data revealed that 860 genes were significantly up-regulated and 776 genes were significantly down-regulated upon SF3B1 knockdown. Differentially expressed genes enriched in the signaling pathways including Ras signaling pathway; cytokine receptor interaction; tight junction; MAPK signaling pathway, Glycine, serine and threonine metabolism. Alternative splicing analysis revealed that exon skipping (SKIP) and cassette exons (MSKIP) were the most common molecular effect upon SF3B1 knockdown. CONCLUSIONS: Our study suggests that SF3B1 may be an important molecular target for breast cancer treatment and provides a new clue for clinical treatment of breast cancer.


Assuntos
Processamento Alternativo , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Movimento Celular , Proliferação de Células , Fosfoproteínas/antagonistas & inibidores , Fatores de Processamento de RNA/antagonistas & inibidores , RNA Interferente Pequeno/genética , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Interferência de RNA , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Células Tumorais Cultivadas
19.
Theranostics ; 10(4): 1798-1813, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32042337

RESUMO

Background: Cancer genomic studies have identified Zinc Finger Protein 750 (ZNF750) was a novel significantly mutated gene in esophageal squamous cell carcinoma (ESCC). This study was designed to determine the clinical value and molecular mechanisms of ZNF750 in the development of ESCC. Methods: Genomic data from 4 reported ESCC cohorts were used to analyze the mutation profile of ZNF750. Tissue microarrays were used to detect its expression in 308 ESCC samples. Furtherly, the effects of ZNF750 on proliferation, colony formation, migration and invasion were tested in ESCC cells. PCR-array, chromatin immunoprecipitation (ChIP), luciferase reporter assays, and rescue assay were used to explore the mechanism of ZNF750. Correlation of ZNF750 with its target genes was analyzed in TCGA data from various SCC types. Results: ZNF750 was frequently mutated in ESCC and the most common type was nonsense mutation. Its nucleus/cytoplasm ratio in ESCC was significantly lower than that in paired non-tumor tissues; it was an independent and potential predictor for survival in ESCC patients. Furtherly, ZNF750 knockdown significantly promoted proliferation, colony formation, migration and invasion in ESCC cells. PCR-array showed epithelial-to-mesenchymal transition (EMT) was the main biologic process affected by ZNF750. Moreover, ZNF750 directly bound to the promoter region of SNAI1 and depressed its activity. Decreased ZNF750 up-regulated SNAI1 expression and promoted EMT phenotype. SNAI1 knockdown partially reversed the malignant phenotype induced by ZNF750 knockdown. Further TCGA data analyses showed ZNF750 expression was positively correlated with E-cadherin and negatively correlated with SNAI1, N-cadherin and Vimentin in ESCC and other SCC samples. Conclusion: Our results suggest that ZNF750 may act as a tumor suppressor by directly repressing SNAI1 and inhibiting EMT process in ESCC and other types of SCC.


Assuntos
Transição Epitelial-Mesenquimal/genética , Carcinoma de Células Escamosas do Esôfago/genética , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Transcrição/genética , Adulto , Idoso , Caderinas/metabolismo , Linhagem Celular Tumoral/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Códon sem Sentido , Carcinoma de Células Escamosas do Esôfago/mortalidade , Feminino , Genes Supressores de Tumor/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias/métodos , Prognóstico , Análise Serial de Tecidos/métodos , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor , Vimentina/metabolismo
20.
Cell Death Dis ; 11(4): 296, 2020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32341351

RESUMO

ZNF750 is one novel significantly mutated gene identified in esophageal squamous cell carcinoma (ESCC) using next-generation sequencing. However, its clinically relevant and potential mechanisms have remained elusive. Using genomic sequencing of 612 ESCC patients, we analyzed the associations of ZNF750 mutations with clinicopathologic features and its prognostic value. We further investigated the function and underlying mechanism of ZNF750 in angiogenesis. The results showed ZNF750 mutations/deletions are significantly associated with malignant progression and poor prognosis of ESCC patients. Decreased ZNF750 in ESCC cells induces enhanced angiogenesis of human umbilical vein endothelial cells (HUVECs) and human arterial endothelial cells (HAECs), and the effect may be indirectly mediated by FOXC2. RNA-seq and ChIP shows lncRNA DANCR is a direct downstream target of ZNF750. Furtherly, knockdown ZNF750 evokes DANCR expression, which prevents miR-4707-3p to interact with FOXC2 as a microRNA sponge in a ceRNA manner, leading to enhanced FOXC2 signaling and angiogenesis. In contrast, ZNF750 expression reverses the effect. Our study reveals a novel mechanism of ZNF750, highlights a significance of ZNF750 as a metastatic and prognostic biomarker, and offers potential therapeutic targets for ESCC patients harboring ZNF750 mutations.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição/metabolismo , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Pessoa de Meia-Idade , Proteínas Supressoras de Tumor
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