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1.
Cancer Invest ; 38(5): 300-309, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32378982

RESUMO

Centrosome amplification leads to aberrant mitosis, giving rise to aneuploidy and it has been associated with poor prognosis in human cancers. This study aimed to evaluate the relationship between polyploidy, centrosome abnormalities, and response to endocrine treatment in progestin-induced mouse mammary carcinomas. We found cells with three or more centrosomes in the polyploid tumors. The endocrine unresponsive tumors showed a higher average number of centrosomes per cell than the responsive tumors. The results suggest an association between polyploidy and centrosome amplification with the resistance to endocrine therapy in this luminal breast cancer model.


Assuntos
Neoplasias da Mama/patologia , Carcinoma/patologia , Centrossomo/patologia , Hormônios/metabolismo , Aneuploidia , Animais , Neoplasias da Mama/metabolismo , Carcinoma/metabolismo , Linhagem Celular Tumoral , Centrossomo/metabolismo , Feminino , Amplificação de Genes/fisiologia , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Mitose/fisiologia , Poliploidia
2.
Nucleic Acids Res ; 48(12): 6855-6873, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32406909

RESUMO

Cells limit energy-consuming mRNA translation during stress to maintain metabolic homeostasis. Sequestration of mRNAs by RNA binding proteins (RBPs) into RNA granules reduces their translation, but it remains unclear whether RBPs also function in partitioning of specific transcripts to polysomes (PSs) to guide selective translation and stress adaptation in cancer. To study transcript partitioning under cell stress, we catalogued mRNAs enriched in prostate carcinoma PC-3 cell PSs, as defined by polysome fractionation and RNA sequencing (RNAseq), and compared them to mRNAs complexed with the known SG-nucleator protein, G3BP1, as defined by spatially-restricted enzymatic tagging and RNAseq. By comparing these compartments before and after short-term arsenite-induced oxidative stress, we identified three major categories of transcripts, namely those that were G3BP1-associated and PS-depleted, G3BP1-dissociated and PS-enriched, and G3BP1-associated but also PS-enriched. Oxidative stress profoundly altered the partitioning of transcripts between these compartments. Under arsenite stress, G3BP1-associated and PS-depleted transcripts correlated with reduced expression of encoded mitochondrial proteins, PS-enriched transcripts that disassociated from G3BP1 encoded cell cycle and cytoprotective proteins whose expression increased, while transcripts that were both G3BP1-associated and PS-enriched encoded proteins involved in diverse stress response pathways. Therefore, G3BP1 guides transcript partitioning to reprogram mRNA translation and support stress adaptation.


Assuntos
DNA Helicases/genética , Estresse Oxidativo/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Biossíntese de Proteínas/genética , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , RNA Mensageiro/genética , Arsenitos/toxicidade , Carcinoma/genética , Carcinoma/metabolismo , Grânulos Citoplasmáticos/genética , Metabolismo Energético/genética , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas de Ligação a RNA/genética
3.
Medicine (Baltimore) ; 99(15): e19707, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282726

RESUMO

BACKGROUND: Increasing studies were performed to explore the prognostic value of E-cadherin in prostatic carcinoma, however, with inconsistent results. Hence, this systematic review is aimed to evaluate the prognostic role of E-cadherin in patients with prostatic carcinoma (PCa). METHODS: A comprehensive literature search in all available databases will be conducted to identify eligible studies. We will employ hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the correlations between E-cadherin expression and overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS), progression-free survival (PFS) and clinicopathological features. Meta-analysis will be performed using Review Manager (Revman) 5.3.5 software (Cochrane Community, London, United Kingdom) and STATA 14 software (version 14.0; Stata Corp, College Station, TX). RESULTS: This study will provide a high-quality synthesis of current evidence of the correlations between snail expression and OS, DFS/RFS, PFS and clinicopathological features. CONCLUSION: The study will provide updated evidence to assess whether the expression of E-cadherin is in association with poor prognosis in patients with PCa. ETHICS AND DISSEMINATION: It is not necessary for ethical approval because individuals cannot be identified. The protocol will be disseminated in a peer-reviewed journal or presented at a relevant conference. PROSPERO REGISTRATION NUMBER: This systematic review protocol has been registered in the PROSPERO network (No. CRD42019128353).


Assuntos
Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Carcinoma/metabolismo , Neoplasias da Próstata/patologia , Antígenos CD/metabolismo , Intervalo Livre de Doença , Humanos , Incidência , Londres/epidemiologia , Masculino , Prognóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/mortalidade , Sensibilidade e Especificidade , Reino Unido/epidemiologia
4.
Int. j. morphol ; 38(2): 247-251, abr. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1056430

RESUMO

Nine tumor and various potential biomarkers were measured and combined the information to diagnose disease, all patients accepted fiber bronchoscopy brush liquid based cytologyand histopathology examination in order to reliably detect lung cancer. The samples from 314 Chinese lung cancer patients were obtained and CK5/6, P63, P40, CK7, TTF-1, NapsinA CD56, Syn and CgA were measured with the immunohistochemical SP method and analyzed correlation of the expression of these markers with pathological and clinical features of squamous cell carcinoma, adenocarcinoma, and small cell lung carcinoma. Squamous cell carcinoma, adenocarcinoma and small cell carcinoma were 61 cases, 114 cases and 139 cases,CK5/6 and P63 expression were more frequent in squamous cell carcinoma, with sensitivity and specificity of 77.05 % and 96.44 %, 83.61 % and 88.93 %,and compared with adenocarcinoma and small cell carcinoma difference was statistically significant (P<0.05), The incidences of a positive P40 expression were 100 % in squamous cell carcinoma, with specificity of 98.81 %.CK7, TTF-1 and NapsinA expression were more frequent in adenocarcinoma, with sensitivity and specificity of 85.09 % and 78.69 %, 79.82 % and 93.44 %, 56.14 % and 95.08 %, and compared with squamous cell carcinoma and small cell carcinoma difference was statistically significant (P<0.05). TTF-1, Syn, CgA and CD56 expression were more frequent in adenocarcinoma, with sensitivity and specificity of 86.33 % and 93.44 %, 89.21 % and 98.36 %, 74.10 % and 100 %, 96.40 % and 96.72 %. The combined detection of CK5/6, P63 and P40 were more useful and specific in differentiating squamous cell carcinoma. CK7, TTF-1 and NapsinA were more useful and specific in differentiating lung adenocarcinoma. The impaired CD56, TTF-1, Syn and CgA reflects the progression of small cell lung cancer.


Se midieron tumores y utilizaron nueve biomarcadores potenciales y se analizó la información para diagnosticar la enfermedad. A todos los pacientes se les realizó citología en líquido con broncoscopía de fibra y examen histopatológico para detectar de manera confiable el cáncer pulmonar. Se obtuvieron muestras de 314 pacientes chinos con cáncer de pulmón y CK5 / 6, P63, P40, CK7, TTF-1, Napsina A, CD56, Syn y CgA se midieron a través de histoquímica SP y analizaron la correlación de la expresión de estos marcadores con características patológicas y clínicas de carcinoma de células escamosas, adenocarcinoma y carcinoma de células pequeñas en el cáncer de pulmón. El carcinoma de células escamosas, el adenocarcinoma y el carcinoma de células pequeñas fueron 61 casos, 114 casos y 139 casos, respectivamente, la expresión de CK5 / 6 y P63 fueron más frecuentes en el carcinoma de células escamosas, con una sensibilidad y especificidad del 77,05 % y 96,44 %, 83,61 % y 88,93 %, y en comparación con el adenocarcinoma y el carcinoma de células pequeñas, la diferencia fue estadísticamente significativa (P <0,05). La incidencia de ap la expresión positiva P40 fue del 100 % en el carcinoma de células escamosas, con una especificidad del 98,81 %. La expresión de CK7, TTF-1 y NapsinA fueron más frecuentes en el adenocarcinoma, con una sensibilidad y especificidad del 85,09 % y 78,69 %, 79,82 % y 93,44 %, 56,14 % y 95,08 %, y en comparación con el carcinoma de células escamosas y la diferencia de carcinoma de células pequeñas fue estadísticamente significativa (P <0,05) .TTF-1, Syn, CgA y la expresión de CD56 fueron más frecuentes en adenocarcinoma, con sensibilidad y especificidad de 86.33 % y 93.44 %, 89.21 % y 98.36 %, 74.10 % y 100 %, 96.40 % y 96.72 %. La detección combinada de CK5 / 6, P63 y P40 fue más útil y específica en la diferenciación del carcinoma de células escamosas. CK7, TTF-1 y NapsinA fueron más útiles y específicos para diferenciar el adenocarcinoma de pulmón. El deterioro de CD56, TTF-1, Syn y CgA refleja la progresión del cáncer de pulmón de células pequeñas.


Assuntos
Humanos , Carcinoma/metabolismo , Carcinoma/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fragmentos de Peptídeos/metabolismo , Fatores de Transcrição/metabolismo , Imuno-Histoquímica , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Sensibilidade e Especificidade , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , Antígeno CD56/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Queratinas Tipo II/metabolismo , Queratina-7/metabolismo , Fator Nuclear 1 de Tireoide/metabolismo
5.
Hum Cell ; 33(3): 790-800, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32304027

RESUMO

Anterior gradient 2 (AGR2) was proved to modulate cancer progression. However, the role of AGR2 on endometrial cancer was not established. Here, we investigated the effects of AGR2 expression on endometrial cancer and explored the regulation mechanism. In the study, we found that AGR2 was overexpressed in tumor tissues of 30 endometrial cancer patients. A high level of AGR2 promoted endometrial cancer cells proliferation, migration and invasion. AGR2 induced the expression of lactate dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), kallikrein 2 (HK2), and enolase 1-α (ENO1), glucose uptake and lactate production. AGR2 could bind to MUC1 and induce MUC1 and hypoxia-inducible factor 1α (HIF-1α). The inhibition effects of AGR2 knockdown on cells proliferation, migration and invasion ability were abolished by the overexpression of MUC1. Besides, the overexpression of MUC1 also reversed the inhibition effects of AGR2 knockdown on the expression of LDHA, HK2, PGK1 and ENO1, glucose uptake and lactate production. AGR2 knockdown inhibited tumor growth, the levels of Ki-67, MUC1, HIF-1α and glycolysis. In conclusion, AGR2 was overexpressed in endometrial cancer and AGR2-induced glucose metabolism facilitated the progression of endometrial carcinoma via the MUC1/HIF-1α pathway. AGR2 may be an effective therapeutic target for endometrial carcinoma.


Assuntos
Carcinoma/genética , Carcinoma/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Glucose/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mucina-1/genética , Mucina-1/metabolismo , Mucoproteínas/fisiologia , Proteínas Oncogênicas/fisiologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma/metabolismo , Carcinoma/terapia , Movimento Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/terapia , Feminino , Expressão Gênica , Hexoquinase/genética , Hexoquinase/metabolismo , Humanos , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Terapia de Alvo Molecular , Mucoproteínas/genética , Mucoproteínas/metabolismo , Invasividade Neoplásica/genética , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Fosfoglicerato Quinase/genética , Fosfoglicerato Quinase/metabolismo , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
6.
Am J Surg Pathol ; 44(7): 962-969, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32205481

RESUMO

Secretory carcinoma (SC) of the salivary glands is a low-grade carcinoma characterized by a well-defined morphology and immunohistochemical features. ETV6-NTRK3 fusions are detected in the great majority of SCs. Recently, other partners fused to ETV6 have been documented in a small portion of SCs, suggesting the presence of alternative genetic fusion. In this study, we examined the genetic fusion of 9 SCs using fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and next-generation sequencing (ArcherDx). Classic ETV6 exon 5-NTRK3 exon 15 fusion was detected in 8 of 9 SCs. The remaining tumor was negative for the ETV6-NTRK3 fusion but harbored a novel fusion, CTNNA1 exon 11-ALK in exon 20. Immunohistochemically, pan-TRK was positive in 8 tumors with ETV6-NTRK3 fusion but negative in an ALK-rearranged SC, while ALK was positive only in the ALK-rearranged tumor. Histologically, the ALK-rearranged tumor showed dominant macrocystic architecture. In conclusion, we found a case of SC with CTNNA1-ALK fusion. Because ALK fusion after exon 20 on the ALK side (upstream of the tyrosine kinase domain) has been reported to activate a carcinogenic kinase in various ALK-rearranged tumors, ALK inhibitors may be a possible therapeutic option for ALK-rearranged SC. In addition, ALK immunohistochemistry can be a screening tool for ALK-rearranged SC. This study also expands the molecular spectrum of this tumor beyond the ETV6 gene.


Assuntos
Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Carcinoma/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Neoplasias das Glândulas Salivares/genética , alfa Catenina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma/diagnóstico , Carcinoma/metabolismo , Carcinoma/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia , alfa Catenina/metabolismo
7.
Gene ; 735: 144402, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32004669

RESUMO

Colon cancer is one of the most common malignancies in the world; there is no effective therapeutic treatment after surgery. Our previous studies indicate that RNA helicase DHX33 plays a critical role in cell proliferation and cell growth. Here in this study, DHX33 is found to be highly expressed in colon cancer tissues and colon cancer cell lines. Knockdown of DHX33 significantly decreased cell proliferation and triggered apoptosis. Mechanistically, DHX33 was found to transcriptionally control multiple critical genes involved in cell cycle, apoptosis and migration. DHX33 deficiency caused decreased tumor growth for colon cancer cells in a xenograft model in vivo. With Wnt/ß-cateninactivator and inhibitors, we further discovered that Wnt/ß-catenin pathway regulates DHX33 transcriptionally. This study for the first time demonstratesthe important role of DHX33 in colon cancer development and reveals the underlying molecular mechanism. We also provide the initial evidence for the relationship between DHX33 and Wnt/ß-catenin signaling pathway in colon cancer development.


Assuntos
Carcinoma/genética , Neoplasias do Colo/genética , RNA Helicases DEAD-box/genética , Via de Sinalização Wnt , Animais , Apoptose , Carcinoma/metabolismo , Carcinoma/patologia , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , RNA Helicases DEAD-box/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
8.
Am J Surg Pathol ; 44(7): e15-e29, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32044806

RESUMO

The combined clinical and molecular heterogeneity of prostate cancer necessitates the use of prognostic, predictive, and diagnostic biomarkers to assist the clinician with treatment selection. The pathologist plays a critical role in guiding molecular biomarker testing in prostate cancer and requires a thorough knowledge of the current testing options. In the setting of clinically localized prostate cancer, prognostic biomarkers such as Ki-67 labeling, PTEN loss or mRNA-based genomic signatures can be useful to help determine whether definitive therapy is required. In the setting of advanced disease, predictive biomarkers, such as the presence of DNA repair deficiency mediated by BRCA2 loss or mismatch repair gene defects, may suggest the utility of poly-ADP ribosylase inhibition or immune checkpoint blockade. Finally, androgen receptor-related biomarkers or diagnostic biomarkers indicating the presence of small cell neuroendocrine prostate cancer may help guide the use of androgen receptor signaling inhibitors and chemotherapy. In this review, we examine the current evidence for several prognostic, predictive and diagnostic tissue-based molecular biomarkers in prostate cancer management. For each assay, we summarize a recent survey of the International Society of Urology Pathology (ISUP) members on current testing practices and include recommendations for testing that emerged from the ISUP Working Group on Molecular Pathology of Prostate Cancer and the 2019 Consultation Conference on Molecular Pathology of Urogenital Cancers.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma/diagnóstico , Neoplasias da Próstata/diagnóstico , Carcinoma/metabolismo , Carcinoma/patologia , Humanos , Masculino , Patologia Clínica , Patologia Molecular , Prognóstico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Sociedades Médicas , Urologia
9.
Infect Immun ; 88(5)2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32041789

RESUMO

Programmed death-ligand 1 (PD-L1/B7-H1) serves as a cosignaling molecule in cell-mediated immune responses and contributes to chronicity of inflammation and the escape of tumor cells from immunosurveillance. Here, we investigated the molecular mechanisms leading to PD-L1 upregulation in human oral carcinoma cells and in primary human gingival keratinocytes in response to infection with Porphyromonas gingivalis (P. gingivalis), a keystone pathogen for the development of periodontitis. The bacterial cell wall component peptidoglycan uses bacterial outer membrane vesicles to be taken up by cells. Internalized peptidoglycan triggers cytosolic receptors to induce PD-L1 expression in a myeloid differentiation primary response 88 (Myd88)-independent and receptor-interacting serine/threonine-protein kinase 2 (RIP2)-dependent fashion. Interference with the kinase activity of RIP2 or mitogen-activated protein (MAP) kinases interferes with inducible PD-L1 expression.


Assuntos
Antígeno B7-H1/metabolismo , Infecções por Bacteroidaceae/metabolismo , Carcinoma/metabolismo , Parede Celular/metabolismo , Neoplasias Bucais/metabolismo , Porphyromonas gingivalis/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Infecções por Bacteroidaceae/microbiologia , Carcinoma/microbiologia , Linhagem Celular Tumoral , Gengiva/metabolismo , Gengiva/microbiologia , Humanos , Queratinócitos/metabolismo , Queratinócitos/microbiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Bucais/microbiologia , Periodontite/metabolismo , Periodontite/microbiologia , Regulação para Cima/fisiologia
10.
PLoS One ; 15(1): e0227855, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999741

RESUMO

The Src substrate Tks5 helps scaffold matrix-remodeling invadopodia in invasive cancer cells. Focus was directed here on how the five SH3 domains of Tks5 impact that activity. Mutations designed to inhibit protein-protein interactions were created in the individual SH3 domains of Tks5, and the constructs were introduced into the LNCaP prostate carcinoma cell line, a model system with intrinsically low Tks5 expression and which our lab had previously showed the dependence of Src-dependent Tks5 phosphorylation on invadopodia development. In LNCaP cells, acute increases in wild-type Tks5 led to increased gelatin matrix degradation. A similar result was observed when Tks5 was mutated in its 4th or 5th SH3 domains. This was in contrast to the 1st, 2nd, and 3rd SH3 domain mutations of Tks5 where each had a remarkable accentuating effect on gelatin degradation. Conversely, in the invadopodia-competent Src-3T3 model system, mutations in any one of the first three SH3 domains had a dominant negative effect that largely eliminated the presence of invadopodia, inhibited gelatin degradation activity, and redistributed both Src, cortactin, and Tks5 to what are likely endosomal compartments. A hypothesis involving Tks5 conformational states and the regulation of endosomal trafficking is presented as an explanation for these seemingly disparate results.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Carcinoma/genética , Neoplasias da Próstata/genética , Quinases da Família src/genética , Proteínas Adaptadoras de Transporte Vesicular/química , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Cortactina/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Gelatina/genética , Gelatina/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Mutação/genética , Fosforilação , Podossomos/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Domínios e Motivos de Interação entre Proteínas/genética , Domínios de Homologia de src/genética
11.
PLoS One ; 15(1): e0227916, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31961892

RESUMO

BACKGROUND: Colorectal cancer remains a deadly cancer due to metastatic disease. To understand the molecular mechanisms of metastasis in colon cancer, we investigated whether the copper chaperone antioxidant-1 (Atox1) protein plays a role in this process. Recent findings indicate that Atox1 protein has transcription factor activities and plays a vital role in cell proliferation in cancer cells. However, the role of Atox1 in metastasis has not been examined. METHODS: Atox1 expression was determined by immunofluorescence in a tissue microarray generated from a spectrum of CRC patients. Subcellular fractionation of colon cancer cell lines SW480 and SW620 cells was used to examine the cellular location of Atox1 in the face of activin A, a cytokine that stimulates colon cancer metastasis. Atox1 expression was genetically manipulated and cellular migration measured through trans-well assay and proliferation measured by colony formation assays. RESULTS: Here we demonstrate that in patients with metastatic colon cancer, there is a significant increase in the expression of nuclear Atox1. Interestingly, the metastatic CRC cell line SW620 has increased nuclear localization of Atox1 compared to its related non-metastatic cell line SW480. Further, inhibition of endogenous Atox1 by siRNA in SW620 decreased colony formation and reactive oxygen species generation via decreased expression of Atox1 targets cyclin D1 and NADPH oxidase subunit p47 phox, respectively. Additionally, overexpression of nuclear-targeted but not copper binding domain-mutated Atox1 in SW480 cells increased colony formation and cell migration that was further augmented by activin A stimulation, a known enhancer of colon cancer metastasis. CONCLUSIONS: Our findings suggest that nuclear Atox1 might be a new therapeutic target as well as a new biomarker for metastatic colorectal cancer.


Assuntos
Ativinas/metabolismo , Carcinoma , Movimento Celular , Neoplasias do Colo , Proteínas de Transporte de Cobre/fisiologia , Chaperonas Moleculares/fisiologia , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos
12.
Biomed Pharmacother ; 122: 109654, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918266

RESUMO

BACKGROUND: Folate deficiency has been long implicated in cancer development. Although the role of folate in preventing cervical cancer is still unclear, emerging evidence shows that microRNAs (miRs) have great influence on tumor cell migration and invasion. OBJECTIVES: The purpose of this study was to conduct an integrated analysis of miR expression in squamous cell carcinoma tissues with adequate or deficient serum folate. Further, study conducted tissue validation and functional analysis of miRs to uncover novel pathogenic mechanisms on the role of folate in squamous cell carcinoma (SCC). MATERIALS AND METHODS: miR expression profiles were obtained from five paired primary SCC tumors with sufficient or deficient serum folate levels through Affymetrix GeneChip microRNA 4.0. This was followed by an integrated bioinformatics analysis and expanded sample size to verify core miRs by molecular biological validation. HeLa and SiHa cells with different concentrations of folate were used to clarify the roles of miR-27a on cell proliferation, migration, and invasion. MiR-27a expression was measured by the quantitative real-time polymerase chain reaction. Cell counting proliferation, wound healing, and transwell invasion assays were used to determine cell survival, proliferation, migration, and invasion abilities, respectively. RESULTS: Our study found increasing miR-27a expression in serum of normal, high-grade squamous intraepithelial lesion (HSIL), and SCC tissues (in order of magnitude), which trend was negatively correlated with serum folate content. Further, there were significant differences in cellular miR-27a expression between 200 nM and 500 nM folate concentrations, with higher folate concentrations showing lower proliferation, migration, and invasion in SCC. Finally, miR-27a promoted proliferation and invasion in HeLa cells, whereas a miR-27a inhibitor blocked cell proliferation and invasion. CONCLUSION: There is a significant association between miR-27a expression and folate during cervical carcinoma progression. Therefore, miR-27a could be used as a new biomarker for SCC diagnosis and prediction, suggesting a new therapeutic strategy for SCC treatment.


Assuntos
Carcinoma/metabolismo , Ácido Fólico/farmacologia , MicroRNAs/efeitos dos fármacos , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Ácido Fólico/sangue , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Células HeLa , Humanos , MicroRNAs/genética , Taxa de Sobrevida
13.
Dis Markers ; 2020: 8459303, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998419

RESUMO

Pathologic features depending on tumor response to preoperative chemoradiotherapy are important to determine the outcomes in patients with rectal cancer. Evaluating the potential predictive roles of biomarker expression and their prognostic impact is a promising challenge. We reported here the immunohistochemical staining of a panel marker of mismatch repair protein (MMR), Ki67, HER-2, and p53. Additionally, identification of somatic mutations of KRAS, NRAS, and BRAF genes were performed by direct sequencing and pyrosequencing in pretreated biopsy tissues from 57 patients diagnosed for rectal cancer. Clinical features and pathological criteria for postneoadjuvant treatment surgical resection specimen's data were collected. Immunohistochemical expression and mutational status were correlated with therapeutic response, overall survival, and disease progression. The mean age of patients was 56 years. Seven (12.3%) out of 57 patients had a complete therapeutic response. Our analysis showed that when using complete therapeutic response (Dworak 4) and incomplete therapeutic response (Dworak 3, 2, and 1) as grouping factor, high p53 expression at the pretreatment biopsy was significantly associated to an incomplete response (p = 0.002). For 20 and 2 out of 57, KRAS and NRAS mutations were detected, respectively. The majority of these mutations affected codon 12. KRAS mutations detected at codon 146 (A146T, A146V) was associated with the appearance of recurrence and distant metastasis (p = 0.019). A high expression of HER-2 corresponding to score 3+ was observed in 3 pretreatment biopsy specimens. This class was significantly associated with a short relapse-free survival (p = 0.002). Furthermore, the high expression of Ki67 was moderately correlated with an older age (p = 0.016, r = 0.319). In addition, this shows that high p53 expression in the pretreatment biopsy was associated with an incomplete response in surgical resection specimens after neoadjuvant treatment, and a HER-2 score 3+ can be a predictive factor of distant metastasis and local recurrence. Larger, prospective, and more studies are needed.


Assuntos
Carcinoma/genética , Terapia Neoadjuvante , Neoplasias Retais/genética , Adulto , Idoso , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma/terapia , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias Retais/metabolismo , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
14.
Am J Surg Pathol ; 44(2): 174-181, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31651527

RESUMO

Programmed death-ligand 1 (PD-L1) is a biomarker that may predict the response to anti-programmed death 1/PD-L1 immunotherapy. We evaluated the expression of PD-L1 in carcinoma cells (Ca) and immune cells (ICs) across histopathologic and The Cancer Genome Atlas (TCGA) molecular subgroups of endometrial carcinoma (EC). Our study included 842 patients with EC. Direct sequencing of polymerase epsilon (POLE) exonuclease domain hot spots and conventional immunohistochemistry (MLH1, PMS2, MSH2, MSH6, p53) were conducted to identify TCGA classification-based molecular subgroups of EC: POLE-mutated, mismatch repair deficient, no specific molecular profile, and p53 aberrant. Multiplex immunohistochemistry was performed to evaluate PD-L1 expression in Ca and tumor-infiltrating ICs. PD-L1 expression in Ca and in ICs was detected in 8.6% and 27.7% of the cases, respectively. A combined positive score (CPS) was ≥1% in 19.4% of the samples. PD-L1 positivity in Ca and ICs, and CPS correlated with tumor T-cell density (P<0.001). POLE-mutated and mismatch repair-deficient tumors were more likely to present PD-L1-expressing ICs, CPS positivity, and abundant tumor-infiltrating lymphocytes compared with other TCGA subgroups (P<0.001). No differences existed in Ca-PD-L1 expression (P=0.366). Within various histotypes, non-endometrioid carcinomas displayed the highest Ca-PD-L1, ICs, and CPS (P<0.03). Advanced cancers showed more frequent Ca-PD-L1 positivity (P=0.016), and CPS (P=0.029) and IC≥1% (P=0.037) positivity compared with early disease. In conclusion, PD-L1 expression profiles differ between molecular subclasses, histologic subtypes, and disease stage of EC. Prospective studies are needed to explore the predictive value of various PD-L1 scoring systems within the subgroups of EC. CPS presents methodological advantages over cell type-specific scoring systems.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma/metabolismo , Neoplasias do Endométrio/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Idoso , Carcinoma/mortalidade , Carcinoma/patologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Serial de Tecidos
15.
Int J Cancer ; 146(7): 1979-1992, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31411736

RESUMO

Removal of colorectal adenomas is an effective strategy to reduce colorectal cancer (CRC) mortality rates. However, as only a minority of adenomas progress to cancer, such strategies may lead to overtreatment. The present study aimed to characterize adenomas by in-depth molecular profiling, to obtain insights into altered biology associated with the colorectal adenoma-to-carcinoma progression. We obtained low-coverage whole genome sequencing, RNA sequencing and tandem mass spectrometry data for 30 CRCs, 30 adenomas and 18 normal adjacent colon samples. These data were used for DNA copy number aberrations profiling, differential expression, gene set enrichment and gene-dosage effect analysis. Protein expression was independently validated by immunohistochemistry on tissue microarrays and in patient-derived colorectal adenoma organoids. Stroma percentage was determined by digital image analysis of tissue sections. Twenty-four out of 30 adenomas could be unambiguously classified as high risk (n = 9) or low risk (n = 15) of progressing to cancer, based on DNA copy number profiles. Biological processes more prevalent in high-risk than low-risk adenomas were related to proliferation, tumor microenvironment and Notch, Wnt, PI3K/AKT/mTOR and Hedgehog signaling, while metabolic processes and protein secretion were enriched in low-risk adenomas. DNA copy number driven gene-dosage effect in high-risk adenomas and cancers was observed for POFUT1, RPRD1B and EIF6. Increased POFUT1 expression in high-risk adenomas was validated in tissue samples and organoids. High POFUT1 expression was also associated with Notch signaling enrichment and with decreased goblet cells differentiation. In-depth molecular characterization of colorectal adenomas revealed POFUT1 and Notch signaling as potential drivers of tumor progression.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fucosiltransferases/genética , Proteínas Oncogênicas/genética , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Biomarcadores Tumorais , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Neoplasias Colorretais/metabolismo , Progressão da Doença , Fucosiltransferases/metabolismo , Humanos , Proteínas Oncogênicas/metabolismo , Reprodutibilidade dos Testes , Microambiente Tumoral
16.
Xenobiotica ; 50(2): 170-177, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30901299

RESUMO

1. 2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a second-generation photosensitizer, has been widely employed in photodynamic therapy (PDT) for the treatment of malignant lesions. The objective of this study was to characterize the pharmacokinetics of HPPH in Chinese patients using a population pharmacokinetic (PopPK) approach.2. For the first time, a PopPK model of HPPH for Chinese (n = 20) was developed (registration number: CTR20160425). The pharmacokinetics of HPPH was described by a three-compartment model with linear elimination. Through the stepwise addition (p < 0.05) and backward elimination (p < 0.001) approach, fat-free mass (FFM) was identified to be the most significant covariate and V1 increased with FFM. Visual predictive check (VPC) was employed for the evaluation of the final model. Subsequent full covariate analysis indicated that FFM has considerable impact (∼30%) on HPPH exposure and fat mass also has a modest (∼25%) impact.3. The simulations suggested that a dose adjustment of HPPH may be necessary for Chinese and the dose of 3 mg/m2 should be appropriate. HPPH exposure increases with fat mass while being inversely related to FFM. HPPH-PDT for overweight patients should be monitored with more caution and PDT conditions should be optimized if necessary.


Assuntos
Carcinoma/metabolismo , Clorofila/análogos & derivados , Neoplasias Esofágicas/metabolismo , Fármacos Fotossensibilizantes/farmacocinética , Grupo com Ancestrais do Continente Asiático , China , Clorofila/farmacocinética , Feminino , Humanos , Masculino , Modelos Teóricos , Fotoquimioterapia
17.
Am J Surg Pathol ; 44(2): 149-161, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31498173

RESUMO

The frequency and prognostic significance of the histologic type in early-stage ovarian cancer (OC) is not as well established as in advanced stages. In addition, histologic typing based only on morphologic features may be difficult, especially in high-grade tumors. In this study, we have analyzed a prospective cohort of 502 early-stage OCs to investigate their frequency, immunohistochemical characteristics, and survival of the 5 main histologic types. Histotype was assigned according to not only the morphologic features but also according to the expression pattern of WT1, p53, Napsin A, and progesterone receptors. In addition, an extended panel including p16, ß-catenin, HER2, Arid1A, HINF1B, CK7, CDX2, and CK20 was used to refine the diagnosis in difficult cases. In this series, the frequency of the 5 major histologic types was as follows: endometrioid carcinoma, 32.7%; clear cell carcinoma, 25.1%; high-grade serous carcinoma (HGSC), 24.7%; mucinous carcinoma, 10.2%; low-grade serous carcinoma, 4.6%; and others, 2.8%. The combination of morphology and immunohistochemistry allowed the reclassification of 23% of OCs. The lowest concordance was found between samples initially diagnosed as endometrioid, but finally classified as high-grade serous tumors (22% error rate). Endometrioid carcinoma was the most favorable histologic type, whereas HGSC and low-grade serous carcinoma had the worst prognosis. Clear cell carcinoma with abnormal p53 immunostaining pattern also had poor prognosis. Although histologic grade was not a prognostic factor among early-stage endometrioid OCs, distinction between grade 3 endometrioid OC and HGSC is recommended, taking into account differences in prognosis and molecular alterations that can guide different treatments.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma/diagnóstico , Carcinoma/patologia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/metabolismo , Carcinoma/mortalidade , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Prognóstico , Estudos Retrospectivos , Espanha , Análise de Sobrevida , Análise Serial de Tecidos
18.
World J Gastroenterol ; 25(46): 6713-6727, 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31857774

RESUMO

BACKGROUND: Aberrant methylation in DNA regulatory regions could downregulate tumor suppressor genes without changing the sequences. However, our knowledge of secreted protein acidic and rich in cysteine (SPARC) and its aberrant methylation in gastric cancer (GC) is still inadequate. In the present research, we performed fundamental research to clarify the precise function of methylation on SPARC and its significance in GC. AIM: To investigate promoter methylation and the effects of the SPARC gene in GC cells and tissues and to evaluate its clinical significance. METHODS: Plasmids that overexpressed the SPARC gene were transfected into human GC BGC-823 cells; non-transfected cells were used as a control group (NC group). Quantitative real-time polymerase chain reaction and western blotting (WB) were then used to detect the expression of SPARC. Methylation-specific polymerase chain reaction was executed to analyze the gene promoter methylation status. Cell viability was measured by the cell counting kit-8 assay. The migration and invasion ability of cells were detected by scratch assays and transwell chamber assays, respectively. Cell cycle events and apoptosis were observed with a flow cytometer. RESULTS: The expression of SPARC mRNA in GC tissues and cells was significantly lower and showed differing degrees of hypermethylation, respectively, than that in normal adjacent tissues and control cells. Treatment with 5-Aza-2'-deoxycytidine (5-Aza-Cdr) was able to restore the expression of SPARC and reverse promoter hypermethylation. Overexpression of the SPARC gene significantly inhibited proliferation, migration, and invasion of GC cells, while also causing cell cycle arrest and apoptosis; the NC group exhibited the opposite effects. CONCLUSION: This study demonstrated that SPARC could function as a tumor suppressor and might be silenced by promoter hypermethylation. Furthermore, in GC cells, SPARC inhibited migration, invasion, and proliferation, caused cell cycle arrest at the G0/G1 phase, and promoted apoptosis.


Assuntos
Carcinoma/metabolismo , Metilação de DNA , Osteonectina/fisiologia , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Decitabina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transfecção
19.
Medicine (Baltimore) ; 98(52): e18449, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876727

RESUMO

Twist and E-cadherin are crucial for the development of different types of cancer; however, their clinical significance in adenocarcinoma of the gastroesophageal junction (AGE) remains unknown. Here, we investigated the correlation between the expression of Twist and E-cadherin and their impact on the clinical outcomes and prognosis of patients with AGE and proximal gastric carcinoma (PGC).Using immunohistochemistry, we determined the expression of Twist and E-cadherin in the tissue samples of patients with AGE and PGC. The correlation of the expression of Twist and E-cadherin with the clinicopathological factors was assessed by using the chi-square test, Fisher exact test, and non-parametric Mann-Whitney U test. The Kaplan-Meier method along with the log-rank test and Cox proportional-hazards model were used to evaluate the correlation of Twist and E-cadherin expression with the overall survival (OS) of patients.Overall, 94 patients with AGE (n = 45, 47.87%) or PGC (n = 49, 52.13%) who underwent primary tumor resection were included in this study. The median follow-up period was 40.5 months. We observed a significant difference in the smoking status (P < .001) and differentiation grade (P = .004) between patients with AGE and PGC. There was a significant association of a high Twist expression with T stage (only in PGC, P = .008), lymph node metastasis (AGE, P = .075; PGC, P = .051), and advanced pathological stages (AGE, P = .019; PGC, P = .006). A low E-cadherin expression showed similar results; however, it was not significantly associated with the advanced pathological stages of AGE (P = .372). A low E-cadherin expression was significantly associated with a low differentiation grade of AGE (P = .002). In addition, a significant inverse relationship was observed between Twist and E-cadherin expression. The Kaplan-Meier survival analysis and Cox regression analysis revealed that a high Twist expression and low E-cadherin expression were independent prognostic factors for short OS of patients with AGE or PGC.A high Twist expression or low E-cadherin expression was associated with unfavorable clinicopathological factors and independently predicted short OS of patients with AGE or PGC.


Assuntos
Adenocarcinoma/metabolismo , Caderinas/metabolismo , Carcinoma/metabolismo , Junção Esofagogástrica/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Gástricas/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Adenocarcinoma/química , Adenocarcinoma/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , Caderinas/análise , Carcinoma/química , Carcinoma/diagnóstico , Junção Esofagogástrica/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/química , Prognóstico , Neoplasias Gástricas/química , Neoplasias Gástricas/diagnóstico , Proteína 1 Relacionada a Twist/química
20.
Medicine (Baltimore) ; 98(51): e18407, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31861005

RESUMO

Ovarian cancer (OC) is one of the most common malignant tumors in female reproductive system and most OC cases are diagnosed at an advanced stage with the overall 5-year survival rate below 40%. The function of CD247 enhances T-cell antigen receptor (TCR) signaling cascade and it is necessary for assembling of the TCR/CD3 complex on the surface of T lymphocytes. It is well established that defective CD247 function leads to impaired activation of T cells upon engagement of the TCR.Flow cytometry was used to examine the difference of CD247 T lymphocyte between the OC and ovarian cyst, immunohistochemistry analysis was used to investigate the correlation between CD247 expression and clinicopathologic features of epithelial OC patients.Our study showed that the expression of CD247 in peripheral blood lymphocytes from patients with OC is decreased compared with ovarian cyst patients and the expression of CD247 in tumor infiltrating lymphocytes with cancer tissue is decreased compared with adjacent tissues. We showed that abnormal expression of CD247 was related with differentiation and classification in OC.Our findings suggested that CD247-targeted treatment could be used as a potential therapeutic strategy for OC.


Assuntos
Complexo CD3/metabolismo , Carcinoma/metabolismo , Neoplasias Ovarianas/metabolismo , Carcinoma/classificação , Carcinoma/patologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/patologia , Ovário/patologia
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