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1.
Braz J Med Biol Res ; 52(8): e8341, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31365693

RESUMO

MicroRNAs (miRNAs), as post-transcriptional regulators, have been reported to be involved in the initiation and progression of various types of cancer, including gastric cancer (GC). The present study aimed to investigate the role of miR-383-5p in gastric carcinogenesis. Cell viability was analyzed using CCK-8 kit. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to evaluate cell apoptosis. The expression levels of miR-383-5p and histone deacetylase 9 (HDAC9) mRNA in GC tissues and cell lines were analyzed using RT-qPCR. The protein expression of HDAC9 was detected by western blotting. We found that HDAC9 was up-regulated and miR-383-5p was down-regulated in GC tissues and cell lines. High HDAC9 expression or low miR-383-5p expression was closely related to poor prognosis and metastasis in GC patients. HDAC9 knockout or miR-383-5p mimics led to growth inhibition and increased apoptosis in AGS and SGC-7901 cells. More importantly, we validated that miR-383-5p as a post-transcriptional regulator inhibited HDAC9 expression and was inversely correlated with HDAC9 expression in GC tissues. miR-383-5p had the opposite effects to HDAC9 in gastric carcinogenesis. miR-383-5p played an important role in gastric carcinogenesis, and it is one of the important mechanisms to regulate oncogenic HDAC9 in GC, which might be helpful in the development of novel therapeutic strategies for the treatment of GC.


Assuntos
Carcinoma/patologia , Histona Desacetilases/metabolismo , MicroRNAs/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/patologia , Apoptose , Carcinogênese/genética , Carcinoma/genética , Carcinoma/metabolismo , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
2.
Medicine (Baltimore) ; 98(28): e15336, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305389

RESUMO

BACKGROUND: Human epididymis protein 4 (HE4) protein has garnered a great degree of interest as a complementary biomarker to carbohydrate antigen 125 (CA125), or even as an independent biomarker for monitoring, diagnosis, and prognostication of ovarian cancer. Its use is currently limited to ovarian cancer. Recent studies have suggested that it could also be used in other types of cancers. METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines was used to design this meta-analysis protocol. The final study will also be conducted under the PRISMA guidelines for systematic reviews and meta-analyses. The core bibliographic database search will be carried out by 2 reviewers working individually, with each conducting an initial screening based on titles and abstracts. The shortlisted articles will be selected for review and statistical analysis based on predefined inclusion and exclusion criteria. Study characteristics, relevant clinicopathological characteristics and statistical data required for meta-analysis (hazard ratios [HRs] and 95% confidence interval [CIs) will be extracted and compiled into a MS Excel datasheet. Meta-analysis will be performed, using a random-effects model, and the results (pooled HR and 95% CI) will be presented in the form of a forest plot. Publication bias will also be assessed by use of Egger bias indicator test and funnel plot symmetry. If data are insufficient, a narrative line of review will be pursued. DISCUSSION: HE4 protein has been shown to have great potential for clinical use as a diagnostic and prognostic marker in epithelial ovarian cancer (EOC). However, HE4 is not only limited to expression in ovarian cancer, but is also overexpressed in lung and endometrial cancers. The effectiveness of HE4 as a biomarker in cancers (other than EOC) has not yet been studied in the form of a comprehensive systematic review and meta-analysis. The results of this study should allow for expanded use of HE4 as a multiutility biomarker in multiple cancer types, thereby, elevating HE4's value as a cancer biomarker. PROSPERO REGISTRATION: CRD42019120326.


Assuntos
Carcinoma/diagnóstico , Carcinoma/metabolismo , Metanálise como Assunto , Proteínas/metabolismo , Revisão Sistemática como Assunto , Biomarcadores Tumorais/metabolismo , Humanos , Prognóstico , Projetos de Pesquisa
3.
Nat Commun ; 10(1): 2406, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160622

RESUMO

Organ-specific colonization suggests that specific cell-cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLex-P-selectin cascade.


Assuntos
Líquido Ascítico , Carcinoma/secundário , Adesão Celular , Hidrodinâmica , Células-Tronco Neoplásicas/metabolismo , Oligossacarídeos/metabolismo , Neoplasias Ovarianas/patologia , Selectina-P/metabolismo , Neoplasias Peritoneais/secundário , Animais , Carcinoma/metabolismo , Linhagem Celular Tumoral , Epitélio/metabolismo , Feminino , Fucosiltransferases/metabolismo , Células HEK293 , Humanos , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Peritônio/metabolismo , Receptor IGF Tipo 1/metabolismo , Estresse Mecânico
4.
Nat Commun ; 10(1): 2450, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164648

RESUMO

Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8+ T cells and immune-stimulatory myeloid subsets. Tumor-associated macrophages (TAMs) isolated from Camkk2-/- mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2-/- macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT. Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8+ T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment. These data, credential CaMKK2 as a myeloid-selective checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.


Assuntos
Neoplasias da Mama/imunologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/imunologia , Carcinoma/imunologia , Neoplasias Mamárias Animais/imunologia , Células Mieloides/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linfócitos T CD8-Positivos/imunologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Proliferação de Células , Quimiocinas/imunologia , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Células Mieloides/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Evasão Tumoral/genética
5.
J Enzyme Inhib Med Chem ; 34(1): 1062-1077, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31072216

RESUMO

Histone deacetylase 6 (HDAC6) is an attractive target for cancer therapeutic intervention. Selective HDAC6 inhibitors is important to minimise the side effects of pan inhibition. Thus, new class of hydroxamic acid-based derivatives were designed on structural basis to perform preferential activity against HDAC6 targeting solid tumours. Interestingly, 1-benzylbenzimidazole-2-thio-N-hydroxybutanamide 10a showed impressive preference with submicromolar potency against HDAC6 (IC50 = 510 nM). 10a showed cytotoxic activity with interesting profile against CCHE-45 at (IC50 = 112.76 µM) when compared to standard inhibitor Tubacin (IC50 = 20 µM). Western blot analysis of acetylated-α-tubulin verified the HDAC6 inhibiting activity of 10a. Moreover, the insignificant difference in acetylated-α-tubulin induced by 10a and Tubacin implied the on-target cytotoxic activity of 10a. Docking of 10a in the binding site of HDAC6 attributed the activity of 10a to π-π stacking with the amino acids of the hydrophobic channel of HDAC6 and capture of zinc metal in bidentate fashion. The therapeutic usefulness besides the on-target activity may define 10a as an interesting safe-lead inhibitor for future development.


Assuntos
Antineoplásicos/farmacologia , Carcinoma/tratamento farmacológico , Neoplasias do Plexo Corióideo/tratamento farmacológico , Desenho de Drogas , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Plexo Corióideo/metabolismo , Neoplasias do Plexo Corióideo/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Estrutura Molecular , Relação Estrutura-Atividade
6.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052182

RESUMO

Class I histone deacetylases (HDACs) generally promote cell proliferation and tumorigenesis, whereas class IIA HDACs like HDAC4 and HDAC5 may promote or impede cancer development in a tissue-dependent manner. In urothelial carcinoma (UC), HDAC5 is often downregulated. Accordingly, HDAC5 was weakly expressed in UC cell lines suggesting a possible tumor-suppressive function. We therefore characterized the effects of stable HDAC5 expression in four UC cell lines (RT112, VM-Cub-1, SW1710 and UM-UC-3) with different phenotypes reflecting the heterogeneity of UC, by assessing proliferation, clonogenicity and migration ability. Further, we detailed changes in the proteome and transcriptome by immunoblotting, mass spectrometry and RNA sequencing analysis. We observed that HDAC5 overexpression in general decreased cell proliferation, but in one cell line (VM-Cub-1) induced a dramatic change from an epitheloid to a mesenchymal phenotype, i.e., epithelial-mesenchymal transition (EMT). These phenotypical changes were confirmed by comprehensive proteomics and transcriptomics analyses. In contrast to HDAC5, overexpression of HDAC4 exerted only weak effects on cell proliferation and phenotypes. We conclude that overexpression of HDAC5 may generally decrease proliferation in UC, but, intriguingly, may induce EMT on its own in certain circumstances.


Assuntos
Carcinoma/metabolismo , Proliferação de Células , Transição Epitelial-Mesenquimal , Histona Desacetilases/genética , Neoplasias da Bexiga Urinária/metabolismo , Urotélio/patologia , Carcinoma/genética , Linhagem Celular Tumoral , Células HEK293 , Histona Desacetilases/metabolismo , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias da Bexiga Urinária/genética , Urotélio/metabolismo
7.
Int J Mol Sci ; 20(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067787

RESUMO

: Neoplastic epithelial cells coexist in carcinomas with various non-neoplastic stromal cells, together creating the tumor microenvironment. There is a growing interest in the cross-talk between tumor cells and stromal fibroblasts referred to as carcinoma-associated fibroblasts (CAFs), which are frequently present in human carcinomas. CAF populations extracted from different human carcinomas have been shown to possess the ability to influence the hallmarks of cancer. Indeed, several mechanisms underlying CAF-promoted tumorigenesis are elucidated. Activated fibroblasts in CAFs are characterized as alpha-smooth muscle actin-positive myofibroblasts and actin-negative fibroblasts, both of which are competent to support tumor growth and progression. There are, however, heterogeneous CAF populations presumably due to the diverse sources of their progenitors in the tumor-associated stroma. Thus, molecular markers allowing identification of bona fide CAF populations with tumor-promoting traits remain under investigation. CAFs and myofibroblasts in wound healing and fibrosis share biological properties and support epithelial cell growth, not only by remodeling the extracellular matrix, but also by producing numerous growth factors and inflammatory cytokines. Notably, accumulating evidence strongly suggests that anti-fibrosis agents suppress tumor development and progression. In this review, we highlight important tumor-promoting roles of CAFs based on their analogies with wound-derived myofibroblasts and discuss the potential therapeutic strategy targeting CAFs.


Assuntos
Carcinogênese/metabolismo , Carcinoma/metabolismo , Fibroblastos/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/patologia , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
8.
Clin Adv Hematol Oncol ; 17(3): 176-183, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30969956

RESUMO

Level 1 evidence supports cisplatin-based neoadjuvant chemotherapy (NAC) in muscle-invasive urothelial bladder cancer (MIUBC). Recent data from small prospective trials with neoadjuvant immune checkpoint inhibitors are encouraging, but long-term follow-up is required. Randomized trials have failed to accrue a sufficient number of patients and have not demonstrated a survival benefit with adjuvant chemotherapy in MIUBC, but for those with high-risk features at surgery, adjuvant cisplatin-based therapy is appropriate. In upper tract urothelial carcinoma, several retrospective trials and one recent phase 2 prospective trial support the use of NAC, and a randomized trial with adjuvant chemotherapy demonstrated improved disease- and metastasis-free survival and a trend toward improved overall survival.


Assuntos
Carcinoma/terapia , Cisplatino/uso terapêutico , Terapia Neoadjuvante/métodos , Assistência Perioperatória/métodos , Neoplasias da Bexiga Urinária/terapia , Carcinoma/metabolismo , Carcinoma/patologia , Ensaios Clínicos Fase II como Assunto , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Urotélio/metabolismo , Urotélio/patologia
9.
APMIS ; 127(7): 491-502, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30942913

RESUMO

Secretory carcinoma (SC) of salivary glands is a newly described low-grade malignancy characterized by the presence of ETV6 rearrangement. Only a few cases and very small series with cytomorphology were reported so far. Six cases of fine-needle aspirations (FNAs) from afterward histologically, immunohistochemically and genetically confirmed SCs were retrieved from the archives of the authors. Ancillary immunocytochemistry (ICC) and translocation detection were performed on cell blocks (CBs). All aspirates were sufficiently cellular and cells were arranged in more or less cohesive groups with only mild nuclear polymorphism. The cytoplasm was eosinophilic, granulated and vacuolated, especially in CBs. Secretory material within the microcystic spaces was periodic acid-Schiff (PAS) positive. Triple positivity of immunomarkers S-100 protein, mammaglobin and vimentin was present. The proliferation index was low. Ancillary techniques suggested the possibility of SC in a few cytology cases; nevertheless, the final diagnosis was based on histomorphology, immunohistochemistry and genetics. The SC of salivary glands is detectable pre-operatively using ICC and genetics. The presence of the diagnostic ETV6 rearrangement increases the accuracy of FNA to the maximum. According to the Milan system, cases genetically not confirmed should be categorized as Suspicious for Malignancy or Salivary Gland Neoplasm of Uncertain Malignant Potential (SUMP), both requiring surgery.


Assuntos
Carcinoma/diagnóstico , Carcinoma/patologia , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/patologia , Glândulas Salivares/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Biópsia por Agulha Fina/métodos , Carcinoma/metabolismo , Citodiagnóstico/métodos , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Repressoras/metabolismo , Proteínas S100/metabolismo , Neoplasias das Glândulas Salivares/metabolismo , Glândulas Salivares/metabolismo , Vimentina/metabolismo , Adulto Jovem
10.
Dis Markers ; 2019: 8040361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019584

RESUMO

Backgrounds: The objective of the present research was to systematically revise the international literature about the genetic biomarkers related to oral cancer (OC) evaluating the recent findings in clinical studies. Methods: A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed database. The authors conducted the search of articles in the English language published from 2008 to 2018. The present systematic review included only papers with significant results about correlation between wound healing, genetic alteration, and OC. Prognostic capacity of genetic markers was not evaluated in vivo. Results: The first analysis with filters recorded about 1884 published papers. Beyond reading and consideration of suitability, only 20 and then 8 papers, with case report exclusion, were recorded for the revision. Conclusion: All the researches recorded the proteomic and genetic alterations in OC human biopsy cells. The gene modification level in the different studies, compared with samples of healthy tissues, has always been statistically significant, but it is not possible to associate publications with each other because each job is based on the measurement of different biomarkers and gene targets. Further investigations should be required in order to state scientific evidence about a clear advantage of using these biomarkers for diagnostic purpose.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma/genética , Estudos de Avaliação como Assunto , Neoplasias Bucais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma/metabolismo , Carcinoma/patologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia
11.
Dis Markers ; 2019: 4586405, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984306

RESUMO

Purpose: To compare the expression level of apelin in muscle-invasive bladder cancer and matched paracarcinoma tissues and investigate the relationship between apelin and clinical prognosis in the patients. Methods: To assess apelin expression by using immunohistochemical method compared with bladder tumors and matched paracarcinoma tissues. Subsequently, the correlation of apelin expression with the clinicopathological features of bladder cancer patients was analyzed. Kaplan-Meier survival curves method was used to analyze apelin prognostic significance for muscle-invasive bladder cancer patients (including 404 muscle-invasive bladder cancer patients and 28 normal bladder tissues, in TCGA dataset). Results: Apelin protein level was overexpressed in bladder tumor tissues compared with paracarcinoma tissues. Furthermore, high apelin expression was associated with high tumor stage (P < 0.05), distant metastasis (P < 0.05), and vascular invasion (P < 0.05). Kaplan-Meier curve analyses showed that the overexpression of apelin was a potential predictor of overall survival and disease-free survival. Conclusion: Apelin was upregulated in bladder tumor tissues compared with matched adjacent noncancer tissues, especially in the high tumor stage, distant metastasis, and vascular invasion. What is more, high expression of apelin in muscle-invasive bladder cancer indicates the poor prognosis. These data suggested that apelin might be a therapeutic potential biomarker in muscle-invasive bladder cancer patients.


Assuntos
Apelina/genética , Biomarcadores Tumorais/genética , Carcinoma/metabolismo , Neoplasias Musculares/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Idoso , Apelina/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma/genética , Carcinoma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/genética , Neoplasias Musculares/secundário , Prognóstico , Regulação para Cima , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
12.
Clin Lab ; 65(3)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30868864

RESUMO

BACKGROUND: Circular RNAs (circRNAs) are potential, novel biomarkers for the early diagnosis of gastric carcinoma. Herein, a meta-analysis was conducted to assess the diagnostic potential for circRNAs in gastric carcinoma. METHODS: Online databases were searched for eligible studies. Study quality was judged using the Quality Assessment for Studies of Diagnostic Accuracy (QUADAS) checklist-II tool. STATA 12.0 and Meta-Disc 1.4 software were used for statistical analysis. RESULTS: Twelve studies consisting of 1,278 patients and 1,250 paired controls were considered for meta-analysis. The pooled sensitivity and specificity of circRNAs for gastric carcinoma were compared to normal controls and found to be 0.68 (95% CI: 0.66 - 0.71) and 0.70 (95% CI: 0.68 - 0.73), respectively. A corresponding area under the receiver operating characteristic curve of 0.78 was identified. Moreover, stratified analysis demonstrated an improved diagnostic value for circRNAs when tissue and plasma specimens were combined. CONCLUSIONS: This meta-analysis demonstrates that circRNAs are promising biomarkers for gastric carcinoma.


Assuntos
Carcinoma/diagnóstico , RNA/metabolismo , Neoplasias Gástricas/diagnóstico , Carcinoma/metabolismo , Humanos , Neoplasias Gástricas/metabolismo
13.
Int J Mol Sci ; 20(6)2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917509

RESUMO

An inverse association exists between physical activity and breast cancer incidence and outcomes. An objective indicator of an individual's recent physical activity exposure is aerobic capacity. We took advantage of the fact that there is an inherited as well as inducible component of aerobic capacity to show that experimentally induced mammary cancer is inversely related to inherent aerobic capacity (IAC). The objective of this study was to determine whether cell signaling pathways involved in the development of mammary cancer differed in rats with low inherent aerobic capacity (LIAC, n = 55) versus high inherent aerobic capacity (HIAC, n = 57). Cancer burden was 0.21 ± 0.16 g/rat in HIAC versus 1.14 ± 0.45 in LIAC, p < 0.001. Based on protein expression, cancer in LIAC animals was associated with upregulated glucose utilization, and protein and fatty acid synthesis. Signaling in cancers from HIAC rats was associated with energy sensing, fatty acid oxidation and cell cycle arrest. These findings support the thesis that pro-glycolytic, metabolic inflexibility in LIAC favors not only insulin resistance and obesity but also tumor development and growth. This provides an unappreciated framework for understanding how obesity and low aerobic fitness, hallmarks of physical inactivity, are associated with higher cancer risk and poorer prognosis.


Assuntos
Carcinoma/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Consumo de Oxigênio , Transdução de Sinais , Animais , Carcinoma/etiologia , Metabolismo Energético , Ácidos Graxos/biossíntese , Feminino , Glucose/metabolismo , Neoplasias Mamárias Experimentais/etiologia , Biossíntese de Proteínas , Ratos
14.
Ann Otol Rhinol Laryngol ; 128(7): 676-680, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30873845

RESUMO

OBJECTIVE: SMARCB1-deficient sinonasal tract carcinomas are an emerging subset of rare tumors recently described in the literature, with less than 100 reported cases. Given the aggressive nature of this tumor, timely diagnosis is especially important. We present a case report of a SMARCB1-deficient carcinoma of the sinonasal tract. METHODS: Case report with review of the literature. RESULTS: The patient was a 53-year-old male with computed tomography (CT)-proven mass of the right ethmoid and sphenoid sinuses. Rigid nasal endoscopy revealed a purple mass completely obstructing the right nasal cavity that extended inferiorly from the posterior ethmoids and sphenoid sinuses. Initial biopsy in the emergency room was nondiagnostic due to extensive tumor necrosis. Magnetic resonance imaging (MRI) revealed T2 hypointense enhancing mass centered in the right posterior ethmoids with invasion into the right orbital apex, classifying it as a T4b tumor. The patient underwent repeat biopsy with frozen section and tumor debulking. Immunohistochemical analysis of subsequent biopsy revealed complete loss of INI-1 and negative staining for other pertinent markers, alluding to the diagnosis of SMARCB1-deficient sinonasal tract carcinoma. CONCLUSION: Tumor necrosis may be problematic in obtaining a diagnosis for SMARCB1-deficient sinonasal carcinomas. Thus, sampling various regions of the tumor during initial biopsy can prevent delays in diagnosis and treatment.


Assuntos
Carcinoma/metabolismo , Seio Etmoidal/diagnóstico por imagem , Neoplasias dos Seios Paranasais/metabolismo , Proteína SMARCB1/metabolismo , Seio Esfenoidal/diagnóstico por imagem , Biomarcadores Tumorais/metabolismo , Carcinoma/diagnóstico por imagem , Carcinoma/patologia , Carcinoma/cirurgia , Procedimentos Cirúrgicos de Citorredução , Seio Etmoidal/patologia , Seio Etmoidal/cirurgia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias dos Seios Paranasais/diagnóstico por imagem , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/cirurgia , Seio Esfenoidal/patologia , Seio Esfenoidal/cirurgia , Tomografia Computadorizada por Raios X
15.
Int J Mol Sci ; 20(5)2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30841620

RESUMO

Cisplatin is ranked as one of the most powerful and commonly prescribed anti-tumor chemotherapeutic agents which improve survival in many solid tumors including non-small cell lung cancer. However, the treatment of advanced lung cancer is restricted due to chemotherapy resistance. Here, we developed and investigated survivin promoter regulating conditionally replicating adenovirus (CRAd) for its anti-tumor potential alone or in combination with cisplatin in two lung cancer cells, H23, H2126, and their resistant cells, H23/CPR, H2126/CPR. To measure the expression of genes which regulate resistance, adenoviral transduction, metastasis, and apoptosis in cancer cells, RT-PCR and Western blotting were performed. The anti-tumor efficacy of the treatments was evaluated through flow cytometry, MTT and transwell assays. This study demonstrated that co-treatment with cisplatin and CRAd exerts synergistic anti-tumor effects on chemotherapy sensitive lung cancer cells and monotherapy of CRAd could be a practical approach to deal with chemotherapy resistance. Combined treatment induced stronger apoptosis by suppressing the anti-apoptotic molecule Bcl-2, and reversed epithelial to mesenchymal transition. In conclusion, cisplatin synergistically increased the tumor-killing of CRAd by (1) increasing CRAd transduction via enhanced CAR expression and (2) increasing p53 dependent or independent apoptosis of lung cancer cell lines. Also, CRAd alone proved to be a very efficient anti-tumor agent in cancer cells resistant to cisplatin owing to upregulated CAR levels. In an exciting outcome, we have revealed novel therapeutic opportunities to exploit intrinsic and acquired resistance to enhance the therapeutic index of anti-tumor treatment in lung cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinoma/metabolismo , Cisplatino/farmacologia , Neoplasias Pulmonares/metabolismo , Vírus Oncolíticos/fisiologia , Replicação Viral , Adenoviridae/fisiologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Células HEK293 , Humanos , Proteína Supressora de Tumor p53/metabolismo
16.
Int J Exp Pathol ; 100(1): 19-24, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30883974

RESUMO

Various studies revealed that elevated expression of CD97 in carcinomas is associated with the dedifferentiation, aggressiveness and metastasis of tumour. CD97 is a protein member of the epidermal growth factor seven-transmembrane (EGF-TM7) family of class II TM7 receptors. Our previous study suggested that the overexpression of CD97 in cervical cancer was correlated with the aggressiveness of the tumour and that CD97 might be an independent poor prognostic factor for cervical cancer patients. Based on these data, we have investigated the role of CD97 small isoform in cervical cancer proliferation, migration and invasion in vitro. Three cervical cancer cell lines were tested and the CD97 small isoform was found to be expressed predominantly in the SiHa cells. The mobile and invasive ability of different cervical cancer cell lines was not correlated positively with total CD97 protein expression but was with the level of the CD97 small isoform. Functional significance was assessed 48 hours after transient knockdown using siRNA targeting CD97 small isoform (CD97/EGF1,2,5) or a scrambled control sequence in cervical cancer cell lines. As a result, decreased ability of migration and invasion was found in CD97 small isoform RNAi cells, which showed, however, no change in cell proliferation. This study shed light on the role of the CD97 small isoform in tumour progression and provides a basis for further studies to determine its function in vivo.


Assuntos
Antígenos CD/metabolismo , Carcinoma/metabolismo , Movimento Celular , Neoplasias do Colo do Útero/metabolismo , Antígenos CD/genética , Carcinoma/genética , Carcinoma/patologia , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Invasividade Neoplásica , Interferência de RNA , Transdução de Sinais , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
17.
Gynecol Oncol ; 153(3): 487-495, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30922603

RESUMO

OBJECTIVE: Approximately 15% of endometrial carcinomas (ECs) arise in young women who may wish to avoid surgical menopause and/or preserve fertility. Our aim was to evaluate the prognostic significance of Proactive Molecular risk classifier for Endometrial Carcinoma (ProMisE) in young (<50 yo) women with EC. METHODS: ProMisE was applied to a retrospective cohort of women with ECs <50 yo at diagnosis, and associations between the four ProMisE molecular subtypes (MMR deficient (MMRd), POLE mutated (POLE), p53 wild type (p53wt), and p53 abnormal (p53abn)) and clinicopathological parameters, including outcomes, were assessed. RESULTS: Of 257 ECs, there were 48 (19%) MMRd, 34 (13%) POLE, 164 (64%) p53wt and 11 (4%) p53abn. ProMisE subtypes were associated with differences in all measured clinicopathological parameters except for presence of synchronous ovarian tumours and fertility. Age at diagnosis was youngest and BMI highest in women with p53wt ECs. MMRd and p53abn tumours were more likely to be advanced stage (III/IV), high-risk (ESMO), and receive chemotherapy. ProMisE subtypes were strongly associated with outcomes (overall, disease-specific, and progression-free survival (p < 0.0001 for all)). Advanced stage, grade, LVSI, myometrial invasion and ESMO risk groups showed associations with some but not all survival parameters. ProMisE maintained a strong association with OS and DSS on multivariable analysis. CONCLUSIONS: ProMisE molecular classification is prognostic in young women with EC, enabling early stratification and risk assignment to direct care. Further studies can assess response to therapy, fertility, and cancer-related outcomes within the framework of molecular subtype.


Assuntos
Carcinoma/classificação , DNA Polimerase II/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/classificação , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteína Supressora de Tumor p53/metabolismo , Adulto , Fatores Etários , Índice de Massa Corporal , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/secundário , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de Sobrevida
18.
Mol Cancer ; 18(1): 33, 2019 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-30825877

RESUMO

BACKGROUND: The long non-coding RNA PVT1 (lncRNA PVT1) has been reported to act as an oncogenic regulator of several cancers. However, its expression and function in gallbladder cancer (GBC) remain largely unknown. METHODS: In situ hybridization (ISH) and quantitative real-time PCR (qPCR) were performed to detect the expression of PVT1 and miR-143 in GBC tissues and cell lines. Immunohistochemistry (IHC) assays were performed to assess the expression of the hexokinase 2 (HK2) protein. The relationships among PVT1, miR-143 and HK2 were evaluated using dual-luciferase reporter, RNA immunoprecipitation (RIP) and biotin pull-down assays. The biological functions of PVT1, miR-143 and HK2 in GBC cells were explored with cell counting kit 8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU), colony formation, transwell, wound healing and glucose metabolism assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of PVT1 and HK2 on GBC. RESULTS: PVT1 was upregulated in GBC tissues and cells and was positively associated with malignancies and worse overall survival. PVT1 knockdown inhibited cell proliferation, migration, and invasion in vitro and restrained tumor growth in vivo. Further studies demonstrated that PVT1 positively regulated HK2 expression via its competing endogenous RNA (ceRNA) activity on miR-143. Additionally, HK2 expression and function were positively correlated with PVT1. Furthermore, we observed that the PVT1/miR-143/HK2 axis promoted cell proliferation and metastasis by regulating aerobic glucose metabolism in GBC cells. CONCLUSIONS: The results of our study reveal a potential ceRNA regulatory pathway in which PVT1 modulates HK2 expression by competitively binding to endogenous miR-143 in GBC cells, which may provide new insights into novel molecular therapeutic targets for GBC.


Assuntos
Carcinoma/genética , Neoplasias da Vesícula Biliar/genética , Regulação Neoplásica da Expressão Gênica , Hexoquinase/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Adolescente , Adulto , Animais , Carcinoma/metabolismo , Carcinoma/mortalidade , Carcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/patologia , Glucose/metabolismo , Glicólise/genética , Hexoquinase/metabolismo , Humanos , Metástase Linfática , Masculino , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Curr Gastroenterol Rep ; 21(2): 5, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30701321

RESUMO

PURPOSE OF REVIEW: This review seeks to provide an informed prospective on the advances in molecular profiling and analysis of colorectal cancer (CRC). The goal is to provide a historical context and current summary on how advances in gene and protein sequencing technology along with computer capabilities led to our current bioinformatic advances in the field. RECENT FINDINGS: An explosion of knowledge has occurred regarding genetic, epigenetic, and biochemical alterations associated with the evolution of colorectal cancer. This has led to the realization that CRC is a heterogeneous disease with molecular alterations often dictating natural history, response to treatment, and outcome. The consensus molecular subtypes (CMS) classification classifies CRC into four molecular subtypes with distinct biological characteristics, which may form the basis for clinical stratification and subtype-based targeted intervention. This review summarizes new developments of a field moving "Back to the Future." CRC molecular subtyping will better identify key subtype specific therapeutic targets and responses to therapy.


Assuntos
Adenoma/genética , Biomarcadores Tumorais/genética , Carcinoma/genética , Neoplasias Colorretais/genética , Adenoma/classificação , Adenoma/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma/classificação , Carcinoma/metabolismo , Neoplasias Colorretais/classificação , Neoplasias Colorretais/metabolismo , Consenso , Humanos , Mutação , Transcriptoma
20.
Acta Otolaryngol ; 139(1): 105-110, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30714463

RESUMO

BACKGROUND: The relationship between infection with human papillomavirus (HPV) and tumorigenesis of salivary gland remains controversial. OBJECTIVES: This study explored the relationship between HPV and salivary gland lesions as well as that of the HPV infection status and p16INK4A immunoreactivity. The HPV DNA loads were also quantitatively evaluated. MATERIALS AND METHODS: Tissue samples from 31 submandibular gland lesions were evaluated. p16INK4A immunohistochemical (IHC) staining, nested polymerase chain reaction (PCR), DNA sequencing, and droplet digital PCR (ddPCR) were performed. RESULTS: Non-neoplastic lesion, benign tumors, and malignant tumors were noted in 9, 16, 6 cases, respectively. p16INK4A immunoreactivity was higher in malignant tumors than in benign tumors (50.0% vs. 6.3%). Single PCR with MY09/11 found that all samples were negative. Nevertheless, nested PCR revealed a high HPV-DNA positivity rate of 96.8%. No relationship between the HPV status and p16INK4A immunoreactivity was shown. HPV-18 was the only subtype identified in this study. ddPCR showed significantly lower HPV-18 DNA loads in submandibular gland lesions than in oropharyngeal cancers. CONCLUSIONS: HPV-DNA positivity and p16INK4A-immunoreactivity were not correlated in submandibular gland lesions. The loads of HPV DNA detected in this study were small. HPV positivity therefore may not be associated with tumorigenesis of the submandibular gland.


Assuntos
Carcinoma/virologia , Papillomaviridae/isolamento & purificação , Cálculos das Glândulas Salivares/virologia , Neoplasias da Glândula Submandibular/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Testes de DNA para Papilomavírus Humano , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias da Glândula Submandibular/metabolismo , Adulto Jovem
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