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1.
Theranostics ; 10(16): 7083-7099, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32641980

RESUMO

Background: Colorectal cancer (CRC) progression and related mortality are highly associated with metabolic disorders. However, the molecular mechanism involved in the regulation of hyperlipidemia-associated CRC metastasis remains unclear. This study aimed to investigate the effects of angiopoietin-like 4 (ANGPTL4) on NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) production, which might provide new targets for improving outcomes in patients with hyperlipidemia-associated CRC metastasis. Methods: The clinical relevance of relationship between NOX4 expression and ANGPTL4 was examined in CRC patients by the Oncomine and TCGA data set. Expressions of NOX4, epithelial-mesenchymal transition (EMT) markers, and gene regulation of NOX4 in free fatty acids (FFAs)-treated CRC cells were determined. The FFAs-triggered metastatic ability of CRC cells under treatments of antioxidants or knockdown of NOX4, ANGPTL4, and MMPs was evaluated in vitro and in vivo. In addition, effects of antioxidants and depletion of metastasis-associated molecules on the correlation between ROS production and FFAs-promoted CRC metastasis were also clarified. Results: In this study, we found that the induction of NOX4, followed by the increased ROS was essential for oleic acid (OA)-promoted CRC cell metastasis. The depletion of ANGPTL4 significantly inhibited c-Jun-mediated transactivation of NOX4 expression, accompanied with reduced levels of ROS, MMP-1, and MMP-9, resulting in the disruption of OA-promoted CRC cell metastasis. Moreover, knockdown of ANGPTL4, NOX4, MMP-1, and MMP-9 or the treatment of antioxidants dramatically inhibited circulating OA-enhanced tumor cell extravasation and metastatic seeding of tumor cells in lungs, indicating that the ANGPTL4/NOX4 axis was critical for dyslipidemia-associated tumor metastasis. Conclusion: The coincident expression of NOX4 and ANGPTL4 in CRC tumor specimens provides the insight into the potential therapeutic targets for the treatment of dyslipidemia-associated CRC metastasis.

2.
Asian J Surg ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31974054

RESUMO

BACKGROUND: The metastatic pattern differs between colon cancer and rectal cancer because of the distinct venous drainage systems. It is unclear whether colon cancer and rectal cancer are associated with different prognostic factors based on the anatomic difference. METHODS: We assessed the prognostic factors and survival outcomes of patients with colorectal cancer who underwent pulmonary metastasectomy (PM), disaggregated by the location of primary colorectal cancer. The Cox proportional hazards model was used to identify variables that influenced the outcomes of pulmonary metastasectomy. RESULTS: Between 2008 and 2017, 179 patients underwent PM classified into colon cancer and rectal cancer groups based on the site of origin of metastasis. The median postoperative follow-up was 2.3 years (range, 0.1-10.6). The post-PM 5-year survival rate in the colon cancer and rectal cancer groups was 42.5% and 39.9%, respectively (p = 0.310). On multivariable Cox proportional hazards analysis, presence of previous liver metastasis [hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.19-4.51; p = 0.013], numbers of tumors (≥2; HR, 6.56; 95% CI, 2.07-20.79; p = 0.001), and abnormal preoperative carcinoembryonic antigen (CEA) level (HR, 2.50; 95% CI, 1.34-4.64; p = 0.001) were independent prognostic factors in patients with metastatic rectal cancer. CONCLUSIONS: Prognostic correlates of post-PM survival differ between colon and rectal cancer. Rectal cancer patients have worse prognosis if they have a history of liver metastasis, multiple pulmonary metastases, or abnormal preoperative CEA. These results may help assess the survival benefit of PM and facilitate treatment decision-making.

3.
Cancer Lett ; 472: 97-107, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31875524

RESUMO

Many Aurora-A inhibitors have been developed for cancer therapy; however, the specificity and safety of Aurora-A inhibitors remain uncertain. The Aurora-A mRNA yields nine different 5'-UTR isoforms, which result from mRNA alternative splicing. Interestingly, we found that the exon 2-containing Aurora-A mRNA isoforms are predominantly expressed in cancer cell lines as well as human colorectal cancer tissues, making the Aurora-A mRNA exon 2 a promising treatment target in Aurora-A-overexpressing cancers. In this study, a selective siRNA, siRNA-2, which targets Aurora-A mRNA exon 2, was designed to translationally inhibit the expression of Aurora-A in cancer cells but not normal cells; locked nucleic acid (LNA)-modified siRNA-2 showed improved efficacy in inhibiting Aurora-A mRNA translation and tumor growth. Xenograft animal models combined with noninvasion in vivo imaging system (IVIS) analysis further confirmed the anticancer effect of LNA-siRNA-2 with improved efficiency and safety and reduced side effects. Mice orthotopically injected with colorectal cancer cells, LNA-siRNA-2 treatment not only inhibited the tumor growth but also blocked liver and lung metastasis. The results of our study suggest that LNA-siRNA-2 has the potential to be a novel therapeutic agent for cancer treatment.


Assuntos
Aurora Quinase A/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Isoformas de Proteínas/genética , Regiões 5' não Traduzidas/efeitos dos fármacos , Processamento Alternativo/genética , Animais , Aurora Quinase A/antagonistas & inibidores , Neoplasias Colorretais/patologia , Células HCT116 , Humanos , Camundongos , Metástase Neoplásica , Oligonucleotídeos/farmacologia , Isoformas de Proteínas/antagonistas & inibidores , RNA Mensageiro/genética , RNA Interferente Pequeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cancer Manag Res ; 11: 7867-7875, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692488

RESUMO

Purpose: Human epidermal growth factor receptor 2 (HER2) is an emerging therapeutic target in colorectal cancer (CRC). Currently, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) have been used to determine HER2-positive CRCs; however, the clinical utility of next-generation sequencing (NGS)-based techniques for determining HER2 status in CRC has been limited. Here, we detail our experience regarding the assessment of HER2 alterations in a CRC cohort. Materials and methods: We prospectively enrolled 73 CRC patients who underwent surgery and received adjuvant oxaliplatin treatment. We then examined HER2 alterations using the Oncomine Comprehensive Assay version 1, as well as clinical outcomes, in this cohort. Results: Using the NGS-based assay, HER2 copy number gains in 12 of 73 CRCs were determined to range from 2.74 to 92.62. Of these 12 tumors, 6 had HER2 high-level copy number gain (92.6, 57.9, 57.0, 52.0, 35.2, and 8.42) and were all defined as HER2-positive CRC using HERACLES Diagnostic Criteria. Nevertheless, other 6 patients with low-level copy number gain (ranging from 2.74 to 3.04) and the remaining 61 patients without increase in HER2 copy number were all HER2-negative. Among the 6 HER2-positive CRCs, KRAS and PIK3CA mutations were detected in 1 (17%; G13D) and 2 (33.3%; 1 Q546R and 1 H1047R) patients, respectively. Moreover, 2 of the 6 (33.3%) HER2-positive patients had recurrent disease, while one patient had a partial response after anti-HER2 therapy. Conclusion: NGS-based tools could assist in the simultaneous detection of HER2 and other genomic alterations in patients with CRC. Only CRCs with HER2 high-level copy number gain were HER2-postive by current diagnostic criteria.

5.
EBioMedicine ; 43: 270-281, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30982765

RESUMO

BACKGROUND: In our preliminary screening, expression of miR-338-5p was found to be higher in primary colorectal cancer (CRC) with metastasis. The autophagy related gene- phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3) appeared to be targeted by miR-338-5p. Here, we provide solid evidence in support of PIK3C3 involved in miR-338-5p related metastasis of CRC in vitro and in vivo. METHODS: The potential clinical relevance of miR-338-5p and its target gene was analysed on benign colorectal polyps and primary CRCs by QPCR. Mouse spleen xenograft experiment was performed to examine the importance of miR-338-5p for metastasis. FINDINGS: PIK3C3 was one of target genes of miR-338-5p. In primary CRCs, expression of miR-338-5p is positively related to tumour staging, distant metastasis and poor patient survival. Patients with higher ratios of miR-338-5p/PIK3C3 also had significantly poor overall survival, supporting their significance in the progression of CRC. Over-expression of miR-338-5p promotes CRC metastasis to the liver and lung in vivo, in which PIK3C3 was down-regulated in the metastatic tumours. In contrast, overexpression of PIK3C3 in miR-338-5p stable cells inhibited the growth of metastatic tumours. Both migration and invasion of CRC in vitro induced by miR-338-5p are mediated by suppression of PIK3C3. Using forward and reverse approaches, autophagy was proved to involve in CRC migration and invasion induced by miR-338-5p. INTERPRETATION: MiR-338-5p induces migration, invasion and metastasis of CRC in part through PIK3C3-related autophagy pathway. The miR-338-5p/PIK3C3 ratio may become a prognostic biomarker for CRC patients. FUND: NCKU Hospital, Taiwan, Ministry of Science and Technology, Taiwan.


Assuntos
Autofagia/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Interferência de RNA , Regiões 3' não Traduzidas , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Metástase Neoplásica , Estadiamento de Neoplasias , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cell Mol Biol Lett ; 23: 47, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30305826

RESUMO

Background: Evidence has shown that endogenous H2S plays an important role in the physiological and pathophysiological processes of many organs. The study aimed to explore whether exogenous H2S has a potential therapeutic effect on a rat ovariectomy-induced model of osteoporosis. Methods: The OVX osteoporosis model was established in female Sprague-Dawley rats by full bilateral ovariectomy. The rats were randomly divided into four groups, with the two experimental groups receiving an intraperitoneal injection of GYY4137 or sodium alendronate. The level of H2S in the plasma was determined and common laboratory indicators to diagnose osteoporosis, such as alkaline phosphatase (ALP) activity and the levels of osteocalcin (OCN), calcitonin, parathyroid hormone and leptin were measured. The bone mineral density (BMD) of the 4th and 5th lumbar vertebrae was measured using dual-energy X-ray absorptiometry. The maximum stress of femoral fracture was obtained through a three-point bending test of the femur. Results: The OVX osteoporosis model was successfully established. GYY4137 was injected to increase the level of H2S in the plasma in one group, designated OVX-GYY during the observation period (p < 0.05). At 12 weeks, the BMD value of the fourth lumbar vertebra in the OVX-GYY group had increased (p < 0.05). The BMD femur value in the OVX-vehicle group had decreased (p < 0.05). Bilateral ovariectomy leads to biochemical disorders related to bone metabolism and hormone levels in rat plasma (all p < 0.05). Ovariectomy also reduced blood calcium, blood phosphate and calcitonin, and increased parathyroid hormone and leptin. The opposite results were obtained for the groups with alendronate sodium or GYY4137 treatment (all p < 0.05). Conclusions: Through the slow release of H2S, GYY4137 did an excellent job of simulating endogenous neuroendocrine gaseous signaling molecules. Exogenous H2S had a regulatory effect on osteoporosis in ovariectomized rats, showing potential value for the treatment of human postmenopausal osteoporosis.


Assuntos
Morfolinas/uso terapêutico , Compostos Organotiofosforados/uso terapêutico , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Ovariectomia/efeitos adversos , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Cálcio/sangue , Modelos Animais de Doenças , Feminino , Hormônios/sangue , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Osteoporose/sangue , Osteoporose/fisiopatologia , Fósforo/sangue , Ratos Sprague-Dawley
7.
Exp Mol Med ; 50(6): 1-14, 2018 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-29884818

RESUMO

Heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, an RNA-binding protein, has been implicated in many post-transcriptional processes, including RNA metabolism and mRNA splicing and translation. However, the role of hnRNP Q1 in tumorigenesis remains unclear. We previously performed RNA immunoprecipitation (RIP)-seq analysis to identify hnRNP Q1-interacting mRNAs and found that hnRNP Q1 targets a group of genes that are involved in mitotic regulation, including Aurora-A. Here, we demonstrate that altering the hnRNP Q1 level influences the expression of the Aurora-A protein, but not its mRNA. Stimulation with epidermal growth factor (EGF) enhances both binding between hnRNP Q1 and Aurora-A mRNA as well as the efficacy of the hnRNP Q1-induced translation of Aurora-A mRNA. The EGF/hnRNP Q1-induced translation of Aurora-A mRNA is mediated by the mTOR and ERK pathways. In addition, we show that hnRNP Q1 up-regulates the translation of a group of spindle assembly checkpoint (SAC) genes. hnRNP Q1 overexpression is positively correlated with the levels of Aurora-A and the SAC genes in human colorectal cancer tissues. In summary, our data suggest that hnRNP Q1 plays an important role in regulating the expression of a group of cell cycle-related genes. Therefore, it may contribute to tumorigenesis by up-regulating the translation of these genes in colorectal cancer.


Assuntos
Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Sistema de Sinalização das MAP Quinases , Mitose , Proteínas de Neoplasias/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fator de Crescimento Epidérmico/genética , Células HCT116 , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Proteínas de Neoplasias/genética
8.
Cancer Res ; 77(16): 4305-4316, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28652251

RESUMO

Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2-derived prostaglandin E2, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE2 biosynthesis or signal transduction ameliorated loss-of-DUSP2-induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens. Cancer Res; 77(16); 4305-16. ©2017 AACR.


Assuntos
Hipóxia Celular/fisiologia , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Fosfatase 2 de Especificidade Dupla/metabolismo , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Regulação para Baixo , Células HCT116 , Células HT29 , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos SCID , Transdução de Sinais
9.
Am J Transl Res ; 9(3): 1183-1192, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28386344

RESUMO

OBJECTIVE: Oxidative stress plays a critical role in the development of osteoporosis. Hydrogen sulfide (H2S), produces anti-oxidant effect in various biological systems. The present study found that GYY4137, a slow H2S releasing compound, stimulated both mRNA level and activity of alkaline phosphatase, the marker of osteoblast differentiation. This research aims to explore the mechanism on how GYY4137 stimulates osteoblastic cell proliferation and differentiation via an ERK1/2-dependent anti-oxidant approach. METHODS: The MC3T3-E1 osteoblast-like cell line was cultured in plate. After pretreatment with GYY4137 (100 µM) for 30 min, the cells were washed twice with PBS solution and then incubated in freshly prepared low serum medium containing 400 µM H2O2 for 4 h. Cells viability was evaluated with the MTT. Cell apoptosis was evaluated by the Hoechst 33342. Then, ALP activity, NO and the superoxide dismutase (SOD) activity is determined by assay kit accordingly, ALP mRNA is identified by RT-PCR. ERK1/2 was analyzed by Western blot. The ROS production was measured with a fluorescence reader. All data was analyzed by SPSS 16.0. RESULTS: We found in the present study that GYY4137, a slow H2S releasing compound, stimulated both mRNA level and activity of alkaline phosphatase, the marker of osteoblast differentiation. RT-PCR shows that GYY4137 stimulated the transcriptional levels of Runx2, a key transcription factor associated with osteoblast differentiation. These data suggest that GYY4137 may stimulate osteoblastic cell proliferation and differentiation. Moreover, GYY4137, which alone at 1-1000 µM had no significant effect, protected MC3T3-E1 osteoblastic cells against hydrogen peroxide (H2O2)-induced cell death and apoptosis. This was mediated by its anti-oxidant effect, as GYY4137 reversed the reduced superoxide dismutase activity and the elevated productions of reactive oxygen species and nitric oxide in the osteoblastic cells treated with H2O2. Western blotting analysis showed that the protective effects of GYY4137 were mediated by suppression of ERK1/2. CONCLUSIONS: GYY4137 stimulates osteoblastic cell proliferation and bone differentiation via an ERK1/2-dependent anti-oxidant mechanism. Our findings suggest that GYY4137 may have a potentially therapeutic value for osteoporosis.

10.
Oncotarget ; 8(21): 35165-35175, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28422723

RESUMO

Colorectal mucinous adenocarcinoma (MAC) and serrated adenocarcinoma (SAC) share many characteristics, including right-side colon location, frequent mucin production, and various molecular features. This study examined the frequency of SAC morphology in MACs. We assessed the correlation of SAC morphology with clinicopathological parameters, molecular characteristics, and patient prognosis. Eighty-eight colorectal MACs were collected and reviewed for SAC morphology according to Makinen's criteria. We sequenced KRAS and BRAF, assessed CpG island methylator phenotype (CIMP) frequency, and analyzed DNA mismatch repair enzyme levels using immunohistochemistry in tumor samples. SAC morphology was observed in 38% of MACs, and was associated with proximal location (P=0.001), BRAF mutation (P=0.042), CIMP-positive status (P=0.023), and contiguous traditional serrated adenoma (P=0.019). Multivariate analysis revealed that MACs without both SAC morphology and CIMP-positive status exhibited 3.955 times greater risk of cancer relapse than MACs having both characteristics or either one (P=0.035). Our results show that two MAC groups with distinct features can be identified using Makinen's criteria, and suggest a favorable prognostic role for the serrated neoplastic pathway in colorectal MAC.


Assuntos
Adenocarcinoma Mucinoso/patologia , Neoplasias Colorretais/patologia , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma Mucinoso/classificação , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/metabolismo , Idoso , Neoplasias Colorretais/classificação , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ilhas de CpG , Metilação de DNA , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , Análise de Sequência de DNA , Análise de Sobrevida
11.
Cell Death Dis ; 8(1): e2555, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-28079881

RESUMO

By using RNA-immunoprecipitation assay following next-generation sequencing, a group of cell cycle-related genes targeted by hnRNP Q1 were identified, including Aurora-A kinase. Overexpressed hnRNP Q1 can upregulate Aurora-A protein, but not alter the mRNA level, through enhancing the translational efficiency of Aurora-A mRNA, either in a cap-dependent or -independent manner, by interacting with the 5'-UTR of Aurora-A mRNA through its RNA-binding domains (RBDs) 2 and 3. By ribosomal profiling assay further confirmed the translational regulation of Aurora-A mRNA by hnRNP Q1. Overexpression of hnRNP Q1 promotes cell proliferation and tumor growth. HnRNP Q1/ΔRBD23-truncated mutant, which loses the binding ability and translational regulation of Aurora-A mRNA, has no effect on promoting tumor growth. The expression level of hnRNP Q1 is positively correlated with Aurora-A in colorectal cancer. Taken together, our data indicate that hnRNP Q1 is a novel trans-acting factor that binds to Aurora-A mRNA 5'-UTRs and regulates its translation, which increases cell proliferation and contributes to tumorigenesis in colorectal cancer.


Assuntos
Aurora Quinase A/genética , Carcinogênese/genética , Neoplasias Colorretais/genética , Ribonucleoproteínas Nucleares Heterogêneas/genética , Aurora Quinase A/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Masculino , Proteínas com Motivo de Reconhecimento de RNA , RNA Mensageiro/genética
12.
Br J Pharmacol ; 174(11): 1226-1243, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27646173

RESUMO

Anthocyanins are a class of water-soluble flavonoids, which show a range of pharmacological effects, such as prevention of cardiovascular disease, obesity control and antitumour activity. Their potential antitumour effects are reported to be based on a wide variety of biological activities including antioxidant; anti-inflammation; anti-mutagenesis; induction of differentiation; inhibiting proliferation by modulating signal transduction pathways, inducing cell cycle arrest and stimulating apoptosis or autophagy of cancer cells; anti-invasion; anti-metastasis; reversing drug resistance of cancer cells and increasing their sensitivity to chemotherapy. In this review, the latest progress on the anticancer activities of anthocyanins and the underlying molecular mechanisms is summarized using data from basic research in vitro and in vivo, from clinical trials and taking into account theory and practice. LINKED ARTICLES: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.


Assuntos
Antocianinas/farmacologia , Antioxidantes/farmacologia , Neoplasias/tratamento farmacológico , Animais , Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/prevenção & controle , Transdução de Sinais/efeitos dos fármacos
13.
Oncotarget ; 7(47): 76852-76866, 2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27764771

RESUMO

MicorRNA-137 is silenced in human colorectal cancer tissues and colon polyps. Our study showed that the decreased expression of miR-137 is significantly different in various types of polyp which maintain different potentials to lead to CRC development. The expression of miR-137 gradually decreases during the process of colorectal carcinogenesis. Receiver operating characteristic curve (ROC) analysis indicates that the loss of miR-137 expression in colon polyps can serve as a biomarker to predict the predisposition of colorectal carcinogenesis. By cell model and xenograft animal model, the enforced expression of miR-137 in colorectal cancer cells can inhibit cell proliferation and tumor formation, induce G2/M arrest, and lead to apoptosis. The expression pattern of miR-137 and Aurora-A or PTGS2 is negatively correlated in human colorectal cancer tissues and colon polyps. Those effects induced by overexpressed miR-137 can be rescued by the overexpression of Aurora-A. In summary, our study suggests that the loss of miR-137 expression in colon polyps can serve as a biomarker to predict the tendency toward to CRC formation through the impaired inhibitory effect of Aurora-A. The investigation of the regulatory mechanism of miR-137-mediated Aurora-A inhibition may shed new light on the early prognosis of cancer therapy for CRC in the future.


Assuntos
Aurora Quinase A/genética , Pólipos do Colo/genética , Neoplasias Colorretais/genética , Ciclo-Oxigenase 2/genética , Metilação de DNA , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias
14.
Am J Hypertens ; 28(12): 1409-17, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25762811

RESUMO

BACKGROUND: LCZ696, an angiotensin receptor-neprilysin inhibitor, has recently been demonstrated to exert more beneficial effects on hypertensive or heart failure patients than conventional renin-angiotensin system blockers. However, the mechanism underlying the benefit of LCZ696 remains to be understood. The present study was undertaken to examine the effect of LCZ696 compared with valsartan on hypertension and cardiovascular injury. METHODS: (i) Using telemetry, we compared the hypotensive effect of LCZ696 and valsartan in spontaneously hypertensive rats (SHR) that were fed a high-salt diet followed by a low-salt diet. (ii) We also examined the comparative effect of LCZ696 and valsartan on salt loaded SHRcp, a model of metabolic syndrome. RESULTS: (i) LCZ696 exerted a greater blood pressure (BP) lowering effect than valsartan in SHR regardless of high-salt or low-salt intake. Additive BP reduction by LCZ696 was associated with a significant increase in urinary sodium excretion and sympathetic activity suppression. (ii) LCZ696 significantly ameliorated cardiac hypertrophy and inflammation, coronary arterial remodeling, and vascular endothelial dysfunction in high-salt loaded SHRcp compared with valsartan. CONCLUSIONS: LCZ696 caused greater BP reduction than valsartan in SHR regardless of the degree of salt intake, which was associated with a significant enhancement in urinary sodium excretion and sympathetic activity suppression. Furthermore, an additive BP lowering effect of LCZ696 led to greater cardiovascular protection in hypertensive rats.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Hipertensão/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Tetrazóis/uso terapêutico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Ritmo Circadiano/efeitos dos fármacos , GMP Cíclico/sangue , Avaliação Pré-Clínica de Medicamentos , Endotélio Vascular/efeitos dos fármacos , Fibrose/tratamento farmacológico , Coração/efeitos dos fármacos , Hipertensão/sangue , Hipertensão/etiologia , Inflamação/tratamento farmacológico , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos Endogâmicos SHR , Sódio na Dieta/efeitos adversos , Sódio na Dieta/urina , Tetrazóis/farmacologia , Valsartana/farmacologia , Remodelação Vascular/efeitos dos fármacos
15.
Materials (Basel) ; 8(4): 1993-1999, 2015 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-28788044

RESUMO

The crystal quality and light output power of GaN-based light-emitting diodes (LEDs) grown on concave patterned sapphire substrate (CPSS) were investigated. It was found that the crystal quality of GaN-based LEDs grown on CPSS improved with the decrease of the pattern space (percentage of c-plane). However, when the pattern space decreased to 0.41 µm (S0.41-GaN), the GaN crystallinity dropped. On the other hand, the light output power of GaN-based LEDs was increased with the decrease of the pattern space due to the change of the light extraction efficiency.

16.
Qual Life Res ; 24(2): 473-84, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25099199

RESUMO

PURPOSE: The purpose of this study was to compare health-related quality of life (HRQoL) and costs associated with 2 adjuvant chemotherapy regimens [capecitabine-based therapy versus 5-fluorouracil/leucovorin (5-FU/LV)-based therapy] in stage III colorectal cancer patients. METHODS: We conducted a prospective, open-label, observational, multicenter study from July 2008 to July 2011. The European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires was used to assess HRQoL before, during, and after treatment. The direct and indirect costs of adjuvant treatment were estimated from a specially prepared questionnaire, the National Health Insurance Research Database, and other published sources. We used propensity scoring to match samples between groups and performed multivariate analyses to adjust for differences in patient demographics and clinical characteristics. RESULTS: A total of 497 patients were enrolled, and 356 completed the surveys. Following propensity score matching, 239 patients were included in the analysis (122 in the capecitabine-based group, 117 in the 5-FU/LV-based group). Global HRQoL scores did not differ significantly between the two groups. However, compared to patients in the 5-FU/LV-based group, patients in the capecitabine-based group had less nausea and vomiting (mid-term, P = 0.024; final, P = 0.013), appetite loss (mid-term, P < 0.0001; final, P = 0.001), and fewer side effects from chemotherapy (mid-term, P = 0.017). In addition, the monthly cost of capecitabine-based therapy was lower than those of 5-FU/LV-based therapy [NT$31,895.46 (US$1063.18) vs. NT$79,159.24 (US$2638.64) per patient]. CONCLUSIONS: Capecitabine is a reasonable alternative and cost-effective treatment option under current conditions for patients with stage III colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Fluoruracila/economia , Nível de Saúde , Leucovorina/economia , Qualidade de Vida , Adulto , Idoso , Antimetabólitos Antineoplásicos/economia , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Análise Custo-Benefício , Desoxicitidina/economia , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários
17.
Nanoscale Res Lett ; 9(1): 596, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25392706

RESUMO

This paper aims to investigate the light output power (LOP) of InGaN-based light-emitting diodes (LEDs) grown on patterned sapphire substrates (PSSs) with different symmetry. The GaN epitaxial layers grown on the hexagonal lattice arrangement PSS (HLAPSS) have a lower compressive strain than the ones grown on the square lattice arrangement PSS (SLAPSS). The quantum-confined Stark effect (QCSE) is also affected by the residual compressive strain. Based on the experimentally measured data and the ray tracing simulation results, the InGaN-based LED with the HLAPSS has a higher LOP than the one with the SLAPSS due to the weaker QCSE within multiple-quantum wells (MQWs).

18.
PLoS One ; 9(3): e93303, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24667656

RESUMO

Serine/threonine kinase 31 (STK31) is one of the novel cancer/testis antigens for which its biological functions remain largely unclear. Here, we demonstrate that STK31 is overexpressed in many human colorectal cancer cell lines and tissues. STK31 co-localizes with pericentrin in the centrosomal region throughout all phases of the cell cycle. Interestingly, when cells undergo mitosis, STK31 also localizes to the centromeres, central spindle, and midbody. This localization behavior is similar to that of chromosomal passenger proteins, which are known to be the important players of the spindle assembly checkpoint. The expression of STK31 is cell cycle-dependent through the regulation of a putative D-box near its C-terminal region. Ectopically-expressed STK31-GFP increases cell migration and invasive ability without altering the proliferation rate of cancer cells, whereas the knockdown expression of endogenous STK31 by lentivirus-derived shRNA results in microtubule assembly defects that prolong the duration of mitosis and lead to apoptosis. Taken together, our results suggest that the aberrant expression of STK31 contributes to tumorigenicity in somatic cancer cells. STK31 might therefore act as a potential therapeutic target in human somatic cancers.


Assuntos
Carcinogênese , Ciclo Celular , Neoplasias Epiteliais e Glandulares/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Centrossomo/metabolismo , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Cinetocoros/metabolismo , Microtúbulos/metabolismo , Mitose , Invasividade Neoplásica , Transporte Proteico , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno/genética
19.
World J Gastroenterol ; 19(11): 1797-804, 2013 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-23555168

RESUMO

AIM: To investigate the 10-year results of treating low rectal cancer by a single surgeon in one institution. METHODS: From Oct 1998 to Feb 2009, we prospectively followed a total of 62 patients with cT2-4 low rectal cancer with lower tumor margins measuring at 3 to 6 cm above the anal verge. All patients received neoadjuvant chemoradiation (CRT) for 6 wk. Among them, 85% of the patients received 225 mg/m(2)/d 5-fluorouracil using a portable infusion pump. The whole pelvis received a total dose of 45 Gy of irradiation in 25 fractions over 5 wk. The interval from CRT completion to surgical intervention was planned to be approximately 6-8 wk. Total mesorectal excision (TME) and routine defunctioning stoma construction were performed by one surgeon. The distal resection margin, circumferential resection margin, tumor regression grade (TRG) and other parameters were recorded. We used TRG to evaluate the tumor response after neoadjuvant CRT. We evaluated anal function outcomes using the Memorial Sloan-Kettering Cancer Center anal function scores after closure of the defunctioning stoma. RESULTS: The median distance from the lower margin of rectal cancer to the anal verge was 5 cm: 6 cm in 9 patients, 5 cm in 32 patients, 4 cm in 10 patients, and 3 cm in 11 patients. Before receiving neoadjuvant CRT, 45 patients (72.6%) had a cT3-4 tumor, and 21 (33.9%) patients had a cN1-2 lymph node status. After CRT, 30 patients (48.4%) had a greater than 50% clinical reduction in tumor size. The final pathology reports revealed that 33 patients (53.2%) had a ypT3-4 tumor and 12 (19.4%) patients had ypN1-2 lymph node involvement. All patients completed the entire course of neoadjuvant CRT. Most patients developed only Grade 1-2 toxicities during CRT. Thirteen patients (21%) achieved a pathologic complete response. Few post-operative complications occurred. Nearly 90% of the defunctioning stomas were closed within 6 mo. The local recurrence rate was 3.2%. Pathologic lymph node involvement was the only prognostic factor predicting disease recurrence (36.5% vs 76.5%, P = 0.006). Nearly 90% of patients recovered sphincter function within 2 year after closure of the defunctioning stoma. CONCLUSION: Neoadjuvant CRT followed by TME, combined with routine defunctioning stoma construction and high-volume surgeon experience, can provide excellent surgical quality and good local disease control.


Assuntos
Quimiorradioterapia Adjuvante , Colostomia , Ileostomia , Terapia Neoadjuvante , Neoplasias Retais/terapia , Estomas Cirúrgicos , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Quimiorradioterapia Adjuvante/efeitos adversos , Quimiorradioterapia Adjuvante/mortalidade , Colostomia/efeitos adversos , Fracionamento da Dose de Radiação , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Hospitais Universitários , Humanos , Ileostomia/efeitos adversos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Estomas Cirúrgicos/efeitos adversos , Taiwan , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
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