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1.
Adv Exp Med Biol ; 1164: 63-71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576540

RESUMO

Gankyrin (also called PSMD10, p28, or p28GANK) is a crucial oncoprotein that is upregulated in various cancers and assumed to play pivotal roles in the initiation and progression of tumors. Although the in vitro function of gankyrin is relatively well characterized, its role in vivo remains to be elucidated. We have investigated the function of gankyrin in vivo by producing mice with liver parenchymal cell-specific gankyrin ablation (Alb-Cre;gankyrinf/f) and gankyrin deletion both in liver parenchymal and in non-parenchymal cells (Mx1-Cre;gankyrinf/f). Gankyrin deficiency both in non-parenchymal cells and parenchymal cells, but not in parenchymal cells alone, reduced STAT3 activity, interleukin-6 production, and cancer stem cell marker expression, leading to attenuated tumorigenic potential in the diethylnitrosamine hepatocarcinogenesis model. Essentially similar results were obtained by analyzing mice with intestinal epithelial cell-specific gankyrin ablation (Villin-Cre;Gankyrinf/f) and gankyrin deletion both in myeloid and epithelial cells (Mx1-Cre;Gankyrinf/f) in the colitis-associated cancer model. Clinically, gankyrin expression in the tumor microenvironment was negatively correlated with progression-free survival in patients undergoing treatment with Sorafenib for hepatocellular carcinomas. These findings indicate important roles played by gankyrin in non-parenchymal cells as well as parenchymal cells in the pathogenesis of liver cancers and colorectal cancers, and suggest that by acting both on cancer cells and on the tumor microenvironment, anti-gankyrin agents would be promising as therapeutic and preventive strategies against various cancers, and that an in vitro cell culture models that incorporate the effects of non-parenchymal cells and gankyrin would be useful for the study of human cell transformation.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Complexo de Endopeptidases do Proteassoma , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/fisiopatologia , Carcinoma Hepatocelular/terapia , Neoplasias Colorretais/genética , Neoplasias Colorretais/fisiopatologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Deleção de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/fisiopatologia , Neoplasias Hepáticas/terapia , Camundongos , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral
2.
Anticancer Res ; 39(10): 5645-5652, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570462

RESUMO

BACKGROUND/AIM: The aim of our study was to assess the predictive role of primary tumour sidedness (PTS) in patients with metastatic colorectal cancer (mCRC) harbouring wild-type RAS and treated with targeted agents. PATIENTS AND METHODS: The cohort included 178 patients treated with first-line chemotherapy plus cetuximab, panitumumab or bevacizumab. RESULTS: We observed longer progression-free survival (PFS) and overall survival (OS) in patients with left-sided (L-CRC) compared to right-sided tumours (R-CRC) treated with anti-EGFR mAbs (p=0.0033 and p=0.0037), while there was no difference in patients treated with bevacizumab (p=0.076 and p=0.56). Finally, we observed longer PFS and OS in patients with L-CRC treated with anti-EGFR mAbs and those with R-CRC treated with bevacizumab compared to the reverse combination (p=0.0002 and p=0.011). CONCLUSION: PTS is a predictive factor for anti-EGFR mAbs, not for bevacizumab. Superior survival was observed when anti-EGFR mAbs were used for L-CRC and bevacizumab for R-CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Idoso , Anticorpos Monoclonais/administração & dosagem , Bevacizumab/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Genes ras/genética , Humanos , Masculino , Panitumumabe/administração & dosagem
3.
Tumour Biol ; 41(9): 1010428319863627, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31500540

RESUMO

Stratification of colorectal cancer for better management and tangible clinical outcomes is lacking in clinical practice. To reach this goal, the identification of reliable biomarker(s) is a prerequisite to deliver personalized colorectal cancer theranostics. Osteopontin (SPP1) is a key extracellular matrix protein involved in several pathophysiological processes including cancer progression and metastasis. However, the exact molecular mechanisms regulating its expression, localization, and molecular functions in cancer are still poorly understood. This study was designed to investigate the SPP1 expression profiles in Saudi colorectal cancer patients, and to assess its prognostic value. Hundred thirty-four (134) archival paraffin blocks of colorectal cancer were collected from King Abdulaziz University Hospital, Saudi Arabia. Tissue microarrays were constructed, and automated immunohistochemistry was performed to evaluate SPP1 protein expression patterns in colorectal cancer. About 20% and 23% of our colorectal cancer samples showed high SPP1 cytoplasmic and nuclear expression patterns, respectively. Cytoplasmic SPP1 did not correlate with age, gender, tumor size, and location. However, significant correlations were observed with tumor grade (p = 0.008), tumor invasion (p = 0.01), and distant metastasis (p = 0.04). Kaplan-Meier survival analysis showed a significantly lower recurrence rate in patients with higher SPP1 cytoplasmic expression (p = 0.05). At multivariate analysis, high SPP1 cytoplasmic expression was an independent favorable prognostic marker (p = 0.02). However, nuclear SPP1 expression did not show any prognostic value (p = 0.712). Our results showed a particular SPP1 prognostic relevance that is not in line with most colorectal cancer previous studies that may be attributed to the molecular pathophysiology of our colorectal cancer cohort. Saudi Arabia has both specific genomic makeup and particular environment that could lead to distinctive molecular roots of cancer. SPP1 has several isoforms, tissue localizations and molecular functions, signaling pathways, and downstream molecular functions. Therefore, a more individualized approach for CRC studies and particularly SPP1 prognosis outcomes' assessment is highly recommended toward precision oncology.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Recidiva Local de Neoplasia/genética , Osteopontina/genética , Idoso , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Medicina de Precisão , Prognóstico , Arábia Saudita/epidemiologia
4.
Anticancer Res ; 39(9): 4659-4666, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519564

RESUMO

BACKGROUND/AIM: Short-chain fatty acids (SCFAs) inhibit human colorectal cancer cell growth and tumorigenicity. We investigated the mechanism of the anti-proliferative effects of SCFAs on human colorectal cancer cells by examining their effects on gene expression. MATERIALS AND METHODS: The DLD-1 cell line was cultured with different SCFAs. Gene groups whose expression levels decreased to <50% or increased >50% compared to untreated cells and the signalling pathways responsible for DLD-1 cell growth inhibition were identified and analyzed. RESULTS: Genes whose expression levels decreased to ≤50% (791 genes) showed remarkable changes in gene function compared to genes whose expression levels increased ≥50%. These genes encode proteins involved in DNA replication and cell cycle/proliferation that contribute to major pathways responsible for suppression of colorectal carcinogenesis pathways. CONCLUSION: SCFAs inhibited the expression of genes encoding proteins involved in DNA replication and cell cycle/proliferation of human colorectal cancer cells and exerted antiproliferative activity via different pathways.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ácidos Graxos Voláteis/metabolismo , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Ácidos Graxos Voláteis/farmacologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Transdução de Sinais
5.
Anticancer Res ; 39(9): 4729-4736, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519572

RESUMO

BACKGROUND/AIM: Amphiregulin (AREG) and epiregulin (EREG) mRNA expression levels are predictors of response to anti-EGFR antibody therapy. Left-sided colon cancer is more sensitive to anti-EGFR antibodies than right-sided, although the mechanism is unclear. The aim of this study was to determine the relationship between AREG, EREG mRNA expression levels and tumor location as well as the efficacy of anti-EGFR antibody agents. MATERIALS AND METHODS: Real-time PCR was used to assess AREG and EREG mRNA expression in metastatic colorectal cancer (CRC) samples from 153 patients. RESULTS: Among KRASwt samples, high AREG expression (AREGHigh) was significantly more common in left-sided tumors than in right-sided. Among patients who received anti-EGFR antibody, response rates were significantly higher in AREGHigh than in AREGLow In the left-sided tumor group, overall survival was significantly longer in patients with high EREG levels than with low levels, whereas the right-sided tumor group showed no survival difference between them. CONCLUSION: AREG and EREG mRNA expression levels in left-sided CRC were higher than in right-sided tumors. This may help explain why left-sided CRC is more responsive to anti-EGFR antibodies.


Assuntos
Anfirregulina/genética , Neoplasias Colorretais/genética , Epirregulina/genética , Regulação Neoplásica da Expressão Gênica , RNA Mensageiro/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Especificidade de Órgãos/genética , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética
6.
Anticancer Res ; 39(9): 4853-4864, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519588

RESUMO

BACKGROUND/AIM: Colorectal cancer (CRC) is the leading cause of cancer mortality worldwide. Its poor prognosis can be ascribed primarily to high recurrence rates. Accordingly, the aim of this study was to identify novel prognostic biomarkers and therapeutic targets for management of CRC. MATERIALS AND METHODS: To develop prognostic biomarkers, we performed RNA-seq analysis and real-time RT-PCR in primary cancer tissues with or without systemic recurrence. To characterize the molecular functions of the encoded proteins, CRC cells underexpressing or overexpressing the candidate genes were established and appropriate cell-based assays were applied. RESULTS: ITGB1 and RHOC mRNA levels were up-regulated in the recurrence group of CRC patients. Overexpression of ITGB1 or RHOC stimulated CRC cell proliferation, invasion and migration, whereas the opposite effects were observed in cells underexpressing either protein. Five-year recurrence-free survival rates were significantly higher in the ITGB1- and RHOC-underexpression groups than those in the overexpression. CONCLUSION: ITGB1 and RHOC are potential predictors of recurrence and therapeutic targets for CRC, possibly predicting a high-risk group of stage II patients.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Integrina beta1/metabolismo , Proteína de Ligação a GTP rhoC/metabolismo , Idoso , Biomarcadores Tumorais , Proliferação de Células , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , RNA Interferente Pequeno/genética , Recidiva , Análise de Sobrevida
7.
Anticancer Res ; 39(9): 4865-4876, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519589

RESUMO

BACKGROUND/AIM: Hypoxia promotes tumor proliferation and metastasis in colorectal cancer (CRC). Since the tumor microenvironment is generally characterized by hypoxia, its understanding is important for cancer therapy. We hypothesized that hypoxia promotes the mitochondrial function, mobility, and proliferation of CRC by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). MATERIALS AND METHODS: To assess the effects of PGC-1α under hypoxia, we investigated the mitochondrial function, cell motility, and sphere formation as well as proliferation and apoptosis of CRC. RESULTS: Under hypoxia, we confirmed the increased expression of PGC-1α and reduced production of reactive oxygen species (ROS) by activating anti-oxidant enzymes. Also, up-regulation of PGC-1α enhanced the motility, sphere formation, and proliferation of CRC. Under the presence of the anti-cancer drug 5-fluorouracil (5FU), up-regulation of PGC-1α under hypoxia promoted resistance of CRC against 5FU-induced apoptosis. CONCLUSION: Targeting PGC-1α could to be a powerful strategy for CRC therapy.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Hipóxia/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Apoptose , Catalase/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Fosforilação Oxidativa , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
8.
Anticancer Res ; 39(9): 4933-4940, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519598

RESUMO

BACKGROUND: Interleukin 2 (IL2) is a significant factor activating T-cell-mediated immune response by stimulation of natural killer cells, T-cells and in development of regulatory T (Treg) cells. Recent studies have that IL2 participates in cancer development by modifying the local immune response. Based on the suggested role of the single nucleotide polymorphisms (SNPs) rs2069762, rs6822844 and rs11938795 of IL2 in the pathogenesis of certain diseases, the relationship of these SNPs with clinicopathological variables and their possible implication for prognosis and disease outcome were evaluated in a cohort of Swedish patients with colorectal cancer (CRC). MATERIALS AND METHODS: TaqMan SNP genotype assays based on polymerase chain reaction were used for analysis of the IL2 SNPs in 467 patients with CRC and 467 healthy controls. Expression analysis of IL2 in plasma and CRC tissue was also performed. RESULTS: The allelic variants T in rs11938795 and G in rs6822844 were significantly associated with a higher risk of CRC. Kaplan-Meier analysis showed that cancer-specific survival was worse for individuals with C allele for rs2069762 with stage II CRC and with T allele for rs6822844 with stage III CRC. CONCLUSION: SNPs rs2069762, rs6822844 and rs11938795 of the IL2 gene may be helpful as prognostic biomarkers in the follow-up and management of the patients.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Variação Genética , Interleucina-2/genética , Adulto , Idoso , Alelos , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imunomodulação , Interleucina-2/sangue , Interleucina-2/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prognóstico , Medição de Risco
9.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(7): 741-748, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31413211

RESUMO

OBJECTIVE: To investigate the expression, clinical significance, and biological function of the long non-coding RNA (lncRNA) ADAMTS9-AS2 in colorectal cancer (CRC).
 Methods: Gene microarray analysis was performed to explore the expression of ADAMTS9-AS2 in CRC. Real-time PCR was used to verify its expression in 20-paired CRC tissues and adjacent non-tumor tissues. We further explored the relationship between ADAMTS9-AS2 expression and clinicopathological features, and its prognostic role in relapse-free survival (RFS) among early stage CRC patients using Kaplan-Meier and Cox regression analyses. In vitro assays, cell counting kit-8 assay, colony formation assay, and Transwell assay were used to evaluate the biological function of ADAMTS9-AS2 in CRC.
 Results: ADAMTS9-AS2 was down-regulated in CRC patients according to the gene microarray analysis, which was confirmed in CRC tissues and cells. High expression of ADAMTS9-AS2 was associated with a higher 5-year RFS rate (83.8% vs 73.5%, P=0.041) and it was an independent prognostic factor for RFS [hazard ratio (HR)=0.528; 95% CI 0.299 to 0.932; P=0.028] at the early stage of CRC. ADAMTS9-AS2 overexpression in CRC cells inhibited cell proliferation, migration, and invasion, while suppression of ADAMTS9-AS2 showed opposite effects.
 Conclusion: ADAMTS9-AS2 is a valuable prognostic factor for CRC and may function as a tumor suppressor in CRC via inhibiting cell proliferation and metastasis.


Assuntos
Proteína ADAMTS9/genética , Neoplasias Colorretais , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Recidiva Local de Neoplasia , RNA Longo não Codificante
10.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(7): 830-836, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31413224

RESUMO

Colorectal cancer is one of the common malignant tumors, which seriously threatens human health. Its morbidity and mortality rank the third and the second among all malignant tumors. The progress of colorectal cancer is a complex process involving the accumulation of genetic and epigenetic changes. Epigenetic changes of colorectal cancer mainly include DNA methylation, histone modification, non-coding RNAs (such as microRNAs and lncRNAs), which are of great significance to early diagnosis and prognosis evaluation, and to chemosensitivity assessment for colorectal cancer, providing a new thought for the treatment of colorectal cancer.


Assuntos
Neoplasias Colorretais , Epigênese Genética , Neoplasias Colorretais/genética , Metilação de DNA , Epigenômica , Histonas , Humanos
11.
J Agric Food Chem ; 67(37): 10321-10329, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31419115

RESUMO

Pterostilbene (PTS) is a phenolic compound with diverse pharmacologic activities. However, its potential for inhibiting obesity-related colorectal cancer (CRC) remains unclear. Our study evaluated the mechanism of inhibitory effects of PTS on adipocyte conditioned-medium (aCM)-induced malignant transformation in HT-29 colorectal adenocarcinoma cells. The results demonstrated that PTS could downregulate the expression of aCM-induced fatty acid-binding protein 5 (FABP5) and prometastatic factors such as vascular endothelial growth factor, matrix metalloproteinase-2 (MMP2), MMP9, and extracellular tumor necrosis factor α via inhibiting aCM-induced nuclear factor-kappa B (NF-κB), ß-catenin, and peroxisome proliferator-activated receptor γ (PPAR-γ). Moreover, PTS can suppress aCM-stimulated phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinases 1/2 (JNK 1/2) signaling pathways activation that are upstream of NF-κB, ß-catenin, and PPAR-γ. Therefore, we suggest that PTS could alleviate adiposity-induced metastasis in CRC via inhibiting cell migration through downregulating FABP5 gene expression.


Assuntos
Adipócitos/metabolismo , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/fisiopatologia , Meios de Cultivo Condicionados/química , Proteínas de Ligação a Ácido Graxo/metabolismo , Estilbenos/farmacologia , Células 3T3 , Animais , Linhagem Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Meios de Cultivo Condicionados/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
J Cancer Res Clin Oncol ; 145(10): 2423-2432, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31456088

RESUMO

PURPOSE: The mortality of colorectal cancer ranked fifth in China according to cancer statistics in 2015. Cancer screening had been repeatedly proved to play a vital role in decreasing the incidence and mortality of colorectal cancer, but the existing screening methods could not meet the requirements. So it is of urgent need to develop a non-invasive, convenient and accurate screening method. METHODS: In this study, stool samples were collected from 102 colorectal cancer, 20 colorectal adenoma, 6 hyperplastic polyps patients and 105 normal controls, and stool DNA was extracted for detection of methylation (BMP3, NDRG4, SDC2 and SFRP2) and KRAS mutations. Meanwhile, hemoglobin in stool samples was detected by immunoassays. Then, the logistic regression model used for classification was built with these biomarkers, and a ROC curve was drawn to evaluate the performance of each biomarker and the panel of them. Meanwhile, conventional serum biomarkers were detected for the comparison of positive rate in colorectal cancer between serum biomarkers and stool DNA biomarkers. RESULTS: As a result, a classification model built with methylation of SDC2 and SFRP2, KRAS mutations and hemoglobin showed a sensitivity of 91.4% for colorectal cancer and 60% for adenoma with the specificity of 86.1%. Compared with it, most of the conventional serum biomarkers showed a sensitivity of less than 20% for colorectal cancer which was significantly lower than stool DNA biomarkers. CONCLUSIONS: A novel panel comprised of stool DNA biomarkers was of much higher sensitivity and specificity in early screening of colorectal neoplasms than conventional serum biomarkers.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/genética , DNA de Neoplasias , Fezes/química , Adenoma/diagnóstico , Adenoma/genética , China/epidemiologia , Pólipos do Colo/diagnóstico , Pólipos do Colo/genética , Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Metilação de DNA , Detecção Precoce de Câncer , Feminino , Humanos , Masculino , Programas de Rastreamento , Mutação , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas p21(ras)/genética , Curva ROC , Sensibilidade e Especificidade
14.
Medicine (Baltimore) ; 98(32): e16709, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393377

RESUMO

CD133 is currently believed to be one of the best colorectal cancer stem cell markers. This study aimed to evaluate prognostic significance of CD133 expression in colorectal cancer patients.A total of 303 patients with stage I to III colorectal cancer who underwent curative surgical resection from 2003 to 2008 at a single institution were included. CD133 expression was evaluated using immunohistochemical staining, and clinicopathological data were retrospectively reviewed. The patients were dichotomized after scoring CD133 expression (0 to 2+: low CD133 expression vs 3+ to 4+: high CD133 expression) according to the extent of area of CD133 positive tumor cells (<50% vs ≥50%) and pattern of staining (membranous staining of the luminal surface and/or staining of cellular debris in the tumor glands and cytoplasm).The 5-year overall survival (OS) (61.9% vs 80.2%, P = .001) and disease-free survival (64.8% vs 75.8%, P = .026) were poorer in the high CD133 expression group than the low CD133 expression group. In the multivariate analysis for risk factors of OS in the whole population, higher nodal stage (N2 compared to N0: hazard ratio [HR] 3.141; 95% confidence interval [CI] 1.718-5.744, P < .001), perineural invasion (HR 2.262; 95% CI 1.347-3.798, P = .002) and high CD133 expression (HR 1.929; 95% CI 1.221-3.048, P = .005) were independent poor prognostic factors of OS. Subgroup analyses according to each TNM stage revealed that CD133 expression was associated with OS only within the stage II patients (HR 3.167 95% CI 1.221-8.216, P = .018). Furthermore, the stage II patients demonstrating the high CD133 expression showed survival benefit of adjuvant chemotherapy, regardless of high-risk feature positivity (HR 0.201 95% CI 0.054-0.750, P = .017).High CD133 expression is correlated with poor prognosis in colorectal cancer patients after radical resection. The CD133 expression may serve as a more potent and informative biomarker for prognosis than conventional high-risk features in the stage II colorectal cancer patients.


Assuntos
Antígeno AC133/metabolismo , Neoplasias Colorretais/genética , Idoso , Biomarcadores Tumorais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Estudos Retrospectivos
15.
Medicine (Baltimore) ; 98(34): e16916, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441872

RESUMO

BACKGROUND: Colorectal Cancer (CRC) is a highly heterogeneous disease. RNA profiles of bulk tumors have enabled transcriptional classification of CRC. However, such ways of sequencing can only target a cell colony and obscure the signatures of distinct cell populations. Alternatively, single-cell RNA sequencing (scRNA-seq), which can provide unbiased analysis of all cell types, opens the possibility to map cellular heterogeneity of CRC unbiasedly. METHODS: In this study, we utilized scRNA-seq to profile cells from cancer tissue of a CRC patient. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to understand the roles of genes within the clusters. RESULTS AND CONCLUSION: The 2824 cells were analyzed and categorized into 5 distinct clusters by scRNA-seq. For every cluster, specific cell markers can be applied, indicating each 1 of them different from another. We discovered that the tumor of CRC displayed a clear sign of heterogenicity, while genes within each cluster serve different functions. GO term analysis also stated that different cluster's relatedness towards the tumor of CRC differs. Three clusters participate in peripheral works in cells, including, energy transport, extracellular matrix generation, etc; Genes in other 2 clusters participate more in immunology processes. Lastly, trajectory plot analysis also supports the viewpoint, in that some clusters present in different states and pseudo-time, while others present in a single state or pseudo time. Our analysis provides more insight into the heterogeneity of CRC, which can provide assistance to further researches on this topic.


Assuntos
Neoplasias Colorretais/genética , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Análise de Sequência de RNA/métodos , Idoso , Biomarcadores Tumorais/genética , Feminino , Humanos
16.
Medicine (Baltimore) ; 98(26): e16131, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261535

RESUMO

BACKGROUND: The FOS gene is located on human chromosome 14q21-31 and encodes the nuclear oncoprotein c-Fos. This study analyzed the correlation between the FOS noncoding region rs7101 and rs1063169 polymorphisms and colorectal cancer susceptibility and prognosis. METHODS: We analyzed the FOS genotypes in 432 colorectal cancer patients and 315 healthy subjects by PCR/Sanger sequencing. Survival was analyzed by Kaplan-Meier and Cox regression analysis. Western blot was used to detect the expression of c-Fos protein in cancer tissues and adjacent tissues in colorectal cancer patients with different genotypes. RESULTS: The presence of a T allele at rs7101 and a T allele at rs1063169 in FOS carried a higher risk of colorectal cancer [adjusted odds ratio (OR) = 1.237, 95% confidence interval (95% CI) = 1.131-1.346, P ≤ .001 and adjusted OR = 1.218, 95% CI = 1.111-1.327, P ≤ .001, respectively]. c-Fos protein levels were significantly higher in variant cancer tissues than in normal mucosa tissues (P < .05), and c-Fos proteins levels were also higher in homozygous variant cancer tissues than in heterozygous variant cancer tissues. The 3-year survival rate of patients with wild-type FOS was higher than that of patients with variant FOS (P < .05). CONCLUSION: The rs7101 and rs1063169 polymorphisms in the noncoding region of FOS are associated with the risk of developing colorectal cancer and the progression of colorectal cancer, which may be because the mutation enhances the expression of c-Fos protein to promote the incidence and development of colorectal cancer.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Seguimentos , Expressão Gênica , Interação Gene-Ambiente , Estudos de Associação Genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
17.
Medicine (Baltimore) ; 98(26): e16207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261569

RESUMO

The cell-surface glycoprotein, mesothelin, is normally present on mesothelial cells. Overexpression of mesothelin has been reported in many tumors and is correlated with poor outcome. We investigated the clinicopathologic significance of mesothelin expression in colorectal adenocarcinoma with microsatellites instability (MSI) status.Mesothelin expression was evaluated immunohistochemically in tissue microarray blocks from 390 colorectal adenocarcinoma samples. Mesothelin expression was interpreted according to the intensity and extent. A score of 2 was considered high expression. We analyzed the correlation between mesothelin expression and clinicopathologic characteristics.High mesothelin expression was observed in 177 (45.4%) out of 390 colorectal adenocarcinoma samples and was significantly associated with high histologic grade (P = .037), lymphatic invasion (P = .028), lymph node metastasis (P = .028), and high AJCC stage (P = .026). Kaplan-Meier survival curves revealed no significant difference between patients with high mesothelin expression and patients with low mesothelin expression in both recurrence-free survival (RFS) and cancer-specific survival (P = .609 and P = .167, respectively). In subgroup survival analyses, high mesothelin expression was associated with poor RFS in the MSI-High group of colorectal adenocarcinoma (P = .004).High mesothelin expression was significantly associated with aggressive phenotypes and poor patient outcome in MSI-High colorectal adenocarcinoma.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteínas Ligadas por GPI/metabolismo , Instabilidade de Microssatélites , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Análise Serial de Tecidos
18.
Zhonghua Yi Xue Za Zhi ; 99(24): 1881-1886, 2019 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-31269584

RESUMO

Objective: To investigate the expression of long non-coding RNA LINC00339 in colorectal cancer patients and its effect and mechanism on proliferation and apoptosis of colorectal cancer cells. Methods: A retrospective analysis of 158 pathology-confirmed colorectal cancer patients, who were enrolled from August 2015 to January 2017, was performed. LINC00339 expression in colorectal cancer tissues and adjacent colorectal sampleswas detected by Real-time PCR. The correlation between LINC00339 expression and clinicopathological features as well as the relationship between LINC00339 and microRNA (miR)-218 expression was assayed. The interaction between LINC00339 and miR-218 was further confirmed by dual luciferase report system. Downregulation of LINC00339 was performed by siRNA interference technology in LoVo and HCT116 cells. Real-time PCR was used to detect miR-218 expression. 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) analysis was carried out to examine cell viability. Flow cytometry was used to determine cell apoptosis. Additionally, LINC00339 siRNA and miR-218 antagomirs (anti-miR-218) were co-transfected into LoVo and HCT116 cells, and then cell viability and apoptosis were detected. Results: LINC00339 expression was significantly increased in colorectal cancer tissues compared with adjacent colorectal tissues (4.69±1.52 vs 1.02±0.38, P<0.05). LINC00339 expression was not related to the age and gender of patients (P>0.05), but was associated with TNM stage, lymphatic metastasis, tumor maximum diameters, and differentiation degree (all P<0.05). LINC00339 expression was negatively correlated with miR-218 expression in colorectal cancer tissues (P<0.05). miR-218 mimics remarkably suppressed the fluorescence intensity of wild-type LINC00339 plasmid (P=0.001), but did not affect the fluorescence intensity of the mutant ones(P=0.88). Knockdown of LINC00339 remarkably inhibited proliferation, but promoted apoptosis of LoVo and HCT116 cells (all P<0.05). Compared with cells transfected with LINC00339 siRNA only, downregulation of miR-218 elevated proliferation and decreased apoptosis of LoVoand HCT116 cells. Conclusions: LINC00339 expression is upregulated in colorectal cancer tissues and correlated with patients' clinicopathological features. LINC00339 promotes proliferation, and suppresses apoptosis of colorectal cancer cells via downregulating miR-218.


Assuntos
Neoplasias Colorretais , RNA Longo não Codificante/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs , Estudos Retrospectivos
19.
Medicine (Baltimore) ; 98(27): e16237, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277140

RESUMO

Aberrant expression of SRY-box 8 (SOX8) is closely correlated with the development and progression of many types of cancers in human. Limited studies report the relationship between SOX8 expression and overall survival in colorectal cancer (CRC). This study aimed to collect the pathological tissues and clinical data in order to analyze the relationship between SOX8 expression and clinicopathological parameters and prognosis of CRC patients. Tissue microarrays were constructed from 424 primary CRC patients with clinicopathological information and follow-up data. Immunohistochemistry (IHC) was performed on tissue microarrays to explore the relationship between SOX8 expression and clinicopathological information and patient's prognosis. The expression of SOX8 was higher in CRC tissues than that in non-tumor adjacent tissues (NATs, P <.001). High expression of SOX8 was associated with tumor stage (P = .04) and shorter overall survival (OS) after operation of patients (P = .004). Subsequently, univariate COX analysis identified that high expression of SOX8 (P = .004), differentiation (P = .006), distant metastasis (P <.001), tumor stage (P = .003), and higher rate of lymph node metastasis (P <.001), all significantly predicted decrease in OS. Multivariate analysis demonstrated that distant metastasis (P <.001), high SOX8 expression, (P = .013) and lymph node metastasis (P <.001) were independent poor prognostic factors in CRC patients. This study showed that SOX8 is over-expressed in patients with high T stage, which affects the outcome of prognosis in CRC patients. High expression of SOX8 usually has a poor independent prognostic factor for CRC.


Assuntos
Neoplasias Colorretais/genética , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Estadiamento de Neoplasias , Fatores de Transcrição SOXE/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , China/epidemiologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Transcrição SOXE/biossíntese , Taxa de Sobrevida/tendências , Análise Serial de Tecidos
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