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1.
Nat Commun ; 11(1): 4469, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901013

RESUMO

Dissecting tumor heterogeneity is a key to understanding the complex mechanisms underlying drug resistance in cancers. The rich literature of pioneering studies on tumor heterogeneity analysis spurred a recent community-wide benchmark study that compares diverse modeling algorithms. Here we present FastClone, a top-performing algorithm in accuracy in this benchmark. FastClone improves over existing methods by allowing the deconvolution of subclones that have independent copy number variation events within the same chromosome regions. We characterize the behavior of FastClone in identifying subclones using stage III colon cancer primary tumor samples as well as simulated data. It achieves approximately 100-fold acceleration in computation for both simulated and patient data. The efficacy of FastClone will allow its application to large-scale data and clinical data, and facilitate personalized medicine in cancers.


Assuntos
Algoritmos , Variações do Número de Cópias de DNA , Neoplasias/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Biologia Computacional/métodos , Simulação por Computador , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Genéticos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Filogenia , Medicina de Precisão , Análise de Sequência de DNA
2.
BMC Bioinformatics ; 21(1): 401, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912137

RESUMO

BACKGROUND: As an important non-coding RNA, microRNA (miRNA) plays a significant role in a series of life processes and is closely associated with a variety of Human diseases. Hence, identification of potential miRNA-disease associations can make great contributions to the research and treatment of Human diseases. However, to our knowledge, many existing computational methods only utilize the single type of known association information between miRNAs and diseases to predict their potential associations, without focusing on their interactions or associations with other types of molecules. RESULTS: In this paper, we propose a network embedding-based method for predicting miRNA-disease associations by preserving behavior and attribute information. Firstly, a heterogeneous network is constructed by integrating known associations among miRNA, protein and disease, and the network representation method Learning Graph Representations with Global Structural Information (GraRep) is implemented to learn the behavior information of miRNAs and diseases in the network. Then, the behavior information of miRNAs and diseases is combined with the attribute information of them to represent miRNA-disease association pairs. Finally, the prediction model is established based on the Random Forest algorithm. Under the five-fold cross validation, the proposed NEMPD model obtained average 85.41% prediction accuracy with 80.96% sensitivity at the AUC of 91.58%. Furthermore, the performance of NEMPD is also validated by the case studies. Among the top 50 predicted disease-related miRNAs, 48 (breast neoplasms), 47 (colon neoplasms), 47 (lung neoplasms) were confirmed by two other databases. CONCLUSIONS: The proposed NEMPD model has a good performance in predicting the potential associations between miRNAs and diseases, and has great potency in the field of miRNA-disease association prediction in the future.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias do Colo/diagnóstico , Biologia Computacional/métodos , Neoplasias Pulmonares/diagnóstico , MicroRNAs/metabolismo , Algoritmos , Área Sob a Curva , Neoplasias da Mama/genética , Neoplasias do Colo/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , MicroRNAs/genética , Curva ROC
3.
Anticancer Res ; 40(10): 5405-5409, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988860

RESUMO

AIM: To investigate the clinical significance of ATP-binding cassette transporter 11 (ABCC11) protein expression in colon cancer. MATERIALS AND METHODS: One hundred thirty nine patients with colon cancer resection between 2009 and 2011 were enrolled. The relationship with immunohistochemical ABCC11 staining and clinicopathological factors was retrospectively analyzed. RESULTS: Median age was 70 years including 67 males and 72 females. The patients with Stage 0, 1, 2, 3a and 4 were 4, 20, 43, 35, 7 and 30, respectively. The patients with curability (Cur) A, B and C were 109, 11 and 19, respectively. Positive expression of ABCC11 was observed in 31 patients (22.3%). There were no significant differences regarding age, gender, location, serum tumor markers, T category, lymphatic invasion and stage in relation to ABCC11 protein expression. Cases with node metastasis and venous invasion as well as unresectable cases were significantly more often found negative for ABCC11 protein (p=0.0246, 0.0285 and 0.0422, respectively). Concerning the 3 year disease free survival (DFS) and the 5 year overall survival (OS) in Stage 2/3 and in Stage 3 with adjuvant chemotherapy, no significant differences were found. However, OS in ABCC11 negative cases was 81.1%, which was significantly lower compared to positive cases, where OS was 96.2%. CONCLUSION: There was significant correlation with ABCC11 expression and lymph node metastasis, venous invasion and curability. The prognosis in ABCC11 negative cases was poor because of increased cases without curative resection.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Proliferação de Células/genética , Neoplasias do Colo/genética , Metástase Linfática/genética , Idoso , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática/patologia , Masculino , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
4.
Anticancer Res ; 40(10): 5611-5620, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988885

RESUMO

BACKGROUND/AIM: Cancer stem cell characteristics and drug resistance of colorectal cancer are associated with failure of cancer treatment. In this study, we investigated the effects of PrPC on cancer stem cell characteristics, migration, invasion, and drug resistance of 5FU-resistant CRC cells. MATERIALS AND METHODS: PrPC negative and PrPC positive cells were isolated from 5FU-resistant CRC cells using magnetic activated cell sorting. Sphere formation, cancer stem cell marker expression, migration, invasion, and drug resistance were analyzed. RESULTS: PrPC positive cells showed increased sphere formation capacity and increased expression of cancer stem cell markers compared to PrPC negative cells. In addition, PrPC positive cells showed increased migration, invasion and drug resistance compared to PrPC negative cells. Furthermore, knockdown of PrPC abolished these effects. CONCLUSION: PrPC expression is important in CRC cell behavior, such as sphere formation, migration, invasion, and drug resistance. PrPC is an important therapeutic target for the treatment of CRC.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Proteínas Priônicas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/genética , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos
5.
Nat Commun ; 11(1): 4551, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917870

RESUMO

Circular RNAs (circRNAs) have recently gained substantial attention in the cancer research field where most, including the putative oncogene ciRS-7 (CDR1as), have been proposed to function as competitive endogenous RNAs (ceRNAs) by sponging specific microRNAs. Here, we report the first spatially resolved cellular expression patterns of ciRS-7 in colon cancer and show that ciRS-7 is completely absent in the cancer cells, but highly expressed in stromal cells within the tumor microenvironment. Additionally, our data suggest that this generally apply to classical oncogene-driven adenocarcinomas, but not to other cancers, including malignant melanoma. Moreover, we find that correlations between circRNA and mRNA expression, which are commonly interpreted as evidence of a ceRNA function, can be explained by different cancer-to-stromal cell ratios among the studied tumor specimens. Together, these results have wide implications for future circRNA studies and highlight the importance of spatially resolving expression patterns of circRNAs proposed to function as ceRNAs.


Assuntos
Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , Microambiente Tumoral/genética , Idoso , Neoplasias do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oncogenes/genética , Estudos Prospectivos , RNA Circular/genética , RNA Longo não Codificante/genética , Análise Espacial
6.
DNA Cell Biol ; 39(10): 1825-1837, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32799546

RESUMO

The objective of this study was to identify the key circular RNAs (circRNAs) related to the development of colon cancer. High-throughput RNA sequencing on eight early-stage (ES) and eight later stage (LS) colon tumor tissues, and eight normal tissues, was performed. Differentially expressed circRNAs and differentially expressed mRNAs were identified. Functional enrichment analysis and the miRNA-circRNA-mRNA network were performed. In addition, the differential expression levels of key circRNAs were verified using real-time quantitative PCR (qPCR). In total, 408, 472, and 278 differentially expressed circRNAs were identified in ES versus normal control (N), LS versus N, and LS versus ES groups, respectively. Functional enrichment analysis showed that circ_052666 was significantly enriched in "extracellular matrix/receptor interaction"; circ_022743 was remarkably enriched in "neurotrophin signaling pathway"; and circ_004452 was observably enriched in "TGF-ß signaling pathway." Moreover, key miRNA-circRNA-mRNA relationships, such as hsa-miR-29b/c-3p-circ_052666-COL1A1 and hsa-miR-1294-circ_004452-left-right determination factor 1 (LEFTY1), were identified. Furthermore, qPCR showed consistent results with RNA sequencing. Our findings indicate that key circRNAs, such as circ_022743, circ_052666, and circ_004452, may be involved in colon cancer development, and could be used as potential biomarkers for the diagnosis and treatment of this disease.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , RNA Circular/genética , Transcriptoma , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , RNA Circular/metabolismo
7.
Gene ; 763: 145072, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32827679

RESUMO

Colon cancer is one of the most common diseases in the world with both a high incidence and high mortality. PLAC1 is activated and expressed in many cancers. We aim to explore the relationship between PLAC1 expression and prognosis in colon cancer patient. The RNA-Seq expression data and clinical information of colon cancer were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed PLAC1 was obtained by the Wilcoxon signed-rank test; the significance difference being that PLAC1 was more highly expressed in tumor rather than normal tissue (p < 0.01). Then patients were classified into high and low risk groups by different risk scores, and the Kaplan-Meier survival analysis showed that colon cancer patients with a high PLAC1 expression had a poorer prognosis than low PLAC1 expression patients (p = 0.0031). Next, in analyzing the clinical pathology associated with PLAC1 expression, logistic regression showed that PLAC1 was expressed high in stage (OR = 4.11 for I vs. IV), lymph nodes (OR = 1.73 for N0 vs. N1+), distant metastasis (OR = 2.8 for M0 vs. M1), and status (OR = 22.81 for normal vs. tumor). Univariate and multivariate cox analyses were employed to identify that PLAC1 could be regarded as an independent prognostic factor. Univariate cox analysis showed PLAC1 had a correlation to overall survival (OS) (HR: 0.46, 95% CI: 0.28-0.77, p = 0.003). Multivariate cox analysis revealed that PLAC1 (HR: 0.51, 95% CI: 0.30-0.86, p = 0.012) could be regarded as an Independent prognostic factor. We also used quantitative real-time polymerase chain reaction (qRT-PCR) to test if PLAC1 was differently expressed in cell lines. The qRT-PCR obtained the significant results that PLAC1 expressed high in colon cancer cell lines (p < 0.05). Finally, Gene Set Enrichment Analysis (GSEA) was utilized to show 14 enriched signaling pathways. Our study discovered that high expression of PLAC1 predicts poor prognosis in colon cancer patients, providing a new biomarker, which can assist physicians in finding new diagnostic and therapy methods for colon cancer.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Proteínas da Gravidez/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Humanos , Metástase Linfática , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Proteínas da Gravidez/metabolismo
8.
Gan To Kagaku Ryoho ; 47(7): 1113-1115, 2020 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-32668864

RESUMO

Here, we report about a woman in her 30s who had peritoneal dissemination and multiple colon cancer with high-frequency microsatellite instability(MSI-H). Her father, paternal grandfather, and maternal grandmother had a history of colorectal cancer treatment. Thus, Lynch syndrome was suspected. We performed R0 resection for peritoneal dissemination and subsequent peritoneal dissemination. A 435-gene panel testing using a next-generation sequencer identified MSH2 and other mutations in the tumor. Hence, we speculated that she could have a germline mutation of MSH2, which causes Lynch syndrome. In the future, if she wishes to receive genetic counseling and undergo germline testing for variants to confirm the diagnosis of Lynch syndrome, we will perform them after receiving informed consent.


Assuntos
Neoplasias do Colo , Proteína 2 Homóloga a MutS/genética , Adulto , Neoplasias do Colo/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL
9.
Nat Commun ; 11(1): 3644, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686686

RESUMO

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Neoplasias/genética , Neoplasias do Colo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Mutação , Prognóstico , Proteína Supressora de Tumor p53/genética
10.
Nat Commun ; 11(1): 3606, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681016

RESUMO

Mitochondrial metabolism has emerged as a promising target against the mechanisms of tumor growth. Herein, we have screened an FDA-approved library to identify drugs that inhibit mitochondrial respiration. The ß1-blocker nebivolol specifically hinders oxidative phosphorylation in cancer cells by concertedly inhibiting Complex I and ATP synthase activities. Complex I inhibition is mediated by interfering the phosphorylation of NDUFS7. Inhibition of the ATP synthase is exerted by the overexpression and binding of the ATPase Inhibitory Factor 1 (IF1) to the enzyme. Remarkably, nebivolol also arrests tumor angiogenesis by arresting endothelial cell proliferation. Altogether, targeting mitochondria and angiogenesis triggers a metabolic and oxidative stress crisis that restricts the growth of colon and breast carcinomas. Nebivolol holds great promise to be repurposed for the treatment of cancer patients.


Assuntos
Antagonistas Adrenérgicos/farmacologia , Indutores da Angiogênese/farmacologia , Neoplasias da Mama/fisiopatologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Nebivolol/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Feminino , Humanos , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , ATPases Mitocondriais Próton-Translocadoras/genética , ATPases Mitocondriais Próton-Translocadoras/metabolismo , NADH Desidrogenase/genética , NADH Desidrogenase/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Proteínas/genética , Proteínas/metabolismo
11.
J Environ Pathol Toxicol Oncol ; 39(1): 39-49, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479011

RESUMO

Colon cancer (CC) is the most common type of gastrointestinal cancer and is the third leading cause of cancer patient's death worldwide. Long non-coding RNAs (lncRNAs) are important regulatory molecules involved in various cellular processes, and many of them are shown as significant prognosis biomarkers of malignant tumors. In the present study, we identified differentially expressed lncRNAs between CC and adjacent normal tissues based on two TCGA database (GEPIA and circlncRNAnet). Over 1500 differentially expressed lncRNAs between CC and adjacent normal tissues were obtained based on these two websites, and 72 lncRNAs (FC > = 2, Log2 (TPM+1) > 1, P < 0.05) were chosen for further analysis. Seventeen of them were CC specific-expressed lncRNAs. We then evaluated the expression of the 17 lncRNAs in diverse tumor stage. LncRNA double homeobox A pseudogene 8 (DUXAP8), RP11-54H7.4, and RP11-138J23.1 showed higher expression in later tumor stages. Built on survival analysis, we found that high expression of DUXAP8 and ELFN1 antisense RNA 1 (ELFN1-AS1) predicts poor prognosis in CC. In addition, high expression of the 17 lncRNAs set predicts poor prognosis in CC. This study provides a new way to evaluate the prognosis of CC.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , RNA Longo não Codificante/genética , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/diagnóstico , Humanos , Prognóstico , RNA Longo não Codificante/metabolismo , Análise de Sobrevida
12.
Tumour Biol ; 42(6): 1010428320924524, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32515296

RESUMO

OBJECTIVE: Several studies indicate that macrophage migration inhibitory factor 1 plays a role for tumor progression in colon cancer. We investigated whether determination of migration inhibitory factor 1 mRNA expression levels in lymph nodes of colon cancer patients could be used as a prognostic marker. METHODS: Expression levels of migration inhibitory factor 1 and carcinoembryonic antigen mRNAs were assessed in primary tumors and regional lymph nodes of 123 colon cancer patients (stages I-IV), and in colon cancer- and immune cell lines using quantitative reverse transcriptase-polymerase chain reaction. Expression of migration inhibitory factor 1 protein was investigated by two-color immunohistochemistry and immunomorphometry. RESULTS: Migration inhibitory factor 1 mRNA was expressed at 60 times higher levels in primary colon cancer tumors compared to normal colonic tissue (medians 8.2 and 0.2 mRNA copies/18S rRNA unit; p < .0001). A highly significant difference in mRNA expression levels was found between hematoxylin-eosin positive lymph nodes and hematoxylin-eosin negative lymph nodes (p < .0001). Migration inhibitory factor 1 and carcinoembryonic antigen proteins were simultaneously expressed in many colon cancer-tumor cells. Kaplan-Meier survival model and hazard ratio analysis, using a cutoff level at 2.19 mRNA copies/18S rRNA unit, revealed that patients with lymph nodes expressing high levels of migration inhibitory factor 1 mRNA had a 3.5-fold (p = .04) higher risk for recurrence, associated with a small, but significant, difference in mean survival time (7 months, p = .03) at 12 years of follow-up. CONCLUSION: Although migration inhibitory factor 1 mRNA expression levels were related to severity of disease and lymph node analysis revealed that colon cancer patients with high levels had a shorter survival time after surgery than those with low levels, the difference was small and probably not useful in clinical practice.


Assuntos
Antígeno Carcinoembrionário/genética , Neoplasias do Colo/genética , Hormônio Inibidor da Liberação de MSH/genética , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Linfonodos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , RNA Mensageiro/genética , RNA Ribossômico 18S/genética
13.
Zhonghua Zhong Liu Za Zhi ; 42(5): 383-390, 2020 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-32482027

RESUMO

Objective: To examine the expression of T-box5 (TBX5) in colorectal cancer tissues and its clinical significance, and explore the effects of TBX5 on the invasion and metastasis of colorectal cancer cells and its mechanism. Methods: The expressions of TBX5 in cancer and adjacent normal tissues were tested by immunohistochemistry (IHC), and the relationship between TBX5 and clinicopathological features and prognosis of colorectal cancer was analyzed. Real-time quantitative PCR (RT-qPCR) and western blot were used to detect the expressions of TBX5 in different colorectal cancer cell lines. TBX5 overexpression plasmid was constructed and transfected into human colorectal cancer cell line HT-29, and cell counting kit-8 (CCK-8) was used to detect the activities of transfection HT-29 cells. Cell scratch test and Transwell assay were used to detect the migration and invasion abilities of cells, while RT-qPCR and western blot were used to detect the mRNA and protein expressions of PCNA, p21, p16, p27, MMP-2, MMP-7 and TIMP-1. Results: The positive rate of TBX5 protein in colorectal cancer tissues was 24.44% (22/90), significantly lower than 65.56% of adjacent normal tissues (P<0.001). The expression of TBX5 was significantly related to lymph node metastasis, depth of invasion and nerve invasion (P<0.05). The survival period of 22 patients with positive TBX5 expression was (60.2±2.4) months, better than (44.3±2.8) months of 68 patients with negative TBX5 expression (P<0.05). Among human colon cancer cell lines of HT29, SW620, SW480, LOVO and HCT116, the expression of TBX5 in HT29 cells was the weakest. After transfection, the expression of TBX5 in transfection group was significantly higher than those in control group and blank group (P=0.043 and P<0.001). Cell viability in transfection group was significantly lower than those in control group and blank group (both P<0.001). The ratio of cells in G(0)/G(1) phase was increased (P=0.009), while in G(2)/M phase was decreased (P<0.001). Cells' abilities of migration and invasion in transfection group were also significantly decreased (both P<0.001). Overexpression of TBX5 downregulated the expressions of PCNA, MMP-2 and MMP-7, while upregulated the expressions of p21, p16, p27 (P<0.05 for all). TBX5 had marginal effect on the expression of TIMP-1 (P>0.05). Conclusions: Downregulation of TBX5 is a marker of poor prognosis in patients with colorectal cancer. TBX5 may inhibit the progression of colorectal cancer by inhibiting proliferation, invasion and metastasis related genes.


Assuntos
Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Invasividade Neoplásica , Reação em Cadeia da Polimerase em Tempo Real
14.
Z Gastroenterol ; 58(6): 533-541, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32544965

RESUMO

Colorectal cancer is one of the leading malignancies and still accounts for almost 25 000 deaths in Germany each year. Although there is accumulating data on the molecular basis, treatment and clinical outcome of patients within clinical trials evidence from the real-world setting is mostly lacking. We started the molecular registry trial Colopredict Plus in 2013 to collect clinical and molecular data from a real-world cohort of patients with early colon cancer stage II and III in 70 German colon cancer centers focusing on the prognostic impact of high microsatellite instability. In this interim report, we characterize a clinical cohort of 2615 patients, of whom 1787 tissue probes were analyzed. Microsatellite status was assessed using immunhistochemistry and fragment length analysis, with a concordance of 91.4 %. These established histopathological methods are sensitive and cost-effective. The median age was 72 years, significantly higher compared to clinical trial populations, with a median Charlson Comorbidity Index of 3. The stage-dependent incidence of microsatellite instability was 23.7 % and was associated with female gender, BRAF-mutation, UICC stage II and localization in the right colon. Survival calculated in disease free, relapse free and overall survival significantly differed between MSI-H and MSS, in favor of MSI-H patients. Multivariate age-adjusted analyses of relapse-free survival, disease-free survival, and overall survival highlighted microsatellite instability as a robust and positive prognostic marker for early colon cancer independent of age.


Assuntos
Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Alemanha , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Sistema de Registros , Taxa de Sobrevida
15.
Cancer Sci ; 111(9): 3268-3278, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32533590

RESUMO

Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross-talk between FGFR4 and EGFR, and the effect of anti-EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab-induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti-EGFR therapy in colon cancer.


Assuntos
Anfirregulina/genética , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Linhagem Celular Tumoral , Cetuximab/farmacologia , Neoplasias do Colo/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
16.
Toxicol Appl Pharmacol ; 401: 115100, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512070

RESUMO

(-)-Epigallocatechin-3-gallate (EGCG) is the main bioactive component in tea (Camellia sinensis) catechins, and exhibits potential antitumor activity against colorectal cancer (CRC). However, the underlying mechanisms are largely unclear. We investigated the effects of EGCG on activities of CRC cells and the exact molecular mechanism. We used human colon cancer cells (HT-29) and exposed them to EGCG at various concentrations. The MTT assay, flow cytometry, and TUNEL staining were used to study the underlying mechanisms of EGCG (proliferation, apoptosis, autophagy). Western blotting was used to measure expression of marker proteins of the cell cycle, apoptosis, and autophagy. Using a combined microarray-based transcriptomic and ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UHPLC-QTOF/MS)-based metabolomic approach, we investigated the perturbed pathways induced by EGCG treatment at transcript and metabolite levels. Transcriptomic analyses showed that 486 genes were differentially expressed between untreated and EGCG-treated cells. Also, 88 differentially expressed metabolites were identified between untreated and EGCG-treated cells. The altered metabolites were involved in the metabolism of glutathione, glycerophospholipids, starch, sucrose, amino sugars, and nucleotide sugars. There was substantial agreement between the results of transcriptomics and metabolomics analyses. Our data indicate that the anticancer activity of EGCG against HT-29 cells is mediated by induction of cell-cycle arrest, apoptosis, and autophagy. EGCG modulates cancer-cell metabolic pathways. These results provide a platform for future molecular mechanistic studies of EGCG.


Assuntos
Anticarcinógenos/farmacologia , Catequina/análogos & derivados , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Metabolômica/métodos , Transcriptoma/efeitos dos fármacos , Anticarcinógenos/uso terapêutico , Catequina/farmacologia , Catequina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Neoplasias do Colo/tratamento farmacológico , Células HT29 , Humanos , Transcriptoma/fisiologia
17.
Life Sci ; 253: 117740, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376265

RESUMO

AIMS: Annexin A2 (ANXA2) is closely associated with tumor malignancy and its N-terminus includes a vital domain for its function. The aims are to explore the correlation between the sites (Tyr23, Ser1, Ser11 and Ser25) in the domain and its roles. MAIN METHODS: We re-expressed ANXA2 with mutated sites in ANXA2-deleted human colonic adenocarcinoma cell line caco2 (ANXA2-/-caco2). A series of analyses were used to determine the correlation of each site with ANXA2 activation, cell malignancy enhancement and motility-associated microstructural development. Bioinformatics and luciferase reporter assays were employed to validate ANXA2-targeted miRNAs. KEY FINDINGS: The in vitro results showed that all single and multiple mutations of the ANXA2 N-terminal sites inhibited ANXA2 phosphorylation at different levels and subsequently inhibited the proliferation, motility, and polymerization of F-actin and ß-tubulin in caco2 cells. Motility-associated microstructures were significantly remodeled when these sites were mutated. The forced expression of miR-206 significantly suppressed the proliferation, motility and epithelial-mesenchymal transition (EMT) of caco2 cells. The in vivo results showed that all the ANXA2 N-terminal site mutations and forced expression of miR-206 significantly inhibited tumor growth. Overall, this study demonstrated that the sites of the ANXA2 N-terminus, especially Tyr23, play crucial roles in maintaining the high malignancy of colonic adenocarcinoma. Furthermore, miR-206 targets ANXA2 and plays a role as a cancer suppressor in colonic adenocarcinoma. SIGNIFICANCE: Our study provided evidence that further elucidates the molecular mechanism of ANXA2 and its roles in colonic adenocarcinoma and suggested potential targets of ANXA2 for colonic adenocarcinoma therapy by using miR-206 as a novel strategy.


Assuntos
Adenocarcinoma/patologia , Anexina A2/genética , Neoplasias do Colo/patologia , MicroRNAs/genética , Actinas/metabolismo , Adenocarcinoma/genética , Animais , Células CACO-2 , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias do Colo/genética , Transição Epitelial-Mesenquimal/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação/genética , Tubulina (Proteína)/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mol Biol (Mosk) ; 54(2): 204-211, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392189

RESUMO

DNA hypermethylation and mutations are key mechanisms for the downregulation of tumor suppressor genes. NotI-microarrays allowed us to detect hypermethylation and/or deletions in 180 NotI sites associated with 188 genes of human chromosome 3, in 24 paired (tumor/normal) colon samples. The most frequent aberrations (in more than 20% of tumor samples) were detected in the promoter regions of 20 genes. Expression and promoter methylation of these genes were analyzed using the data for paired colon samples from The Cancer Genome Atlas project. Three genes - ALDH1L1, PLCL2, and PPP2R3A - revealed a more than two-fold average decrease in expression and a negative correlation between mRNA level and promoter hypermethylation. The expression of these three genes was then evaluated in 30 paired colon samples by quantitative PCR. Frequent (in more than 60% of cases) and significant (5-9-fold on average) mRNA level decrease was found for each of the genes in the tumor samples. The results indicate a suppressor role of the ALDH1L1, PLCL2, and PPP2R3A genes in colon cancer, as well as functional significance of hypermethylation in the downregulation of these genes.


Assuntos
Neoplasias do Colo/genética , Metilação de DNA , Peptídeos e Proteínas de Sinalização Intracelular/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Proteína Fosfatase 2/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética
19.
PLoS One ; 15(5): e0233717, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469983

RESUMO

Metastasis is known as a key step in cancer recurrence and could be stimulated by multiple factors. Calumenin (CALU) is one of these factors which has a direct impact on cancer metastasis and yet, its underlined mechanisms have not been completely elucidated. The current study was aimed to identify CALU co-expressed genes, their signaling pathways, and expression status within the human cancers. To this point, CALU associated genes were visualized using the Cytoscape plugin BisoGenet and annotated with the Enrichr web-based application. The list of CALU related diseases was retrieved using the DisGenNet, and cancer datasets were downloaded from The Cancer Genome Atlas (TCGA) and analyzed with the Cufflink software. ROC curve analysis was used to estimate the diagnostic accuracy of DEGs in each cancer, and the Kaplan-Meier survival analysis was performed to plot the overall survival of patients. The protein level of the signature biomarkers was measured in 40 biopsy specimens and matched adjacent normal tissues collected from CRC and lung cancer patients. Analysis of CALU co-expressed genes network in TCGA datasets indicated that the network is markedly altered in human colon (COAD) and lung (LUAD) cancers. Diagnostic accuracy estimation of differentially expressed genes showed that a gene panel consisted of CALU, AURKA, and MCM2 was able to successfully distinguish cancer tumors from healthy samples. Cancer cases with abnormal expression of the signature genes had a significantly lower survival rate than other patients. Additionally, comparison of CALU, AURKA, and MCM2 proteins between healthy samples, early and advanced tumors showed that the level of these proteins was increased through normal-carcinoma transition in both types of cancers. These data indicate that the interactions between CALU, AURKA, and MCM2 has a pivotal role in cancer development, and thereby needs to be explored in the future.


Assuntos
Aurora Quinase A , Proteínas de Ligação ao Cálcio , Neoplasias do Colo , Bases de Dados de Ácidos Nucleicos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Componente 2 do Complexo de Manutenção de Minicromossomo , Aurora Quinase A/biossíntese , Aurora Quinase A/genética , Proteínas de Ligação ao Cálcio/biossíntese , Proteínas de Ligação ao Cálcio/genética , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Componente 2 do Complexo de Manutenção de Minicromossomo/biossíntese , Componente 2 do Complexo de Manutenção de Minicromossomo/genética , Metástase Neoplásica , Taxa de Sobrevida
20.
PLoS One ; 15(5): e0231948, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32369483

RESUMO

In our search for bioactive mushrooms native to British Columbia, we determined that the ethanol extracts from fruiting bodies of the terrestrial polypore Albatrellus flettii had potent anti-cell viability activity. Using bioassay-guided fractionation, mass spectrometry and nuclear magnetic resonance, we successfully isolated three known compounds (grifolin, neogrifolin and confluentin). These compounds represent the major anti-cell viability components from the ethanol extracts of A. flettii. We also identified a novel biological activity for these compounds, specifically in down-regulating KRAS expression in two human colon cancer cell lines. Relatively little is known about the anti-cell viability activity and mechanism of action of confluentin. For the first time, we show the ability of confluentin to induce apoptosis and arrest the cell cycle at the G2/M phase in SW480 human colon cancer cells. The oncogenic insulin-like growth factor 2 mRNA-binding protein 1 (IMP1) has been previously shown to regulate KRAS mRNA expression in colon cancer cells, possibly through its ability to bind to the KRAS transcript. Using a fluorescence polarization assay, we show that confluentin dose-dependently inhibits the physical interaction between KRAS RNA and full-length IMP1. The inhibition also occurs with truncated IMP1 containing the KH1 to KH4 domain (KH1to4 IMP1), but not with the di-domain KH3 and KH4 (KH3&4 IMP1). In addition, unlike the control antibiotic neomycin, grifolin, neogrifolin and confluentin do not bind to KRAS RNA. These results suggest that confluentin inhibits IMP1-KRAS RNA interaction by binding to the KH1&2 di-domains of IMP1. Since the molecular interaction between IMP1 and its target RNAs is a pre-requisite for the oncogenic function of IMP1, confluentin should be further explored as a potential inhibitor of IMP1 in vivo.


Assuntos
Basidiomycota/química , Neoplasias do Colo/genética , Fenóis/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Resorcinóis/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Relação Dose-Resposta a Droga , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Terpenos/farmacologia
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