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1.
Nat Commun ; 12(1): 5006, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408135

RESUMO

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.


Assuntos
Tecido Adiposo/citologia , Reprogramação Celular , Neoplasias do Colo/fisiopatologia , Células-Tronco Neoplásicas/citologia , Nicho de Células-Tronco , Tecido Adiposo/metabolismo , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , Células-Tronco/citologia , Células-Tronco/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
2.
FASEB J ; 35(9): e21834, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403553

RESUMO

Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Biological properties of CMS1 (MSI-H type) can affect therapeutic efficiencies of agents used in the treatment of CRC, and therefore become a new predictive factor of the treatment. But, the predictive impact of MSI-H status for adjuvant chemotherapy remains controversial. This study will assess whether there is any unnecessary or inappropriate use of treatment agents recommended for adjuvant therapy of stage 2 and 3 of disease and for palliative or curative treatment of liver metastatic disease in microsatellite instability high group, a molecular subtype of colon cancer. Within this scope, the efficiencies of fluorouracil- and oxaliplatin-based chemotherapeutic agents will be shown on stage 3 microsatellite instability high colon tumor cell lines first, and then a microfluidic model will be created, imitating the metastasis of colon cancer to the liver. In the microfluidic chip model, we will create in liver tissue, where the metastasis of microsatellite instability high colon cancer will be simulated; the effectiveness of chemotherapeutic agents, immunotherapy agents, and targeted agents on tumor cells as well as drug response will be assessed according to cell viability through released biomarkers from the cells. The proposed hypothesis study includes the modeling and treatment of patient-derived post-metastatic liver cancer in microfluidics which has priority at the global and our region and consequently develop personal medication.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Dispositivos Lab-On-A-Chip , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Instabilidade de Microssatélites , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/uso terapêutico , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/secundário , Modelos Biológicos , Metástase Neoplásica/patologia , Especificidade de Órgãos , Oxaliplatina/uso terapêutico
3.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(4): 402-406, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34374261

RESUMO

Objective: To investigate the effects of miR-335-5p targeting glucose-6-phosphate dehydrogenase (G6PD) on the proliferation and apoptosis of colon cancer cells. Methods: Normal colon cell group, blank control group, NC group and miRNA-335-5p mimic group were set up. Colonic epithelial cells (IEC) and human colon cancer cells SW480 were cultured in vitro, and the cells in the NC group and miRNA-335-5p mimic group cells were transfected. RT-qPCR was used to detect the expression levels of miR-335-5p and G6PD mRNA in each group of cells. The targeting effect of miR-335-5p on G6PD was verified by Double Luciferase Report experiment. MTT assay was used to detect cell proliferation. Flow cytometry was used to detect the apoptosis rate. The expressions of G6PD, Bax, Bcl-2 and caspase-3 were detected by Western blot. Results: Compared with normal colon cells, the relative expression levels of miR-335-5p in SW480 cells of colon cancer in the blank control group and NC group were decreased, and the relative expression level of G6PD mRNA was increased (P<0.05); compared with the blank control group and NC group, the expression level of miR-335-5p in miR-335-5p mimic group was increased significantly, and the expression of G6PD mRNA was decreased significantly (P<0.05). Compared with the blank control group and NC group, the proliferative activity of colon cancer SW480 cells in miR-335-5p mimic group was decreased significantly, and the apoptosis rate was increased significantly (P<0.05). The relative activity of luciferase in miR-335-5p mimic + WT-G6PD 3 '- UTR group was lower than that in miR-335-5p NC + WT-G6PD 3' - UTR group (P<0.05). Compared with the blank control group, the relative expression levels of G6PD and bcl-2 protein in miR-335-5p mimic group were decreased significantly, and the expression levels of Bax and caspase-3 protein were increased significantly (P<0.05). Conclusion: MiR-335-5p may inhibit the proliferation and promote apoptosis of colon cancer cells by targeting G6PD.


Assuntos
Neoplasias do Colo , MicroRNAs , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/genética , Glucosefosfato Desidrogenase/genética , Humanos , MicroRNAs/genética
4.
Oncoimmunology ; 10(1): 1936758, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34221700

RESUMO

Emerging evidence has revealed the crucial role of transcriptional RNA methyladenosine modification in immune response. However, the potential role of RNA N1-methyladenosine (m1A) modification of immune cells in the tumor microenvironment (TME) still remains unclear. In this study, we identified three distinct m1A modification patterns based on the integrated analyses of nine m1A regulators, which are significantly related to Relapse-free survival (RFS), Overall survival (OS), and TME infiltration cells in colon cancer patients. Furthermore, the m1AScore was generated by using principal components analysis (PCA) of expression of the 71 m1A-related genes to further demonstrate the characteristics of m1A patterns in colon cancer. In summary, a low m1AScore could be characterized by lower EMT, pan-F TBRS, and TNM stages, as well as less presence of lymphatic invasion, and, hence, good prognosis. At the same time, a low m1AScore could also be linked to CD8 + T effector proliferation, in addition to high microsatellite instability (MSI), neoantigen burden and PD-L1 expression, showing prolonged survival and better response after undergoing an anti-PD-L1 immunotherapy regimen in the public immunotherapy cohort. Our work reveals that m1A modification patterns play a key role in the formation of TME complexity and diversity in the context of immune cell infiltration. Accordingly, this m1AScore system provides an efficient method by which to identify and characterize TME immune cell infiltration, thereby allowing for more personalized and effective antitumor immunotherapy strategies.


Assuntos
Neoplasias do Colo , Microambiente Tumoral , Neoplasias do Colo/genética , Humanos , Linfócitos do Interstício Tumoral , Instabilidade de Microssatélites , Recidiva Local de Neoplasia , Microambiente Tumoral/genética
5.
Anticancer Res ; 41(7): 3567-3572, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230152

RESUMO

BACKGROUND/AIM: Medullary carcinoma (MC) of the colon is a rare subtype of colorectal adenocarcinoma (CRC) with unique histomorphology and frequent mismatch repair (MMR) deficiency. MC with exclusive squamous differentiation has not been reported. We report an unusual case of MC with squamous differentiation and tested this differentiation potential in other MMR-deficient CRC cases. CASE REPORT: A 68-year-old woman presented with a large ascending colon mass and biopsy showed squamoid tumor morphology with immunoprofile concerning for squamous cell carcinoma (SCC). She underwent right hemicolectomy. Immunohistochemistry and next-generation sequencing (NGS) were performed for tumor classification. Macroscopically, the tumor was large and locally advanced. It metastasized to the lung without lymph node metastasis. Microscopically, the tumor cells were monotonous with cytological features of both MC and SCC. Immunostains were diffusely positive for p40 and CK5/6, but negative for other lineage markers including CDX2, CK20, and SATB2. The tumor was MMR deficient with loss of MLH1 and PMS2. NGS confirmed BRAF V600E mutation. In comparison, a tissue microarray comprising 64 previously diagnosed MMR deficient CRC was tested for squamous differentiation, and only 1 case showed focal CK5/6 expression, but none was positive for p40. CONCLUSION: MC with exclusive squamous differentiation not only posed significant diagnostic challenges, but also unveiled unrecognized differentiation plasticity in this tumor type.


Assuntos
Carcinoma Medular/patologia , Carcinoma de Células Escamosas/patologia , Diferenciação Celular/fisiologia , Neoplasias do Colo/patologia , Idoso , Carcinoma Medular/genética , Carcinoma de Células Escamosas/genética , Diferenciação Celular/genética , Colo/patologia , Neoplasias do Colo/genética , Feminino , Humanos , Mutação/genética
6.
Scand J Gastroenterol ; 56(8): 920-928, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34218733

RESUMO

AIMS: Epigenetic alterations of genes involved in colorectal carcinogenesis are likely to be informative biomarkers for early detection. We assessed the methylation profile of a panel of seven colon cancer-related genes comparing normal colon, colorectal cancer (CRC) precursor lesions and cancer tissues from a Brazilian cohort. METHODS: The cohort comprised 114 CRC patients, including 40 matched normal tissue, 47 patients with adenomas, 33 with serrated polyps and 8 with normal colonic biopsy. DNA methylation status of SEPT9, ALX4, NDRG4, BMP3, APC, p16 and MLH1 was determined by pyrosequencing and correlated with clinicopathological features. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for all genes using cancer endpoint. RESULTS: The most frequently methylated genes in cancer and in precancer lesions were SEPT9, ALX4, NDRG4, and BMP3, ranging from 55.3 to 95% of the samples. Overall, the frequency of methylation of these four genes in normal colonic tissue was significantly lower as compared to cancer or precursor lesions both in adenoma-carcinoma (p < .001 and p < .050) and serrated (sessile-serrated lesion) (p < .001 and p < .050) pathways. Additionally, sensitivity for the cancer endpoint ranged from 65.6 to 91.8%, and specificity from 17.9 to 62.9% for SEPT9, ALX4, NDRG4, and BMP3 genes. Moreover, the comethylation of ≥4 genes was higher in sessile-serrated lesion (87.5%) and conventional adenomas (78.7%) than in hyperplastic polyps (43.7%) (p = .025) and was significantly associated with proximal cancers (p = .042). CONCLUSIONS: Our study suggests the DNA methylation can constitute potential biomarkers in CRC screening of Brazilian population.


Assuntos
Adenoma , Neoplasias do Colo , Pólipos do Colo , Neoplasias Colorretais , Adenoma/genética , Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Pólipos do Colo/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Metilação de DNA , Detecção Precoce de Câncer , Humanos
7.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201061

RESUMO

BRAFV600E mutations are found in approximately 10% of colorectal cancer patients and are associated with worse prognosis and poor outcomes with systemic therapies. The aim of this study was to identify novel druggable features of BRAFV600E-mutated colon cancer (CC) cells associated with the response and resistance to BRAFV600E inhibitor vemurafenib. Towards this aim, we carried out global proteomic profiling of BRAFV600E mutant vs. KRAS mutant/BRAF wild-type and double wild-type KRAS/BRAF CC cells followed by bioinformatics analyses. Validation of selected proteomic features was performed by immunohistochemistry and in silico using the TCGA database. We reveal an increased abundance and activity of nucleophosmin (NPM1) in BRAFV600E-mutated CC in vitro, in silico and in tumor tissues from colon adenocarcinoma patients and demonstrate the roles of NPM1 and its interaction partner c-Myc in conveying the resistance to vemurafenib. Pharmacological inhibition of NPM1 effectively restored the sensitivity of vemurafenib-resistant BRAF-mutated CC cells by down-regulating c-Myc expression and activity and consequently suppressing its transcriptional targets RanBP1 and phosphoserine phosphatase that regulate centrosome duplication and serine biosynthesis, respectively. Altogether, findings from this study suggest that the NPM1/c-Myc axis could represent a promising therapeutic target to thwart resistance to vemurafenib in BRAF-mutated CC.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mutação , Proteínas Nucleares/metabolismo , Proteoma/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Vemurafenib/farmacologia , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Proteoma/análise , Células Tumorais Cultivadas
8.
J Transl Med ; 19(1): 280, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193174

RESUMO

BACKGROUND: Colorectal cancer is the third most common diagnosis. Oxaliplatin is used as first-line treatment of colon cancer. However, oxaliplatin resistance greatly reduces its therapeutic effect. SRPK1 involves in pre-mRNA splicing and tumorigenesis. How SRPK1 mediates drug resistance in colon cancer is unknown. METHODS: The expression of SRPK1 was analyzed in the TCGA and the CPTAC pan-cancer samples and detected in colon cancer cell lines and tissues by IHC and western blot. The MTT and TUNEL assay were used to verify the anti-apoptosis ability of colon cancer cell. The activation of NF-κB was determined by luciferase assay and qRT-PCR. AKT, IKK, IκB and their phosphorylation level were verified by western blot. RESULTS: We found that SRPK1 expression was the second highest in TCGA and the CPTAC pan-cancer samples. The mRNA and protein levels of SRPK1 were increased in tissues from patients with colon cancer. SRPK1 was associated with clinical stage and TNM classifications in 148 cases of colon cancer patients. High SRPK1 levels correlated with poor prognosis (p < 0.001). SRPK1 overexpression enhanced the anti-apoptosis ability of colon cancer cells, whereas SRPK1 silencing had the opposite effect under oxaliplatin treatment. Mechanistically, SRPK1 enhances IKK kinase and IκB phosphorylation to promote NF-κB nuclear translocation to confer oxaliplatin resistance. CONCLUSIONS: Our findings suggest that SRPK1 participates in colon cancer progression and enhances the anti-apoptosis capacity to induce drug resistance in colon cancer cells via NF-κB pathway activation, and thus might be a potential pharmaceutically target for colon cancer treatment.


Assuntos
Neoplasias do Colo , NF-kappa B , Apoptose , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Humanos , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-akt
9.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206240

RESUMO

The development of colon cancer, one of the most common malignancies, is accompanied with numerous lipid alterations. However, analyses of whole tumor samples may not always provide an accurate description of specific changes occurring directly in tumor epithelial cells. Here, we analyzed in detail the phospholipid (PL), lysophospholipid (lysoPL), and fatty acid (FA) profiles of purified EpCAM+ cells, isolated from tumor and adjacent non-tumor tissues of colon cancer patients. We found that a number of FAs increased significantly in isolated tumor cells, which also included a number of long polyunsaturated FAs. Higher levels of FAs were associated with increased expression of FA synthesis genes, as well as with altered expression of enzymes involved in FA elongation and desaturation, including particularly fatty acid synthase, stearoyl-CoA desaturase, fatty acid desaturase 2 and ELOVL5 fatty acid elongase 5 We identified significant changes in ratios of specific lysoPLs and corresponding PLs. A number of lysophosphatidylcholine and lysophosphatidylethanolamine species, containing long-chain and very-long chain FAs, often with high numbers of double bonds, were significantly upregulated in tumor cells. Increased de novo synthesis of very long-chain FAs, or, altered uptake or incorporation of these FAs into specific lysoPLs in tumor cells, may thus contribute to reprogramming of cellular phospholipidome and membrane alterations observed in colon cancer.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Ácidos Graxos/metabolismo , Regulação Neoplásica da Expressão Gênica , Metabolismo dos Lipídeos , Fosfolipídeos/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Idoso , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Células Epiteliais/enzimologia , Células Epiteliais/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Humanos , Lipidômica , Lipogênese , Masculino , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
10.
Aging (Albany NY) ; 13(12): 16600-16619, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34182539

RESUMO

Evidence suggests that abnormal DNA methylation patterns play a crucial role in the etiology and pathogenesis of colon adenocarcinoma (COAD). In this study, we identified a total of 97 methylation-driven genes (MDGs) through a comprehensive analysis of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate Cox regression analysis identified four MDGs (CBLN2, RBM47, SLCO4C1, and TMEM220) associated with overall survival (OS) in COAD patients. A risk prediction model was then developed based on these four MDGs to predict the prognosis of COAD patients. We also created a nomogram that incorporated risk scores, age, and TNM stage to promote a personalized prediction of OS in COAD patients. Compared with the traditional TNM staging system, our new nomogram was better at predicting the OS of COAD patients. In cell experiments, we confirmed that the mRNA expression levels of CLBN2 and TMEM220 were regulated by the methylation of their promoter regions. Moreover, immunohistochemistry showed that CBLN2 and TMEM220 were potential prognostic biomarkers for COAD patients. In summary, we have established a risk prediction model and nomogram that might be effectively utilized to promote the prediction of OS in COAD patients.


Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , Metilação de DNA/genética , Genes Neoplásicos , Modelos Biológicos , Nomogramas , Medição de Risco , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Reprodutibilidade dos Testes , Análise de Sobrevida
11.
Nat Commun ; 12(1): 3464, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103493

RESUMO

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFß signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFß-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFß-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.


Assuntos
Carcinogênese/metabolismo , Neoplasias do Colo/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinogênese/patologia , Diferenciação Celular , Sobrevivência Celular , Colo/patologia , Neoplasias do Colo/genética , Células Epiteliais/metabolismo , Feto/patologia , Inflamação/patologia , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt
12.
Aging (Albany NY) ; 13(12): 16513-16526, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34157681

RESUMO

Colon adenocarcinoma (COAD) is a common cancer of the digestive system. It's high morbidity and mortality make it one of the leading causes of cancer deaths. In this study, we studied the microenvironment of colon cancer to find new diagnostic markers and immunotherapy targets for colon cancer. Tumor purity of colon cancer samples in TCGA database were obtained by ESTIMATE algorithm. Then, we analyzed the association of Immune, Stromal, and Estimate scores with tumor prognosis and clinicopathological features. By comparing the gene expression profiles between tumor and normal samples, the high and low immune score groups, 117 intersecting differentially expressed genes (DEGs) were obtained. The function, molecular pathway, and prognostic value of these 117 DEGs pointed toward the importance of deoxyribonuclease 1-like 3 (DNASE1L3). Validation results from multiple databases showed low expression of DNASE1L3 in colon cancer. A single GSEA and correlation analysis of immune cells indicated that DNASE1L3 was closely related to immunity. The low expression of DNASE1L3 in colon cancer samples was measured with qRT-PCR. The scratch and cell proliferation experiments suggested that DNASE1L3 may affect cell migration. Therefore, we concluded that DNASE1L3 might be a biomarker associated with prognosis and immune infiltration in colon cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/imunologia , Endodesoxirribonucleases/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Bases de Dados Genéticas , Endodesoxirribonucleases/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Mapas de Interação de Proteínas/genética , Reprodutibilidade dos Testes , Análise de Sobrevida , Transcriptoma
13.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062897

RESUMO

Cancer is a phenomenon broadly related to ageing in various ways such as cell cycle deregulation, metabolic defects or telomerases dysfunction as principal processes. Although the tumor cell is the main actor in cancer progression, it is not the only element of the disease. Cells and the matrix surrounding the tumor, called the tumor microenvironment (TME), play key roles in cancer progression. Phenotypic changes of the TME are indispensable for disease progression and a few of these transformations are produced by epigenetic changes including miRNA dysregulation. In this study, we found that a specific group of miRNAs in the liver TME produced by colon cancer called geromiRs, which are miRNAs related to the ageing process, are significantly downregulated. The three principal cell types involved in the liver TME, namely, liver sinusoidal endothelial cells, hepatic stellate (Ito) cells and Kupffer cells, were isolated from a murine hepatic metastasis model, and the miRNA and gene expression profiles were studied. From the 115 geromiRs and their associated hallmarks of aging, which we compiled from the literature, 75 were represented in the used microarrays, 26 out of them were downregulated in the TME cells during colon cancer colonization of the liver, and none of them were upregulated. The histone modification hallmark of the downregulated geromiRs is significantly enriched with the geromiRs miR-15a, miR-16, miR-26a, miR-29a, miR-29b and miR-29c. We built a network of all of the geromiRs downregulated in the TME cells and their gene targets from the MirTarBase database, and we analyzed the expression of these geromiR gene targets in the TME. We found that Cercam and Spsb4, identified as prognostic markers in a few cancer types, are associated with downregulated geromiRs and are upregulated in the TME cells.


Assuntos
Neoplasias do Colo/genética , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , MicroRNAs/genética , Animais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica/genética , Células Estreladas do Fígado/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/patologia , Fígado/patologia , Camundongos , MicroRNAs/classificação
14.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073365

RESUMO

Ferroptosis is a new type of programmed cell death, which occurs with iron dependence. Previous studies have showed that ferroptosis plays an important regulatory role in the occurrence and development of tumors. Colon cancer is one of the major morbidities and causes of mortality in the world. This study used RNA-seq and colon cancer clinical data to explore the relationship between ferroptosis-related genes and colon cancer. Based on the fifteen prognostic ferroptosis-related genes, two molecular subgroups of colon cancer were identified. Surprisingly, we also found cluster2 was characterized by lower mutation burden and expression of checkpoint genes, better survival, and higher expression of NOX1. Moreover, cluster2 has fewer BRAF mutations. We also found the expression of NOX1 is related to the status of BRAF. Finally, using 15 ferroptosis-related genes from The Cancer Genome Atlas cohort, we constructed a prognosis model, and this model may be used to predict the prognosis of patients in clinics.


Assuntos
Neoplasias do Colo/metabolismo , Bases de Dados de Ácidos Nucleicos , Ferroptose , Regulação Neoplásica da Expressão Gênica , Modelos Biológicos , NADPH Oxidase 1/biossíntese , Proteínas Proto-Oncogênicas B-raf/biossíntese , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Humanos , NADPH Oxidase 1/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , RNA-Seq
15.
World J Surg Oncol ; 19(1): 177, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127021

RESUMO

PURPOSE: Colon cancer (CC) is a very common gastrointestinal tumor that is prone to invasion and metastasis in the late stage. This study aims to observe the expression of Na+/Ca2+ exchangers (NCXs) and analyze the correlation between NCXs and the prognosis of CC. METHODS: Specimens of 111 stage II-IV CC patients were collected. We used western blotting, qPCR, and immunohistochemical staining to observe the distributions and expression levels of NCX isoforms (NCX1, NCX2, and NCX3) in CC and distal normal tissues. Cox proportional hazards models were used to assess prognostic factors for patients. RESULTS: The expression of NCXs in most tumor specimens was lower than that in normal tissues. The NCX expression levels in tumor tissues from the primary tumor, local lymph node metastasis sites, and distant liver metastasis sites were increasingly significantly lower than those in normal tissues. The results of the Kaplan-Meier survival curves showed that the downregulation of any NCX isoform was closely related to the worse prognosis of advanced CC. CONCLUSION: NCXs can be used as independent prognostic factors for CC. Our research results are expected to provide new targets for the treatment of CC.


Assuntos
Neoplasias do Colo , Trocador de Sódio e Cálcio , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Regulação para Baixo , Humanos , Prognóstico , Trocador de Sódio e Cálcio/genética , Trocador de Sódio e Cálcio/metabolismo
16.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063570

RESUMO

Understanding the global metabolic changes during the senescence of tumor cells can have implications for developing effective anti-cancer treatment strategies. Ionizing radiation (IR) was used to induce senescence in a human colon cancer cell line HCT-116 to examine secretome and metabolome profiles. Control proliferating and senescent cancer cells (SCC) exhibited distinct morphological differences and expression of senescent markers. Enhanced secretion of pro-inflammatory chemokines and IL-1, anti-inflammatory IL-27, and TGF-ß1 was observed in SCC. Significantly reduced levels of VEGF-A indicated anti-angiogenic activities of SCC. Elevated levels of tissue inhibitors of matrix metalloproteinases from SCC support the maintenance of the extracellular matrix. Adenylate and guanylate energy charge levels and redox components NAD and NADP and glutathione were maintained at near optimal levels indicating the viability of SCC. Significant accumulation of pyruvate, lactate, and suppression of the TCA cycle in SCC indicated aerobic glycolysis as the predominant energy source for SCC. Levels of several key amino acids decreased significantly, suggesting augmented utilization for protein synthesis and for use as intermediates for energy metabolism in SCC. These observations may provide a better understanding of cellular senescence basic mechanisms in tumor tissues and provide opportunities to improve cancer treatment.


Assuntos
Senescência Celular/genética , Neoplasias do Colo/genética , Redes e Vias Metabólicas/genética , Metaboloma/genética , Senescência Celular/efeitos da radiação , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Interleucina-1/genética , Interleucina-27/genética , Redes e Vias Metabólicas/efeitos da radiação , Metaboloma/efeitos da radiação , Radiação Ionizante , Fator de Crescimento Transformador beta1/genética , Fator A de Crescimento do Endotélio Vascular/genética
17.
J Int Med Res ; 49(6): 3000605211014998, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34130530

RESUMO

OBJECTIVE: Colon cancer has high morbidity and mortality rates, and proliferation, invasion and migration play an important role in colon cancer progression. Here, the effects of inhibin subunit beta A (INHBA) on cell proliferation, invasion and migration were investigated. METHODS: The UALCAN database was used to assess INHBA expression in colon cancer tissues and predict the survival of patients with high and low INHBA expression. The relevant proteins were detected by RT-qPCR and western blot. Cell transfection was performed to overexpress or inhibit INHBA and versican (VCAN). The high correlation between INHBA and VCAN found through LinkedOmics and StarBase databases was verified by immunoprecipitation assays. Cell proliferation was detected by cell counting kit-8 and colony formation assays. Wound healing and Transwell assays were used to assess migration and invasion. RESULTS: INHBA expression was upregulated in colon cancer tissues and cells. INHBA inhibition impaired the proliferation, migration and invasion of these cells. In addition, we confirmed the correlation between INHBA and VCAN in colon cancer cells. Finally, we found that INHBA interference inhibited the aggressive behavior of colon cancer cells by downregulating VCAN. CONCLUSION: INHBA promotes the proliferation, migration and invasion of colon cancer cells through the upregulation of VCAN.


Assuntos
Neoplasias do Colo , Versicanas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidades beta de Inibinas , Invasividade Neoplásica/genética , Regulação para Cima , Versicanas/genética
18.
Int J Mol Sci ; 22(10)2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065633

RESUMO

The circadian clock coordinates biological and physiological functions to day/night cycles. The perturbation of the circadian clock increases cancer risk and affects cancer progression. Here, we studied how BMAL1 knockdown (BMAL1-KD) by shRNA affects the epithelial-mesenchymal transition (EMT), a critical early event in the invasion and metastasis of colorectal carcinoma (CRC). In corresponding to a gene set enrichment analysis, which showed a significant enrichment of EMT and invasive signatures in BMAL1_high CRC patients as compared to BMAL1_low CRC patients, our results revealed that BMAL1 is implicated in keeping the epithelial-mesenchymal equilibrium of CRC cells and influences their capacity of adhesion, migration, invasion, and chemoresistance. Firstly, BMAL1-KD increased the expression of epithelial markers (E-cadherin, CK-20, and EpCAM) but decreased the expression of Twist and mesenchymal markers (N-cadherin and vimentin) in CRC cell lines. Finally, the molecular alterations after BMAL1-KD promoted mesenchymal-to-epithelial transition-like changes mostly appeared in two primary CRC cell lines (i.e., HCT116 and SW480) compared to the metastatic cell line SW620. As a consequence, migration/invasion and drug resistance capacities decreased in HCT116 and SW480 BMAL1-KD cells. Together, BMAL1-KD alerts the delicate equilibrium between epithelial and mesenchymal properties of CRC cell lines, which revealed the crucial role of BMAL1 in EMT-related CRC metastasis and chemoresistance.


Assuntos
Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Neoplasias do Colo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Antígenos CD/metabolismo , Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Bases de Dados Genéticas , Molécula de Adesão da Célula Epitelial/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Técnicas de Silenciamento de Genes , Humanos , Queratina-20/metabolismo , Invasividade Neoplásica/genética , Oxaliplatina/farmacologia , Transporte Proteico , Vimentina/metabolismo , beta Catenina/metabolismo
19.
Dis Colon Rectum ; 64(5): 545-554, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33939386

RESUMO

BACKGROUND: The influence of microsatellite instability on prognosis in high-risk stage II colon cancer is unknown. OBJECTIVE: This study aimed to investigate the relationship between microsatellite instability and overall survival in high-risk stage II colon cancer. DESIGN: This is a retrospective review of the National Cancer Database from 2010 to 2016. SETTINGS: This study included national cancer epidemiology data from the American College of Surgeons Commission on Cancer. PATIENTS: Included were 16,788 patients with stage II colon adenocarcinoma and known microsatellite status (1709 microsatellite unstable). MAIN OUTCOME MEASURES: The primary outcome measured was overall survival. RESULTS: Microsatellite unstable cancers with high-risk features had significantly better overall survival than microsatellite stable cancers with high-risk features (5-year survival 80% vs 72%, p = 0.01), and had survival equivalent to microsatellite stable cancers with low-risk features (5-year survival, 80%). When stratified by specific high-risk features, patients with lymphovascular invasion, perineural invasion, or high-grade histology had overall survival similar to patients without these features, only in microsatellite unstable cancers. However, patients with high-risk features of T4 stage, positive margins, and <12 lymph nodes saw no survival benefit based on microsatellite status. This was confirmed on multivariable Cox regression modeling. A subgroup analysis of patients who did not receive chemotherapy similarly demonstrated that microsatellite unstable cancers with lymphovascular invasion, perineural invasion, or high-grade histology had overall survival similar to microsatellite unstable cancers without those features. LIMITATIONS: The study is limited by the lack of specific clinical data and potential treatment bias. CONCLUSIONS: In microsatellite unstable cancers, lymphovascular invasion, perineural invasion, and high-grade histology are not associated with worse overall survival, even when deferring adjuvant chemotherapy. These data support National Comprehensive Cancer Network recommendations to forego chemotherapy in stage II cancers with microsatellite instability and these features. In contrast, some high-risk features were associated with worse survival despite microsatellite unstable biology, and therapies to improve survival need to be explored. See Video Abstract at http://links.lww.com/DCR/B500. ¿EL ESTADO MICROSATÉLITE ESTÁ ASOCIADO CON EL PRONÓSTICO EN EL CÁNCER DE COLON EN ESTADIO II CON CARACTERÍSTICAS DE ALTO RIESGO: Se desconoce la influencia de la inestabilidad microsatélite en el pronóstico del cáncer de colon en estadio II de alto riesgo.Investigar la relación entre la inestabilidad microsatélite y la supervivencia general en el cáncer de colon en estadio II de alto riesgo.Revisión retrospectiva de la base de datos nacional del cáncer de 2010 a 2016.Este estudio incluyó datos nacionales de epidemiología del cáncer de la Comisión de Cáncer del Colegio Americano de Cirujanos.16,788 pacientes con adenocarcinoma de colon en estadio II y estado microsatélite conocido (1,709 microsatélite inestables).Supervivencia global.Los cánceres microsatélite inestables con características de alto riesgo tuvieron una supervivencia general significativamente mejor que los cánceres microsatélite estables con características de alto riesgo (supervivencia a 5 años 80% vs 72%, p = 0.01), y tuvieron una supervivencia equivalente a los cánceres microsatélite estables con características de bajo riesgo (supervivencia a 5 años 80%). Al estratificar por características específicas de alto riesgo, los pacientes con invasión linfovascular, invasión perineural o histología de alto grado tuvieron una supervivencia general similar a la de los pacientes sin estas características, solo en cánceres microsatélite inestables. Sin embargo, los pacientes con características de alto riesgo en estadio T4, márgenes positivos y <12 ganglios linfáticos no tuvieron ningún beneficio de supervivencia basado en el estado de microsatélites. Esto se confirmó en un modelo de regresión de Cox multivariable. Un análisis de subgrupos de pacientes que no recibieron quimioterapia demostró de manera similar que los cánceres microsatélite inestables con invasión linfovascular, invasión perineural o histología de alto grado tenían una supervivencia general similar a los cánceres microsatélite inestables sin esas características.El estudio está limitado por la falta de datos clínicos específicos y el posible sesgo de tratamiento.En los cánceres microsatélite inestables, la invasión linfovascular, la invasión perineural y la histología de alto grado no se asocian con una peor sobrevida general, incluso cuando se aplaza la quimioterapia adyuvante. Estos datos respaldan las recomendaciones de la National Comprehensive Cancer Network de omitir la quimioterapia en los cánceres en estadio II con inestabilidad microsatélite y estas características. Por el contrario, algunas características de alto riesgo se asociaron con una peor supervivencia a pesar de la biología microsatélite inestable, y es necesario considerar las terapias para mejorar la supervivencia.Consulte Video Resumen en http://links.lww.com/DCR/B500. (Traducción-Dr. Jorge Silva Velazco).


Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , Instabilidade de Microssatélites , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Colectomia , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Feminino , Humanos , Excisão de Linfonodo , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida
20.
Cell Mol Life Sci ; 78(12): 5179-5195, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33974094

RESUMO

Despite new advances on the functions of ER chaperones at the cell surface, the translocation mechanisms whereby these chaperones can escape from the ER to the cell surface are just emerging. Previously we reported that in many cancer types, upon ER stress, IRE1α binds to and triggers SRC activation resulting in KDEL receptor dispersion from the Golgi and suppression of retrograde transport. In this study, using a combination of molecular, biochemical, and imaging approaches, we discovered that in colon and lung cancer, upon ER stress, ER chaperones, such as GRP78 bypass the Golgi and unconventionally traffic to the cell surface via endosomal transport mediated by Rab GTPases (Rab4, 11 and 15). Such unconventional transport is driven by membrane fusion between ER-derived vesicles and endosomes requiring the v-SNARE BET1 and t-SNARE Syntaxin 13. Furthermore, GRP78 loading into ER-derived vesicles requires the co-chaperone DNAJC3 that is regulated by ER-stress induced PERK-AKT-mTOR signaling.


Assuntos
Membrana Celular/metabolismo , Neoplasias do Colo/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Choque Térmico/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Proteínas de Choque Térmico/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutagênese Sítio-Dirigida , Mutação , Transporte Proteico , Transdução de Sinais , Células Tumorais Cultivadas
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