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The extracellular matrix (ECM) is an important component of the tumor microenvironment (TME), having several important roles related to the hallmarks of cancer. In cancer, multiple components of the ECM have been shown to be altered. Although most of these alterations are represented by the increased or decreased quantity of the ECM components, changes regarding the functional alteration of a particular ECM component or of the ECM as a whole have been described. These alterations can be induced by the cancer cells directly or by the TME cells, with cancer-associated fibroblasts being of particular interest in this regard. Because the ECM has this wide array of functions in the tumor, preclinical and clinical studies have assessed the possibility of targeting the ECM, with some of them showing encouraging results. In the present review, we will highlight the most relevant ECM components presenting a comprehensive description of their physical, cellular and molecular properties which can alter the therapy response of the tumor cells. Lastly, some evidences regarding important biological processes were discussed, offering a more detailed understanding of how to modulate altered signalling pathways and to counteract drug resistance mechanisms in tumor cells.
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Resistencia a Medicamentos , Matriz Extracelular , Neoplasias , Matriz Extracelular/patología , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Microambiente TumoralRESUMEN
INTRODUCTION: Squamous cell carcinoma (SCC) is the most common skin cancer with a high rate of death. Different lymphocyte populations play an important role in modulating the immune response in the tumor microenvironment. The increase in the proportion of cluster of differentiation (CD)4+ CD25+ regulatory T-cell (Treg) lymphocytes is associated, in different studies, with the increase of the cell multiplication rate. AIM: To analyze the Treg lymphocyte subpopulations and to correlate the results with the presence of the CD8+ cytotoxic T-cell (Tc) lymphocyte population. MATERIALS AND METHODS: Sixty primary skin SCC specimens were incubated with anti-CD8 (clone SP57) rabbit monoclonal antibody and anti-CD25 (clone 4C9) mouse monoclonal antibody. RESULTS: The ratio of the intratumoral∕peritumoral CD4+ CD25+ forkhead box protein p3 (Foxp3) lymphocytes was 0.46, emphasizing that at tumor margins, where tumor aggressiveness is higher, these lymphocytes subpopulations facilitate tumor progression. The comparative analysis of the tumor microenvironment profile revealed that in the case of intratumoral immune response, the number of Tc-type lymphocytes (CD8+) was 3.34 times higher compared to Treg lymphocytes (p<0001). In the peritumoral area, the number of Tc lymphocytes was 5.05 times higher compared to Treg lymphocytes (p<0001). CONCLUSIONS: Treg lymphocytes inhibition may cause the suppression of the antitumoral cell immune response in the tumor environment. We believe that Treg lymphocytes should represent a focus of interest for a new personalized therapy. New studies are needed to better understand the immune response in the tumor microenvironment.
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Carcinoma de Células Escamosas , Linfocitos T Reguladores , Animales , Linfocitos T CD4-Positivos , Factores de Transcripción Forkhead , Ratones , Microambiente TumoralRESUMEN
Colon adenocarcinoma (COAD) remains an important cause of cancer-related mortality worldwide. Epithelial-mesenchymal transition (EMT) is a key mechanism, promoting not only the invasive or metastatic phenotype but also resistance to therapy. Using bioinformatics approaches, we studied the alteration on EMT related genes and its implication on COAD prognostic based on public datasets. For the EMT mechanisms, two overexpressed genes were identified (NOX4 and IGF2BP3), as well as five downregulated genes (BMP5, DACT3, EEF1A2, GCNT2 and SFRP1) that were related to prognosis in COAD. A qRT-PCR validation step was conducted in a COAD patient cohort comprising of 29 tumor tissues and 29 normal adjacent tissues, endorsing the expression level for BMP5, as well as for two of the miRNAs targeting key EMT related genes, revealing upregulation of miR-27a-5p and miR-146a-5p. The EMT signature can be used to develop a panel of biomarkers for recurrence prediction in COAD patients, which may contribute to the improvement of risk stratification for the patients.
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Colon cancer is the third most common cancer type worldwide and is highly dependent on DNA mutations that progressively appear and accumulate in the normal colon epithelium. Mutations in the TP53 gene appear in approximately half of these patients and have significant implications in disease progression and response to therapy. miR-125b-5p is a controversial microRNA with a dual role in cancer that has been reported to target specifically TP53 in colon adenocarcinomas. Our study investigated the differential therapeutic effect of miR-125b-5p replacement in colon cancer based on the TP53 mutation status of colon cancer cell lines. In TP53 mutated models, miR-125b-5p overexpression slows cancer cells' malignant behavior by inhibiting the invasion/migration and colony formation capacity via direct downregulation of mutated TP53. In TP53 wild type cells, the exogenous modulation of miR-125b-5p did not significantly affect the molecular and phenotypic profile. In conclusion, our data show that miR-125b-5p has an anti-cancer effect only in TP53 mutated colon cancer cells, explaining partially the dual behavior of this microRNA in malignant pathologies.
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Psoriasis is a chronic autoimmune disease affecting over 2% of the worldwide population. From an anatomopathological point of view, psoriasis is characterized by immune cells infiltration, epidermal hyperproliferation, and abnormal keratinocyte differentiation. Understanding the pathogenesis of psoriasis will allow clinicians to manage this complex disease. Under these conditions, the application of effective treatments requires a thorough knowledge of all the pathogenetic mechanisms that lead to psoriasis. Numerous immunopathological pathways play crucial roles in the development of new therapies, such as biological therapies, which have been a breakthrough in psoriasis's treatment. Pharmacogenetics is an essential factor in the patient's response to treatment. One important pathway targeted by modern treatments is the interleukin (IL)-23∕T-helper (Th)17 axis. Like IL-17 inhibitors, IL-23 blockers are a very effective therapy for this autoimmune disease. It is considered that micro-ribonucleic acids (microRNAs) are the starting point for any autoimmune disease. Studying certain microRNA (miR) involved in the inflammatory pathway in psoriasis can find direct targets to future treatments that can even be more specific than actual biological therapies. As such, miR-210 has proven to be up-regulated in psoriasis, also leading to the up-regulation of the Th1∕Th17 axis. On the other hand, miR-187 was found to be down-regulated, influencing the outcome of psoriasis by increasing the proliferation of IL-6 stimulated keratinocytes and consecutively generating epidermal thickening. In this review, we are aiming to do an up-to-date briefing of psoriasis histopathology and pharmacogenetic factors that are considered for the accurate evaluation of treatment response.
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Enfermedades Autoinmunes , MicroARNs , Psoriasis , Proliferación Celular , Humanos , Queratinocitos/metabolismo , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
BACKGROUND AND AIMS: Although colon cancer has a decreasing incidence trend in Europe, because of its still high frequency and not fully understood pathogenesis, this malignancy still remains a subject of intense research. The aim of this study was to investigate the role of microRNA-194 and microRNA-1228 in colon cancer proliferation. METHODS: RNA was extracted from patients with colon cancer with or without advanced disease and microRNA expression levels were determined through qRT-PCR. Assays were performed on HCT116 cell line and included qRT-PCR, western blotting and cell counting. RESULTS: We observed that both microRNAs 194 and 1228 were altered in patients with colon cancer compared with healthy individuals. We observed a lower expression of both microRNA-194 and microRNA-1228 in patients with advanced colon cancer. To validate their pathogenetic role we performed viability and invasion assays on HCT116 cell line transfected with mimics or inhibitors of the mentioned microRNAs, with observable changes in viability and invasion. Furthermore, to determine the altered signaling induced by these microRNAs, we performed western blotting for phospho S6 on HCT116 cells transfected with mimic and inhibitor of the above-mentioned microRNAs with observable differences. CONCLUSION: In the current study we have shown that both microRNA-194 and microRNA-1228 alteration was correlated with the presence of advanced colon cancer, a fact that was further validated in vitro through an invasion assay. Moreover, we have also shown that their effect might be mediated through phospho S6 expression.
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Adenocarcinoma/sangre , Biomarcadores de Tumor/sangre , Proliferación Celular , MicroARN Circulante/sangre , Neoplasias del Colon/sangre , MicroARNs/sangre , Proteínas Quinasas S6 Ribosómicas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Movimiento Celular , MicroARN Circulante/genética , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Femenino , Células HCT116 , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Invasividad Neoplásica , FosforilaciónRESUMEN
The small nucleolar RNA host genes (SNHGs) are a group of long non-coding RNAs, which are reported in many studies as being overexpressed in various cancers. With very few exceptions, the SNHGs (SNHG1, SNHG3, SNHG5, SNHG6, SNHG7, SNHG12, SNHG15, SNHG16, SNHG20) are recognized as inducing increased proliferation, cell cycle progression, invasion, and metastasis of cancer cells, which makes this class of transcripts a viable biomarker for cancer development and aggressiveness. Through our literature research, we also found that silencing of SNHGs through small interfering RNAs or short hairpin RNAs is very effective in both in vitro and in vivo experiments by lowering the aggressiveness of solid cancers. The knockdown of SNHG as a new cancer therapeutic option should be investigated more in the future.
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An increasing number of studies suggest the implication of microRNAs (miRNAs) in colorectal (CRC) carcinogenesis and disease progression. Nevertheless, the basic mechanism is not yet clear. We determined plasma miRNA expression levels using Agilent microarray technology followed by overlapping with The Cancer Genome Atlas (TCGA) tissue data and a qRT-PCR validation step and analysis of the altered miRNA signatures to emphasize new mechanistic insights. For TGCA dataset, we identified 156 altered miRNAs (79 downregulated and 77 upregulated) in colorectal tissue samples versus normal tissue. The microarray experiment is based on 16 control samples, 38 CRC plasma samples from colorectal cancer patients who have not undergone chemotherapy, and 17 chemo-treated samples. In the case of the analysis of CRC cancer versus healthy control we identified 359 altered miRNAs (214 downregulated and 60 upregulated), considering as the cutoff value a fold-change of ±1.5 and p < 0.01. An additional microarray analysis was performed on plasma from untreated colorectal cancer (n = 38) and chemotherapy-treated colorectal cancer patients (n = 17), which revealed 15 downregulated miRNAs and 53 upregulated miRNAs, demonstrating that the plasma miRNA pattern is affected by chemotherapy and emphasizing important regulators of drug resistance mechanisms. For the validation of the microarray data, we selected a panel of 4 miRNAs from the common miRNA signatures for colon and rectal cancer (miR-642b-3p, miR-195-5p and miR-4741). At the tissue level, the expression levels were in agreement with those observed in colorectal plasma. miR-1228-3p, the top upregulated miRNA in CRC, was chosen to be validated on tissue and plasma samples, as it was demonstrated to be downregulated at tissue level in our patient cohort. This was confirmed by TCGA data and was one example of ta ranscript that has a different expression level between tumor tissue and plasma. Developing more efficient investigation methods will help explain the mechanisms responsible for miRNAs released in biofluids, which is the most upregulated transcript in colorectal plasma samples and which can function as a prediction tool within the oncological field.
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Lung cancer is one of the main causes of cancer-related death in the world, especially due to its frequency and ineffective therapeutically approaches in the late stages of the disease. Despite the recent advent of promising new targeted therapies, lung cancer diagnostic strategies still have difficulty in identifying the disease at an early stage. Therefore, the characterizations of more sensible and specific cancer biomarkers have become an important goal for clinicians. Circular RNAs (circRNAs), a type of RNA with covalently closed continuous loop structures that display high structural resistance and tissue specificity pointed toward a potential biomarker role. Current investigations have identified that circRNAs have a prominent function in the regulation of oncogenic pathways, by regulating gene expression both at transcriptional and post-transcriptional level. The aim of this review is to provide novel information regarding the implications of circRNAs in lung cancer, with an emphasis on the role in disease development and progression. Initially, we explored the potential utility of circRNAs as biomarkers, focusing on function, mechanisms, and correlation with disease progression in lung cancer. Further, we will describe the interaction between circRNAs and other non-coding species of RNA (particularly microRNA) and their biological significance in lung cancer. Describing the nature of these interactions and their therapeutic potential will provide additional insight regarding the altered molecular landscape of lung cancer and consolidate the potential clinical value of these circular transcripts. This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.
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Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , ARN Circular/genética , Animales , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Terapia Molecular Dirigida , Interferencia de ARN , ARN Circular/química , Transducción de Señal , Relación Estructura-ActividadRESUMEN
Concomitant with advances in research regarding the role of miRNAs in sustaining carcinogenesis, major concerns about their delivery options for anticancer therapies have been raised. The answer to this problem may come from the world of nanoparticles such as liposomes, exosomes, polymers, dendrimers, mesoporous silica nanoparticles, quantum dots and metal-based nanoparticles which have been proved as versatile and valuable vehicles for many biomolecules including miRNAs. In another train of thoughts, the general scheme of miRNA modulation consists in inhibition of oncomiRNA expression and restoration of tumor suppressor ones. The codelivery of two miRNAs or miRNAs in combination with chemotherapeutics or small molecules was also proposed. The present review presents the latest advancements in miRNA delivery based on nanoparticle-related strategies.
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MicroARNs/administración & dosificación , Neoplasias/terapia , Animales , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Humanos , MicroARNs/genética , MicroARNs/farmacocinética , MicroARNs/uso terapéutico , Nanomedicina/métodos , Nanopartículas/química , Neoplasias/genéticaRESUMEN
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Current treatment options for inoperable HCCs have decreased therapeutic efficacy and are associated with systemic toxicity and chemoresistance. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent enzyme that is frequently overexpressed in HCC, where it promotes tumorigenicity, metastasis, and chemoresistance. SIRT1 also maintains the tumorigenic and self-renewal proprieties of liver cancer stem cells. Multiple tumor-suppressive microRNAs (miRNAs) are downregulated in HCC and, as a consequence, permit SIRT1-induced tumorigenicity. However, either directly targeting SIRT1, combining conventional chemotherapy with SIRT1 inhibitors, or upregulating tumor-suppressive miRNAs may improve therapeutic efficacy and patient outcomes. Here, we present the interaction between SIRT1, miRNAs, and liver cancer stem cells and discuss the consequences of their interplay for the development and treatment of HCC.
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The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies.
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PURPOSE: Surface-enhanced Raman scattering (SERS) spectroscopy on serum and other biofluids for cancer diagnosis represents an emerging field, which has shown promising preliminary results in several types of malignancies. The purpose of this study was to demonstrate that SERS spectroscopy on serum can be employed for the differential diagnosis between five of the leading malignancies, ie, breast, colorectal, lung, ovarian and oral cancer. PATIENTS AND METHODS: Serum samples were acquired from healthy volunteers (n=39) and from patients diagnosed with breast (n=42), colorectal (n=109), lung (n=33), oral (n=17), and ovarian cancer (n=13), comprising n=253 samples in total. SERS spectra were acquired using a 532 nm laser line as excitation source, while the SERS substrates were represented by Ag nanoparticles synthesized by reduction with hydroxylamine. The classification accuracy yielded by SERS was assessed by principal component analysis-linear discriminant analysis (PCA-LDA). RESULTS: The sensitivity and specificity in discriminating between cancer patients and controls was 98% and 91%, respectively. Cancer samples were correctly assigned to their corresponding cancer types with an accuracy of 88% for oral cancer, 86% for colorectal cancer, 80% for ovarian cancer, 76% for breast cancer and 59% for lung cancer. CONCLUSION: SERS on serum represents a promising strategy of diagnosing cancer which can discriminate between cancer patients and controls, as well as between cancer types such as breast, colorectal, lung ovarian and oral cancer.
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Neoplasias/diagnóstico , Espectrometría Raman/métodos , Anciano , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico , Estudios de Casos y Controles , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/diagnóstico , Diagnóstico Diferencial , Análisis Discriminante , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/diagnóstico , Masculino , Nanopartículas del Metal/química , Nanopartículas del Metal/ultraestructura , Persona de Mediana Edad , Neoplasias de la Boca/sangre , Neoplasias de la Boca/diagnóstico , Neoplasias/sangre , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico , Análisis de Componente Principal , Plata/químicaRESUMEN
BACKGROUND: Phytochemicals are natural compounds synthesized as secondary metabolites in plants and represent an important source of molecules with therapeutic applications. Attention is accorded to their potential in anti-cancer therapies as single agents or adjuvant treatment. Herby, we evaluated the in vitro effects of a panel of natural compounds with focus on caffeic acid phenethyl ester (CAPE) and Kaempferol for the treatment of human colon cancer. METHODS: We exposed two human colon cancer cell lines, RKO and HCT-116, followed by functional examination of cell viability, cell proliferation and invasion, cell cycle, apoptosis, and autophagy. Modifications in gene expression were investigated through microarray and detection of existing mutations and finding of new ones was done with the help of Next Generation Sequencing (NGS). RESULTS: Both CAPE and Kaempferol inhibit cell proliferation, motility and invasion, and stimulate apoptosis and autophagy, concomitant with modifications in coding and noncoding genes' expression. Moreover, there are pathogenic mutations that are no longer found upon treatment with CAPE and Kaempferol. CONCLUSIONS: Our findings indicate that CAPE and Kaempferol have the ability to negatively influence the development and advancement of colon cancer in vitro by specifically altering the cells at the molecular level; this activity can be exploited in possible adjuvant therapies once the optimal dose concentration with minimal side effects but with cancer inhibitory activity is set in vivo.
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Antineoplásicos/farmacología , Ácidos Cafeicos/farmacología , Neoplasias del Colon/tratamiento farmacológico , Quempferoles/farmacología , Invasividad Neoplásica/prevención & control , Alcohol Feniletílico/análogos & derivados , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Células HCT116 , Humanos , Invasividad Neoplásica/patología , Alcohol Feniletílico/farmacologíaRESUMEN
Cancer represents a heterogeneous disease with multiple levels of regulation and a dynamic environment that sustains the evolution of the malignant mass. This dynamic is in part sustained by a class of extracellular vesicles termed exosomes that are able to imprint the pathological state by incorporating differential cargos in order to facilitate cell-to-cell communication. Exosomes are stable within the extracellular medium and function as shuttles secreted by healthy or pathological cells, being further taken by the accepting cell with direct effects on its phenotype. The exosomal trafficking is deeply involved in multiple levels of cancer development with roles in all cancer hallmarks. Nowadays, studies are constantly exploring the ability of exosomes to sustain the malignant progression in order to attack this pathological trafficking and impair the ability of the tumor mass to expand within the organisms. As important, the circulatory characteristics of exosomes represent a steady advantage regarding the possibility of using them as minimally invasive diagnosis tools, where cancer patients' present modified exosomal profiles compared to the healthy ones. This last characteristic, as novel diagnosis tools, has the advantage of a possible rapid transition within the clinic, compared to the studies that evaluate the therapeutic meaning.
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Exosomas/patología , Neoplasias/diagnóstico , Neoplasias/patología , Animales , Muerte Celular , Proliferación Celular , Progresión de la Enfermedad , Exosomas/metabolismo , Humanos , Invasividad Neoplásica/diagnóstico , Invasividad Neoplásica/patología , Neoplasias/metabolismo , Neovascularización Patológica/diagnóstico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Transducción de SeñalRESUMEN
Cancer, and particularly colon cancer, is associated with an increasing number of cases resistant to chemotherapy. One approach to overcome this, and to improve the prognosis and outcome of patients, is the use of adjuvant therapy alongside the standard chemotherapy regiment. In the present study, the effect of deuterium-depleted water (DDW) as a potential modulator of adjuvant therapy on DLD-1 colorectal cancer models was assessed. A number of functionality assays were performed, including MTT, apoptosis and autophagy, and mitochondrial activity and senescence assays, in addition to assessing the capacity to modify the pattern of released miRNA via microarray technology. No significant effect on cell viability was identified, but an increase in mitochondrial activity and a weak pro-apoptotic effect were observed in the treated DLD-1 cells cultured in DDW-prepared medium compared with those grown in standard conditions (SC). Furthermore, the findings revealed the capacity of DDW medium to promote senescence to a higher degree compared with SC. The exosome-released miRNA pattern was significantly modified for the cells maintained in DDW compared with those maintained in SC. These findings suggest that DDW may serve as an adjuvant treatment; however, a better understanding of the underlying molecular mechanism of action will be useful for developing novel and efficient therapeutic strategies, in which the transcriptomic pattern serves an important role.
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EMT represents the dominant program within advanced stages of colon cancer, where cells acquire migratory characteristics in order to invade secondary tissues and form metastasis. Where the majority of the therapeutic strategies are concentrated on the reduction of the tumor mass through different apoptotic mechanisms, the present study advocates an important role for miR-205-5p in impairment of colon cancer cells migration and restoration of the epithelial phenotype. Upon identification of a homogenous downregulated profile for miR-205-5p in colon adenocarcinoma patients, functional studies demonstrated that experimental upregulation of this sequence is able to significantly raise the levels of E-cadherin through direct inhibition of ZEB1. Moreover, the elevation in CDH1 expression was translated into functional parameters where cells lost their invasion and migratory characteristics and formed homogenous clusters through adhesion interactions. Survival analysis of colon adenocarcinoma patients revealed that low levels of miR-205-5p are associated with an unfavorable prognostic compared to those with increased expression, demonstrating the possible clinical utility of miR-205-5p replacement. Exogenous administration of miRNA mimics was not associated with significant changes in cell viability or inflammatory pathways. Therefore, the proposed strategy is aiming towards inhibition of metastasis and limitation of the tumor borders in advanced stages patients in order to prolong the survival time and to increase the efficiency of the current therapeutic strategies.
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Antígenos CD/genética , Cadherinas/genética , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Regulación hacia Arriba/genética , Uniones Adherentes/metabolismo , Anciano , Anciano de 80 o más Años , Antígenos CD/metabolismo , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Adhesión Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Neoplasias del Colon/ultraestructura , Regulación hacia Abajo/genética , Femenino , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Fenotipo , Pronóstico , Análisis de Supervivencia , Vimentina/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismoRESUMEN
OBJECTIVE: MicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis. DESIGN: We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by quantitative real-time PCR (qRT-PCR). We tested metastatic activity of selected miRNAs and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analysed in six sets of CRC cases (n=449), including The Cancer Genome Atlas (TCGA) consortium and correlated with miR-224 status. We used the Kaplan-Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression. RESULTS: MiR-224 expression increases consistently with tumour burden and microsatellite stable status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target and observed negative correlation (Spearman Rs=-0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR-224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037, respectively), and shorter metastasis-free survival (HR 6.51, 95% CI 1.97 to 21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (HR 4.12, 95% CI 1.1 to 15.41, p=0.0175). CONCLUSIONS: MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for survival of patients with CRC.
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Adenocarcinoma/diagnóstico , Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/diagnóstico , MicroARNs/sangre , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Animales , Austria , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas In Vitro , Italia , Estimación de Kaplan-Meier , Masculino , Ratones , Persona de Mediana Edad , Invasividad Neoplásica , Valor Predictivo de las Pruebas , Rumanía , Sensibilidad y Especificidad , Reino UnidoRESUMEN
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies of the digestive tract. Gastric localization is the most frequent. The aim of this study is to evaluate the importance of immunohistochemical factors (CD117, CD34, α-SMA, vimentin, p53, Ki67) in diagnostic and size tumor and mitotic activity as prognostic factors for these tumors. We present the case of a 66-year-old male patient with a giant gastric GIST. Like in the vast majority, the symptomatology in this patient has long been faint, despite the large tumor size, and when it became manifest, it was nonspecific. Imagery wise, the computer tomography (CT) scan was the most efficient, showing the origin of the tumor from the greater curvature of the stomach, its dimensions, as well as the relations with the other abdominal viscera. Surgery in this patient was en-bloc, according to the principles of GIST. The histological aspect is characterized by a proliferation of spindle cells positive for CD117 and CD34. Despite complete microscopic resection, the size of the tumor (25×20×27 cm) and the mitotic activity (21÷5 mm2) remains important relapse factor.
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Mucosa Gástrica/metabolismo , Tumores del Estroma Gastrointestinal/diagnóstico , Proteínas Proto-Oncogénicas c-kit/metabolismo , Neoplasias Gástricas/metabolismo , Actinas/metabolismo , Anciano , Antígenos CD34/metabolismo , Biomarcadores de Tumor/metabolismo , Progresión de la Enfermedad , Tumores del Estroma Gastrointestinal/diagnóstico por imagen , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/terapia , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Masculino , Recurrencia Local de Neoplasia , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: The prognosis of colorectal cancer (CRC) varies considerably, and there is a compelling need to identify novel biomarkers with prognostic significance. The aim of the present study was to evaluate the prognostic value of a panel of six genes (CDH1, SMAD3, TGFß1, ICAM-1, TIMP-1 and MUC12) in CRC patients. METHODS. We evaluated these genes by qRT-PCR in normal and CRC tumor tissue, and correlated the relative gene expression values with clinical, pathological aspects and other biological factors. RESULTS. RNA expression levels of CDH1, SMAD3, TGFß1, ICAM-1, TIMP-1 and MUC12 were measured by qRT-PCR in a set of 39 tumor samples and non-cancer tissue. Statistically significant increases in expression levels were found for ICAM-1 and TIMP-1 when comparing tumor samples to the non-tumor group. CONCLUSIONS. Among the genes which displayed differential expressions between tumor tissue and adjoining normal tissue, the ones that presented statistically significant correlations were TIMP-1 and SMAD3, possibly with prognostic significance.