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Membrane transporters are proteins responsible for facilitating the movement of molecules within biological membranes. They play a vital role in maintaining cellular homeostasis by regulating the transport of nutrients, ions, and other molecules into and out of cells. Our aim is to identify biomarkers in colorectal cancer using membrane transporter proteins. We utilized COAD TCGA data for this purpose. Subsequently, we conducted differential gene analysis and feature selection using membrane transporter proteins. Furthermore, we identified two potential genes, including ANO7 and SLC38A4. To validate the expression profiles of ANO7 and SLC38A4, key genes in this context, RT-qPCR was employed on colorectal cancer samples and adjacent normal tissues. Additionally, utilizing GEPIA2, Kaplan-Meier survival analysis, and cBioPortal, we assessed the status of these genes in various cancers, examining their methylation and mutation patterns. In conclusion, we suggest that ANO7 and SLC38A4 serve as prognostic biomarkers in colorectal cancer.
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The Gasdermin E gene (GSDME) plays roles in deafness and cancers. However, the roles and mechanisms in cancers are complex, and the same gene exhibits different mechanisms and actions in different types of cancers. Online databases, such as GEPIA2, cBioPortal, and DNMIVD, were used to comprehensively analyze GSDME profiles, DNA methylations, mutations, diagnosis, and prognosis in patients with tumor tissues and matched healthy tissues. Western blotting and RT-PCR were used to monitor the regulation of GSDME by Cordycepin (CD) in cancer cell lines. We revealed that GSDME expression is significantly upregulated in eight cancers (ACC, DLBC, GBM, HNSC, LGG, PAAD, SKCM, and THYM) and significantly downregulated in seven cancers (COAD, KICH, LAML, OV, READ, UCES, and UCS). The overall survival was longer only in ACC, but shorter in four cancers, including COAD, KIRC, LIHC, and STAD, when GSDME was highly expressed in cancers compared with the corresponding normal tissues. Moreover, the high expression of GSDME was negatively correlated with the poor prognosis of ACC, while the low expression of GSDME was negatively correlated with the poor prognosis of COAD, suggesting that GSDME might serve as a good prognostic factor in these two cancer types. Accordingly, results indicated that the DNA methylations of those 7 CpG sites constitute a potentially effective signature to distinguish different tumors from adjacent healthy tissues. Gene mutations for GSDME were frequently observed in a variety of tumors, with UCES having the highest frequency. Moreover, CD treatment inhibited GSDME expression in different cancer cell lines, while overexpression of GSDME promoted cell migration and invasion. Thus, we have systematically and successfully clarified the GSDME expression profiles, diagnostic values, and prognostic values in pan-cancers. Targeting GSDME with CD implies therapeutic significance and a mechanism for antitumor roles in some types of cancers via increasing the sensitivity of chemotherapy. Altogether, our study may provide a strategy and biomarker for clinical diagnosis, prognostics, and treatment of cancers by targeting GSDME.
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Breast cancer (BC) is the most common tumor in women worldwide. TRIM28 (RNF96) plays pleiotropic biological functions, such as silencing target genes, facilitating DNA repair, stimulating cellular proliferation and differentiation, and contributing to cancer progression. TRIM28 plays an increasingly crucial role in cancer, but its impact on BC, including breast invasive carcinoma, remains poorly understood. In the current study, analyses of online databases, quantitative real-time quantitative PCR, immunohistochemistry, and western blotting were performed on patients with breast invasive carcinoma (BRCA). Cordycepin (CD) was used to monitor BC progression and TRIM28 expression in vivo. As a result, we observed that TRIM28 is highly expressed in breast invasive carcinoma tissues compared with the corresponding normal tissues and is correlated with metastatic / invasive progression. High expression of TRIM28 might serve as a prognostic marker for long-term survival in triple-negative BC, advanced BC, or breast invasive carcinoma. Although TRIM28 methylation in tumor tissues of breast invasive carcinoma is not significantly changed compared to the matched normal tissues, the expressions and methylation of TRIM28 are significantly reversely correlated. TRIM28 expression was inhibited by CD in the mouse model, indicating its role in preventing BC progression. Thus, TRIM28 might be a potentially valuable molecular target for forecasting the progression / prognosis of patients with breast invasive carcinoma. CD, which represses BC growth/metastasis, may be involved partially through suppressing TRIM28 expression.
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Osteoporosis, characterized by compromised bone density and microarchitecture, represents a significant global health challenge, particularly in aging populations. This comprehensive review delves into the intricate signaling pathways implicated in the pathogenesis of osteoporosis, providing valuable insights into the pivotal role of signal transduction in maintaining bone homeostasis. The exploration encompasses cellular signaling pathways such as Wnt, Notch, JAK/STAT, NF-κB, and TGF-ß, all of which play crucial roles in bone remodeling. The dysregulation of these pathways is a contributing factor to osteoporosis, necessitating a profound understanding of their complexities to unveil the molecular mechanisms underlying bone loss. The review highlights the pathological significance of disrupted signaling in osteoporosis, emphasizing how these deviations impact the functionality of osteoblasts and osteoclasts, ultimately resulting in heightened bone resorption and compromised bone formation. A nuanced analysis of the intricate crosstalk between these pathways is provided to underscore their relevance in the pathophysiology of osteoporosis. Furthermore, the study addresses some of the most crucial long non-coding RNAs (lncRNAs) associated with osteoporosis, adding an additional layer of academic depth to the exploration of immune system involvement in various types of osteoporosis. Finally, we propose that SKP1 can serve as a potential biomarker in osteoporosis.
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Osteoporose , Transdução de Sinais , Osteoporose/imunologia , Osteoporose/genética , Osteoporose/metabolismo , Humanos , Animais , Remodelação Óssea , Osteoclastos/metabolismo , Osteoclastos/imunologia , Osteoblastos/metabolismo , Osteoblastos/imunologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
SARS-CoV-2 has triggered an international outbreak of the highly contagious acute respiratory disease known as COVID-19. Identifying key targets in the virus infection lifecycle is crucial for developing effective prevention and therapeutic strategies against it. Furin is a serine endoprotease that belongs to the family of proprotein convertases and plays a critical role in the entry of host cells by SARS-CoV-2. Furin can cleave a specific S1/S2 site, PRRAR, on the spike protein of SARS-CoV-2, which promotes viral transmission by facilitating membrane fusion. Hence, targeting furin could hold clinical implications for the prevention and treatment of COVID-19. This review offers an overview of furin's structure, substrates, function, and inhibitors, with a focus on its potential role in SARS-CoV-2 infection.
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Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Furina , SARS-CoV-2 , Furina/metabolismo , Humanos , COVID-19/prevenção & controle , Antivirais/farmacologia , Antivirais/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
Colorectal cancer (CRC) is a major worldwide health issue, with high rates of both occurrence and mortality. Dysregulation of the transforming growth factor-beta (TGF-ß) signaling pathway is recognized as a pivotal factor in CRC pathogenesis. Notably, the INHBA gene and long non-coding RNAs (lncRNAs) have emerged as key contributors to CRC progression. The aim of this research is to explore the immunological roles of INHBA and PELATON in CRC through a combination of computational predictions and experimental validations, with the goal of enhancing diagnostic and therapeutic strategies. In this study, we utilized bioinformatics analyses, which involved examining differential gene expression (DEG) in the TCGA-COAD dataset and exploring the INHBA gene in relation to the TGF-ß pathway. Additionally, we analyzed mutations of INHBA, evaluated the microenvironment and tumor purity, investigated the INHBA's connection to immune checkpoint inhibitors, and measured its potential as an immunotherapy target using the TIDE score. Utilizing bioinformatics analyses of the TCGA-COAD dataset beside experimental methodologies such as RT-qPCR, our investigation revealed significant upregulation of INHBA in CRC. As results, our analysis of the protein-protein interaction network associated with INHBA showed 10 interacting proteins that play a role in CRC-associated processes. We observed a notable prevalence of mutations within INHBA and explored its correlation with the response to immune checkpoint inhibitors. Our study highlights INHBA as a promising target for immunotherapy in CRC. Moreover, our study identified PELATON as a closely correlated lncRNA with INHBA, with experimental validation confirming their concurrent upregulation in CRC tissues. Thus, these findings highlight the importance of INHBA and PELATON in driving CRC progression, suggesting their potential utility as diagnostic and prognostic biomarkers. By integrating computational predictions with experimental validations, this research enhances our understanding of CRC pathogenesis and uncovers prospects for personalized therapeutic interventions.
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Neoplasias Colorretais , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Subunidades beta de Inibinas , Mapas de Interação de Proteínas , Transdução de Sinais , Fator de Crescimento Transformador beta , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Humanos , Biologia Computacional/métodos , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genética , Mapas de Interação de Proteínas/genética , Subunidades beta de Inibinas/genética , Subunidades beta de Inibinas/metabolismo , RNA Longo não Codificante/genética , Microambiente Tumoral/genética , Mutação , Biomarcadores Tumorais/genéticaRESUMO
Hereditary hemorrhagic telangiectasia (HHT), also called Rendu-Osler syndrome, is a group of rare genetic diseases characterized by autosomal dominance, multisystemic vascular dysplasia, and age-related penetrance. This includes arteriovenous malformations (AVMs) in the skin, brain, lung, liver, and mucous membranes. The correlations between the phenotype and genotype for HHT are not clear. An HHT Chinese pedigree was recruited. Whole exome sequencing (WES) analysis, Sanger verification, and co-segregation were conducted. Western blotting was performed for monitoring ENG/VEGFα signaling. As a result, a nonsense, heterozygous variant for ENG/CD105: c.G1169A:p. Trp390Ter of the proband with hereditary hemorrhagic telangiectasia type 1 (HHT1) was identified, which co-segregated with the disease in the M666 pedigree. Western blotting found that, compared with the normal levels associated with non-carrier family members, the ENG protein levels in the proband showed approximately a one-half decrease (47.4% decrease), while levels of the VEGFα protein, in the proband, showed approximately a one-quarter decrease (25.6% decrease), implying that ENG haploinsufficiency, displayed in the carrier of this variant, may affect VEGFα expression downregulation. Pearson and Spearman correlation analyses further supported TGFß/ENG/VEGFα signaling, implying ENG regulation in the blood vessels. Thus, next-generation sequencing including WES should provide an accurate strategy for gene diagnosis, therapy, genetic counseling, and clinical management for rare genetic diseases including that in HHT1 patients.
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Telangiectasia Hemorrágica Hereditária , Humanos , Endoglina/genética , Endoglina/metabolismo , Telangiectasia Hemorrágica Hereditária/genética , Genótipo , Heterozigoto , ChinaRESUMO
BACKGROUND: Hotspot mutations occurring in the p110α domain of the PIK3CA gene, specifically p110αH1047R/L increase tumor metastasis and cell motility in triple-negative breast cancer (TNBC). These mutations also affect the transcriptional regulation of ΔNp63α, a significant isoform of the p53 protein involved in cancer progression. This study attempts to investigate the transcriptional impact of p110αH1047R/L mutations on the PIK3CA/ΔNp63α complex in TNBC carcinogenesis. METHODS: We performed site-directed mutagenesis to introduce p110αH1047R/L mutations and evaluated their oncogenic effects on the growth, invasion, migration, and apoptosis of three different TNBC cell lines in vitro. We investigated the impact of these mutations on the p110α/ΔNp63α complex and downstream transcriptional signaling pathways at the gene and protein levels. Additionally, we used bioinformatics techniques such as molecular dynamics simulations and protein-protein docking to gain insight into the stability and structural changes induced by the p110αH1047R/L mutations in the p110α/ΔNp63α complex and downstream signaling pathway. RESULTS: The presence of PIK3CA oncogenic hotspot mutations in the p110α/ΔNp63α complex led to increased scattering of TNBC cells during growth, migration, and invasion. Our in vitro mutagenesis assay showed that the p110αH1047R/L mutations activated the PI3K-Akt-mTOR and tyrosine kinase receptor pathways, resulting in increased cell proliferation, invasion, and apoptosis in TNBC cells. These mutations decreased the repressing effect of ΔNp63α on the p110α kinase domain, leading to the enhancement of downstream signaling pathways of PI3K and tyrosine kinase receptors and oncogenic transformation in TNBC. Additionally, our findings suggest that the physical interaction between the DNA binding domain of ΔNp63α and the kinase domain of p110α may be partially impaired, potentially leading to alterations in the conformation of the p110α/ΔNp63α complex. CONCLUSION: Our findings suggest that targeting the p110αH1047R/L mutations in TNBC could be a promising strategy for developing transcriptional-based therapies. Restoring the interaction between ΔNp63α and the p110α kinase domain, which is disrupted by these mutations, may provide a new approach to treating TNBC.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Fosfatidilinositol 3-Quinases , Mutação , Transdução de Sinais/genética , Classe I de Fosfatidilinositol 3-Quinases/genéticaRESUMO
INTRODUCTION: Colorectal cancer (CRC) is one of the most malignant tumors and in which various efforts for screening is inconclusive.The intracrine FGF panel, the non-tyrosine kinase receptors (NTKR) FGFs and affiliated antisenses play a pivotal role in FGF signaling.The expression levels of coding and non-coding intracrine FGFs were assessed in CRC donors.Also, substantial costs and slow pace of drug discovery give high attraction to repurpose of previously discovered drugs to new opportunities. OBJECTIVES: The aim of present study was to evaluate the potential role of the coding and non-coding intracrine FGFs as a new biomarkers for CRC cases and defining drug repurposing to alleviate FGF down regulation. METHODS: RNA-seq data of colon adenocarcinomas (COAD) was downloaded using TCGA biolinks package in R.The DrugBank database (https://go.drugbank.com/) was used to extract interactions between drugs and candidate genes. A total of 200 CRC patients with detailed criteria were enrolled.RNAs were extracted with TRIzol-based protocol and amplified via LightCycler® instrument.FGF11 and FGF13 proteins validation was performed by used of immunohistochemistry technique in tumor and non-tumoral samples.Pearson's correlation analysis and ROC curve plotted by Prism 8.0 software. RESULTS: RNA-seq data from TCGA was analyzed by normalizing with edgeR.Differentially expressed gene (DEG) analysis was generated. WCC algorithm extracted the most significant genes with a total of 47 genes. Expression elevation of iFGF antisenses (12AS,13As,14AS) compared with the normal colon tissue were observed (P = 0.0003,P = 0.042,P = 0.026, respectively). Moreover,a significant decrease in expression of the corresponding sense iFGF genes was detected (P < 0.0001).Plotted receiver operating characteristic (ROC) curves for iFGF components' expression showed an area of over 0.70 (FGF11-13: 0.71% and FGF12-14: 0.78%, P < 0.001) for sense mRNA expression, with the highest sensitivity for FGF12 (92.8%) and lowest for FGF11 (61.41%).The artificial intelligence (AI) revealed the valproic acid as a repurposing drug to relief the down regulation of FGF12 and 13 in CRC patients. CONCLUSION: Intracrine FGFs panel was down regulated versus up regulation of dependent antisenses. Thus, developing novel biomarkers based on iFGF can be considered as a promising strategy for CRC screening.In advanced, valporic acid detected by AI as a repurposing drug which may be applied in clinical trials for CRC treatment.
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Nanopartículas , Neoplasias , Humanos , Inteligência Artificial , Reposicionamento de Medicamentos , Algoritmos , Biomarcadores , Nanopartículas/uso terapêutico , Fatores de Crescimento de Fibroblastos/genéticaRESUMO
To discover vulnerabilities associated with dermokine (DMKN) as a new trigger of the epithelial-mesenchymal transition (EMT) -driven melanoma, we undertook a genome-wide genetic screening using transgenic. Here, we showed that DMKN expression could be constitutively increased in human malignant melanoma (MM) and that this correlates with poor overall survival in melanoma patients, especially in BRAF-mutated MM samples. Furthermore, in vitro, knockdown of DMKN inhibited the cell proliferation, migration, invasion, and apoptosis of MM cancer cells by the activation of ERK/MAPK signaling pathways and regulator of STAT3 in downstream molecular. By interrogating the in vitro melanoma dataset and characterization of advanced melanoma samples, we found that DMKN downregulated the EMT-like transcriptional program by disrupting EMT cortical actin, increasing the expression of epithelial markers, and decreasing the expression of mesenchymal markers. In addition, whole exome sequencing was presented with p.E69D and p.V91A DMKN mutations as a novel somatic loss of function mutations in those patients. Moreover, our purposeful proof-of-principle modeled the interaction of ERK with p.E69D and p.V91A DMKN mutations in the ERK-MAPK kinas signaling that may be naturally associated with triggering the EMT during melanomagenesis. Altogether, these findings provide preclinical evidence for the role of DMKN in shaping the EMT-like melanoma phenotype and introduced DMKN as a new exceptional responder for personalized MM therapy.
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Melanoma , Neoplasias Cutâneas , Humanos , Transição Epitelial-Mesenquimal/genética , Melanoma/genética , Mutação , Neoplasias Cutâneas/genética , Melanoma Maligno CutâneoRESUMO
INTRODUCTION: Oral squamous cell carcinoma (OSCC) is the most common cancers arising from the head and neck region. There is growing evidence that lncRNAs play an important role in OSCC progression. The study aims to investigate correlations between the expression levels of LncRNAs of PARROT, MYCNUT, DANCR, and KTN1-AS1 with clinicopathological characteristics and finding suitable biomarkers for OSCC. MATERIAL AND METHOD: Total lncRNAs related to cancers and HNSC trascriptomics data were downloaded from lncRNADisease v2.0 database and xenabrowser, respectively. Then, ACO was perfomed on shared of LncRNAs between two databases. Finally, some lncRNAs were proposed as potential biomarkers. Thirty biopsies samples from patients with the OSCC and 30 healthy subjects were collected by the surgery. Questionnaires including clinical and demographic data were filled for all cases. Using Real-time PCR, the expression levels of PARROT, MYCNUT, DANCR, and KTN1-AS1 lncRNAs were quantified. RESULT: According to the results,17 novel gene symbol was identified.All the candidate lncRNAs the expression levels of PARROT, MYCNUT, DANCR, and KTN1-AS1 were remarkably upregulated in OSCC tumors in comparison with control group (RQ: 10.00 (P < 0.0001), RQ: 2.920 (P < 0.0001), RQ: 1.623 (P = 0.002), and 4.467 (P < 0.0001), respectively). Also, we found significant associations between tumor lncRNAs expression of PARRPT and DANCER and tumor metastasis (P = 0.009, and P = 0.005, respectively). Additionally, lncRNA KTN1-AS1 expression level was significantly higher in the patients with tumor size more than 3 cm, in comparison with tumor less than 3 cm (P = 0.005). According ROC analysis, all these candidate lncRNAs can be a significant predictor for OSCC (AUC of PARROT lncRNA = 69.72%, AUC of MYCNUT = 98.22%, AUC of DANCR = 74.83%, and AUC of KTN1-AS1 = 99.22%). CONCLUSION: we found that overexpression levels of PARROT, MYCNUT, DANCR, and KTN1-AS1 lncRNAs were correlated with poor clinicopathological characteristics in patients with OSCC. Also, PARROT, MYCNUT, DANCR, and KTN1-AS1 are novel biomarker for the detection of OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , RNA Longo não Codificante , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Proteínas de Membrana/genéticaRESUMO
Vasculogenic mimicry (VM) describes a new tumor microvascular paradigm of non-endothelial cells, where aggressive cancer cells independent of angiogenesis acquire the ability to fluid-conducting vessels. VM shows worse 5-year overall survival in cancer that suggesting that VM could be a promising surgical and effective adjuvant therapy strategy in prognostics of metastatic cancer patients. The current chapter is a comprehensive review on "Main Staining Methods and Protocols in Vasculogenic Mimicry." Here, we provide most up-to-date and detailed information upon microscopy and histology protocols for the identification and understanding of VM process in both in vitro and in vivo.
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Neovascularização Patológica , Humanos , Neovascularização Patológica/patologia , Coloração e RotulagemRESUMO
Lung cancer is the most common cancer in men and women. This cancer is divided into two main types, namely non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Around 85 to 90 percent of lung cancers are NSCLC. Repositioning potent candidate drugs in NSCLC treatment is one of the important topics in cancer studies. Drug repositioning (DR) or drug repurposing is a method for identifying new therapeutic uses of existing drugs. The current study applies a computational drug repositioning method to identify candidate drugs to treat NSCLC patients. To this end, at first, the transcriptomics profile of NSCLC and healthy (control) samples was obtained from the GEO database with the accession number GSE21933. Then, the gene co-expression network was reconstructed for NSCLC samples using the WGCNA, and two significant purple and magenta gene modules were extracted. Next, a list of transcription factor genes that regulate purple and magenta modules' genes was extracted from the TRRUST V2.0 online database, and the TF-TG (transcription factors-target genes) network was drawn. Afterward, a list of drugs targeting TF-TG genes was obtained from the DGIdb V4.0 database, and two drug-gene interaction networks, including drug-TG and drug-TF, were drawn. After analyzing gene co-expression TF-TG, and drug-gene interaction networks, 16 drugs were selected as potent candidates for NSCLC treatment. Out of 16 selected drugs, nine drugs, namely Methotrexate, Olanzapine, Haloperidol, Fluorouracil, Nifedipine, Paclitaxel, Verapamil, Dexamethasone, and Docetaxel, were chosen from the drug-TG sub-network. In addition, nine drugs, including Cisplatin, Daunorubicin, Dexamethasone, Methotrexate, Hydrocortisone, Doxorubicin, Azacitidine, Vorinostat, and Doxorubicin Hydrochloride, were selected from the drug-TF sub-network. Methotrexate and Dexamethasone are common in drug-TG and drug-TF sub-networks. In conclusion, this study proposed 16 drugs as potent candidates for NSCLC treatment through analyzing gene co-expression, TF-TG, and drug-gene interaction networks.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Dexametasona , Doxorrubicina , Reposicionamento de Medicamentos , Feminino , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Metotrexato , Corantes de RosanilinaRESUMO
BACKGROUND: Vascular endothelial growth factor (VEGF) is a critical regulator of malignant pleural effusion (MPE) in non-small-cell lung cancer (NSCLC). Bevacizumab (BEV) and apatinib (APA) are novel VEGF blockers that inhibit lung cancer cell proliferation and the development of pleural effusion. METHODS: In this study, we established Lewis lung cancer (LLC) xenograft mouse models to compare the therapeutic effect of APA and BEV in combination with cisplatin (CDDP) against MPE. The anti-tumour and anti-angiogenic effects of this combination therapy were evaluated by 18F-FDG PET/CT imaging, TUNEL assay and Immunohistochemistry. RESULTS: The triple drug combination significantly prolonged the overall survival of the tumour-bearing mice by reducing MPE and glucose metabolism and was more effective in lowering VEGF/soluble VEGFR-2 levels in the serum and pleural exudates compared to either of the monotherapies. Furthermore, CDDP + APA + BEV promoted in vivo apoptosis and decreased microvessel density. CONCLUSIONS: Mechanistically, LLC-induced MPE was inhibited by targeting the VEGF-MEK/ERK pathways. Further studies are needed to establish the synergistic therapeutic effect of these drugs in NSCLC patients with MPE.KEY MESSAGESCombined treatment of MPE with apatinib, bevacizumab and cisplatin can prolong the survival time of mice, reduce the content of MPE, decrease the SUVmax of thoracic tumour tissue, down-regulate the content of VEGF and sVEGFR-2 in serum and pleural fluid, and promote the apoptosis of tumour cells. Angiogenesis and MPE formation can be inhibited by down-regulation of HIF-1α, VEGF, VEGFR-2, MEK1 and MMP-2 molecular signalling pathway proteins.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Derrame Pleural Maligno , Animais , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Derrame Pleural Maligno/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/uso terapêuticoRESUMO
BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies in the world and has a high mortality rate. It is believed that dysfunction in the expression of mucins and aberrant expression of some lncRNAs are associated with the occurrence and development of CRC. Therefore, the aim of the present study was to investigate the expression of MUC15, MUC16, MUC20, PCAT1, CCAT1 and HOTAIR genes in colorectal cancer and its relationship with clinicopathological variables. MATERIALS AND METHODS: This research was prospective case-control study. Tumors from CRC patients were collected from the Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. RNA extraction and cDNA synthesis were performed using the corresponding kits. The gene primer was designed and RT-PCR was used to evaluate gene expression. The t-test and ANOVA were employed to examine the differences between groups. Data analysis was performed using Prism8 software. RESULTS: The results of the present study showed that the expression of MUC15 (P = 0.0012), MUC20 (P = 0.009) and CCAT1 (P = 0.001) genes in patients with colorectal cancer were significantly different from tumor margin samples. There were also associations between the expression of the studied genes and clinicopathological variables such as grade and stage of colorectal cancer tumor as well as the age of the patients. The area under the curves (AUC) for the MUC15 0.953 (95% CI 7565-0.9897, P = 0.0003), MUC20 0.782 (95% CI 0.6163-0.9482, P = 0.008) and CCAT1 0.917 (95% CI 0.8015-1, P = 0.0003) were calculated by ROC analysis. CONCLUSION: The current experiment revealed changes in expression level of mucin genes and lncRNAs in CRC and its different stages, showing that they can be considered as biomarkers for diagnosis of this cancer.
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Neoplasias Colorretais , RNA Longo não Codificante , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Humanos , Irã (Geográfico) , Mucinas/genética , Mucinas/metabolismo , RNA Longo não Codificante/genéticaRESUMO
This study aimed to identify a novel disease-associated differentially co-expressed mRNA-microRNA (miRNA) that is associated with vasculogenic mimicry (VM) and epithelial-to-mesenchymal transition (EMT) network at different stages of melanoma. By applying weighted gene co-expression network analysis, we constructed a VM+EMT biological network with the available microarray dataset downloaded from a public database. Quantitative real-time PCR, immunohistochemical staining, and CD31-periodic acid solution dual staining were performed to confirm the expression of genes associated with EMT and VM formation in subjects with malignant melanoma (n = 18) and primary melanoma (n = 13) and in healthy subjects (n = 10). Our findings suggested that phosphatidylserine-specific phospholipase A1-alpha (PLA1A) and dermokine (DMKN) genes function as oncogenes that trigger VM and EMT processes during melanomagenesis on interaction with miR-370, miR-563, and miR-770-5p. PLA1A and DMKN genes can be considered potential VM+EMT network-based diagnostic biomarkers for distinguishing between melanoma patients. We postulate that a network with altered PLA1A/miR-563 and DMNK/miR-770-5p/miR-370 may contribute to melanomagenesis by triggering the EMT signaling pathway and VM formation. This study provides a potentially valuable approach for the early diagnosis and prognosis of melanoma progression.
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In this study, we perform a meta-analysis and meta-regression analysis for the article entitled "Prognostic value of systemic hemato-immunological indices in uterine cervical cancer: A systemic review, meta-analysis, and meta-regression of observational studies." [1] We implemented quantitative meta-analyses and time series meta-regression analysis to determine whether systemic hemato-immunological indices, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), thrombocyte-to-lymphocyte ratio (TLR), and C-reactive protein/albumin ratio (CAR) are associated with an increased risk of cervical collision cancer. In all, 9558 patients from 22 studies were included after a systematic data search, performed comprehensively using the following databases: MEDLINE, Web of Science, Embase, and Cochrane. The meta-analysis was conducted with a random-effects model using the Review Manager software (Revman version 5.3). The overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) data were compared among each observational study. All data are expressed as hazard ratios (HRs) and 95% confidence intervals (CIs), and were calculated using the generic inverse of variance method. Statistical heterogeneity was quantified using Cochrane's Q statistic and Higgins I2 statistic. Subgroup analysis was performed to investigate the sources of heterogeneity. Furthermore, quality assessment of the included datasets was presented according to the Newcastle-Ottawa Scale method. Additionally, sensitivity analysis was conducted to explore the sources of heterogeneity and analyze whether the results were stable and reliable. Meta-analysis random-effect approach was used for the regression to evaluate the effect of age, presence of squamous cell carcinoma patients, and number of evaluated NLR and PLR parameters on patient survival.
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BRAF and NRAS are the most reported mutations associated to melanomagenesis. The lack of accurate diagnostic markers in response to therapeutic treatment in BRAF/NRAS-driven melanomagenesis is one of the main challenges in melanoma personalized therapy. In order to assess the diagnostic value of phosphatidylserine-specific phospholipase A1-alpha (PLA1A), a potent lysophospholipid mediating the production of lysophosphatidylserine, PLA1A mRNA and serum levels were compared in subjects with malignant melanoma (n = 18), primary melanoma (n = 13), and healthy subjects (n = 10). Additionally, the correlation between histopathological subtypes of BRAF/NRAS-mutated melanoma and PLA1A was analyzed. PLA1A expression was significantly increased during melanogenesis and positively correlated to disease severity and histopathological markers of metastatic melanoma. PLA1A mRNA and serum levels were significantly higher in patients with BRAF-mutated melanoma compared to the patients with NRAS-mutated melanoma. Notably, PLA1A can be used as a diagnostic marker for an efficient discrimination between naïve melanoma samples and advanced melanoma samples (sensitivity 91%, specificity 57%, and AUC 0.99), as well as BRAF-mutated melanoma samples (sensitivity 62%, specificity 61%, and AUC 0.75). Our findings suggest that PLA1A can be considered as a potential diagnostic marker for advanced and BRAF-mutated melanoma.
Assuntos
Biomarcadores Tumorais/biossíntese , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Melanoma , Fosfolipases A1/biossíntese , Proteínas Proto-Oncogênicas B-raf/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/enzimologia , Melanoma/genética , Pessoa de Meia-Idade , Fosfolipases A1/genética , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
OBJECTIVE: To estimate the prognostic efficacy of several systemic hemato-immunological indices for the treatment of cervical cancer as well as to determine whether the systemic hemato-immunological indices are associated with an increased risk of cervical collision cancer. METHODS: A systematic search was conducted to identify studies that evaluated the prognostic impact of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), thrombocyte-to-lymphocyte ratio (TLR), C-reactive protein/albumin ratio (CAR), and systemic immune-inflammation index (SII) in cervical cancer patients. The endpoints were overall survival (OS) or progression-free survival (PFS) and clinicopathologic parameters. A meta-analysis using random-effect models was performed to calculate hazard ratios (HRs) or odds ratios with 95% confidence intervals. RESULTS: Twenty-two retrospective cohort studies involving 9558 patients were included. Our results show that high NLR, PLR, TLR, and CAR indicated poor prognosis for patients with cervical cancer (HRs = 2.46, 1.88, 3.70, and 3.94, respectively; all P ≤ 0.001). Subgroup analysis suggested that the highest NLR and PLR were more precise biomarkers in patients who were diagnosed with FIGO stage I-III cervical cancer after treatment with chemo-radiotherapy. High TLR and high LMR displayed significant prognostic value in late-FIGO stage III-IV cervical cancer (HRs = 4.33 and 2.032, respectively). Additionally, CAR was associated with poor survival in patients with advanced-FIGO stage cervical cancer and larger tumor size. According to the difference of NLR, the younger (43-51 years old) cervical cancer patients had a tendency of increased collision risk. However, cervical cancer patients in the 52-61 years age group were more vulnerable than their respective counterparts using the pooled estimate for PLR. CONCLUSION: Our findings support a prognostic role for elevated CAR and TLR besides that of NLR and PLR in advanced-FIGO stage cervical cancer.
Assuntos
Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/imunologia , Plaquetas/imunologia , Plaquetas/patologia , Estudos de Coortes , Feminino , Humanos , Linfócitos/imunologia , Linfócitos/patologia , Monócitos/imunologia , Monócitos/patologia , Estudos Observacionais como Assunto , Prognóstico , Análise de Regressão , Estudos RetrospectivosRESUMO
The genomewide copy number analysis of circulating tumor cells (CTCs) provides a promising prognostic biomarker for survival in breast cancer liver metastasis (BCLM) patients. The present study aimed to confirm the prognostic value of the presence of CTCs in BCLM patients. We previously developed an assay for the genomewide pattern differences in copy number variations (CNVs) as an adjunct test for the routine imaging and histopathologic diagnosis methods to distinguish newly diagnosed liver metastases and recurrent liver metastases. Fortythree breast cancer patients were selected for this study in which 23 newly diagnosed and 20 recurrent liver metastases were diagnosed by histopathology and 18FFDG PET/CT imaging. CTCs were counted from all patients using the CellSearch system and were confirmed by cytomorphology and threecolor immunocytochemistry. Genomic DNA of single CTCs was amplified using multiple annealing and looping based amplification cycles (MALBAC). Then, we compared the CTC numbers of newly diagnosed and recurrent BCLM patients using Illumina platforms. A high CTC frequency (>15 CTCs/7.5 ml blood) was found to be correlated with disease severity and metastatic progression, which suggests the value for CTCs in the diagnosis of BCLM in comparison with pathohistology and PET/CT imaging (P>0.05). Moreover, CTCs isolated from BCLM patients remained an independent prognostic detection factor associated with overall survival (P=0.0041). Comparison between newly diagnosed and recurrent liver metastases revealed different frequencies of CNVs (P>0.05). Notably, the CNV pattern of isolated CTCs of recurrent BCLM patients was similar to recurrent liver metastases (nearly 82% of the gain/loss regions). Functional enrichment analysis identified 25 genes as a CNV signature of BCLM. Among them, were defensin and ßdefensin genes, which are significantly associated with antiangiogenesis and immunomodulation signaling pathways. High CTC frequencies are effective in the evaluation and differentiation between newly diagnosed liver metastases from recurrent liver metastases. Future clinical studies will be necessary to fully determine the prognostic potential of CTC cluster signatures in patients with BCLM.