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1.
Int J Mol Sci ; 22(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064637

RESUMO

(1) Background: Glioblastoma multiforme (GBM) is among the most aggressive cancers with a poor prognosis. Treatment options are limited, clinicians lack efficient prognostic and predictive markers. Circulating miRNAs-besides being important regulators of cancer development-may have potential as diagnostic biomarkers of GBM. (2) Methods: In this study, profiling of 798 human miRNAs was performed on blood plasma samples from 6 healthy individuals and 6 patients with GBM, using a NanoString nCounter Analysis System. To validate our results, five miRNAs (hsa-miR-433-3p, hsa-miR-362-3p, hsa-miR-195-5p, hsa-miR-133a-3p, and hsa-miR-29a-3p) were randomly chosen for RT-qPCR detection. (3) Results: In all, 53 miRNAs were significantly differentially expressed in plasma samples of GBM patients when data were filtered for FC 1 and FDR 0.1. Target genes of the top 39 differentially expressed miRNAs were identified, and we carried out functional annotation and pathway enrichment analysis of target genes via GO and KEGG-based tools. General and cortex-specific protein-protein interaction networks were constructed from the target genes of top miRNAs to assess their functional connections. (4) Conclusions: We demonstrated that plasma microRNA profiles are promising diagnostic and prognostic molecular biomarkers that may find an actual application in the clinical practice of GBM, although more studies are needed to validate our results.


Assuntos
Biomarcadores Tumorais/genética , MicroRNA Circulante/genética , Redes Reguladoras de Genes , Glioblastoma/genética , Glioblastoma/patologia , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , MicroRNA Circulante/metabolismo , Biologia Computacional , Perfilação da Expressão Gênica , Glioblastoma/sangue , Humanos , Prognóstico , Mapas de Interação de Proteínas
2.
Int J Mol Sci ; 22(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064635

RESUMO

Ovarian cancer is a fatal gynecological malignancy. Although first-line chemotherapy and surgical operation are effective treatments for ovarian cancer, its clinical management remains a challenge owing to intrinsic or acquired drug resistance and relapse at local or distal lesions. Cancer stem cells (CSCs) are a small subpopulation of cells inside tumor tissues, and they can self-renew and differentiate. CSCs are responsible for the cancer malignancy involved in relapses as well as resistance to chemotherapy and radiation. These malignant properties of CSCs are regulated by cell surface receptors and intracellular pluripotency-associated factors triggered by internal or external stimuli from the tumor microenvironment. The malignancy of CSCs can be attenuated by individual or combined restraining of cell surface receptors and intracellular pluripotency-associated factors. Therefore, targeted therapy against CSCs is a feasible therapeutic tool against ovarian cancer. In this paper, we review the prominent roles of cell surface receptors and intracellular pluripotency-associated factors in mediating the stemness and malignancy of ovarian CSCs.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Animais , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Microambiente Tumoral
3.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068040

RESUMO

The epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 (ELTD1), is a member of the G-protein coupled receptors (GPCRs) superfamily. Although discovered in 2001, ELTD1 has been investigated only by a few research groups, and important data about its role in normal and tumor cells is still missing. Even though its functions and structure are not yet fully understood, recent studies show that ELTD1 has a role in both physiological and pathological angiogenesis, and it appears to be a very important biomarker and a molecular target in cancer diseases. Upregulation of ELTD1 in malignant cells has been reported, and correlated with poor cancer prognosis. This review article aims to compile the existing data and to discuss the current knowledge on ELTD1 structure and signaling, and its role in physiological and neoplastic conditions.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias/patologia , Receptores Acoplados a Proteínas G/metabolismo , Humanos , Neoplasias/metabolismo , Transdução de Sinais
4.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068078

RESUMO

Anthracyclines remain a cornerstone of induction chemotherapy for acute myeloid leukemia (AML). Refractory or relapsed disease due to chemotherapy resistance is a major obstacle in AML management. MicroRNAs (miRNAs) have been observed to be involved in chemoresistance. We previously observed that miR-15a-5p was overexpressed in a subgroup of chemoresistant cytogenetically normal AML patients compared with chemosensitive patients treated with daunorubicin and cytarabine. MiR-15a-5p overexpression in AML cells reduced apoptosis induced by both drugs in vitro. This study aimed to elucidate the mechanisms by which miR-15a-5p contributes to daunorubicin resistance. We showed that daunorubicin induced autophagy in myeloid cell lines. The inhibition of autophagy reduced cell sensitivity to daunorubicin. The overexpression of miR-15a-5p decreased daunorubicin-induced autophagy. Conversely, the downregulation of miR-15a-5p increased daunorubicin-induced autophagy. We found that miR-15a-5p targeted four genes involved in autophagy, namely ATG9a, ATG14, GABARAPL1 and SMPD1. Daunorubicin increased the expression of these four genes, and miR-15a-5p counteracted this regulation. Inhibition experiments with the four target genes showed the functional effect of miR-15a-5p on autophagy. In summary, our results indicated that miR-15a-5p induces chemoresistance in AML cells through the abrogation of daunorubicin-induced autophagy, suggesting that miR-15a-5p could be a promising therapeutic target for chemoresistant AML patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Daunorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/tratamento farmacológico , MicroRNAs/genética , Adulto , Antibióticos Antineoplásicos/farmacologia , Apoptose , Autofagia , Biomarcadores Tumorais/genética , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células Tumorais Cultivadas
5.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068110

RESUMO

The aim of the study was to investigate the anticancer potential of LY294002 (PI3K inhibitor) and temozolomide using glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cells. Apoptosis, autophagy, necrosis, and granules in the cytoplasm were identified microscopically (fluorescence and electron microscopes). The mitochondrial membrane potential was studied by flow cytometry. The activity of caspases 3, 8, and 9 and Akt was evaluated fluorometrically, while the expression of Beclin 1, PI3K, Akt, mTOR, caspase 12, and Hsp27 was determined by immunoblotting. SiRNA was used to block Hsp27 and PI3K expression. Cell migration and localization of Hsp27 were tested with the wound healing assay and immunocytochemistry, respectively. LY294002 effectively diminished the migratory potential and increased programmed death of T98G and MOGGCCM. Autophagy was dominant in MOGGCCM, while apoptosis was dominant in T98G. LY294002 with temozolomide did not potentiate cell death but redirected autophagy toward apoptosis, which was correlated with ER stress. A similar effect was observed after blocking PI3K expression with siRNA. Transfection with Hsp27 siRNA significantly increased apoptosis related to ER stress. Our results indicate that inhibition of the PI3K/Akt/mTOR pathway sensitizes glioma cells to apoptosis upon temozolomide treatment, which was correlated with ER stress. Hsp27 increases the resistance of glioma cells to cell death upon temozolomide treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Cromonas/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Temozolomida/farmacologia , Antineoplásicos Alquilantes/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Potencial da Membrana Mitocondrial , Necrose , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/genética , Células Tumorais Cultivadas
6.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068442

RESUMO

Advanced glycation end products (AGEs) are produced in response to a high-glucose environment and oxidative stress and exacerbate various diseases. Nε-(Carboxymethyl)lysine (CML) is an AGE that is produced by the glycation of lysine residues of proteins. There are a few reports on alterations in protein function due to CML modification; however, its association with cancer is not clear. We investigated the significance of CML modification in high mobility group box protein-1 (HMGB1), a cytokine that is significantly associated with cancer progression. Treatment of the gastric cancer cell lines TMK1 and MKN74 with glyoxal or glucose resulted in increased CML modification compared to untreated cells. CML-HMGB1 was modified via oxidation and more pronouncedly activated the receptor for AGE and downstream AKT and NF-κB compared to naïve HMGB1 and oxidized HMGB1. CML-HMGB1 bound with reduced affinity to DNA and histone H3, resulting in enhanced extranuclear translocation and extracellular secretion. Treatment of gastric cancer cells with CML-HMGB1 enhanced cell proliferation and invasion, sphere formation, and protection from thapsigargin-induced apoptosis, and decreased 5-FU sensitivity in comparison to HMGB1. Further, CML-HMGB1 was detected at various levels in all the 10 gastric cancer tumor specimens. HMGB1 levels correlated with primary tumor progression and distant metastasis, whereas CML-HMGB1 levels were associated with primary tumor progression, lymph node metastasis, distant metastasis, and stage. In addition, CML-HMGB1 levels correlated with oxidative stress in cancer tissues and resistance to neoadjuvant therapy. Therefore, CML modification of HMGB1 enhanced the cancer-promoting effect of HMGB1. In this study, CML-HMGB1 has been highlighted as a new therapeutic target, and analysis of the molecular structure of CML-HMGB1 is desired in the future.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Produtos Finais de Glicação Avançada/metabolismo , Proteína HMGB1/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Neoplasias Gástricas/patologia , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Glicosilação , Proteína HMGB1/genética , Humanos , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas
7.
World J Gastroenterol ; 27(21): 2871-2894, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34135559

RESUMO

BACKGROUND: Alternative splicing (AS) increases the diversity of mRNA during transcription; it might play a role in alteration of the immune microenvironment, which could influence the development of immunotherapeutic strategies against cancer. AIM: To obtain the transcriptomic and clinical features and AS events in stomach adenocarcinoma (STAD) from the database. The overall survival data associated with AS events were used to construct a signature prognostic model for STAD. METHODS: Differentially expressed immune-related genes were identified between subtypes on the basis of the prognostic model. In STAD, 2042 overall-survival-related AS events were significantly enriched in various pathways and influenced several cellular functions. Furthermore, the network of splicing factors and overall-survival-associated AS events indicated potential regulatory mechanisms underlying the AS events in STAD. RESULTS: An eleven-AS-signature prognostic model (CD44|14986|ES, PPHLN1|21214|AT, RASSF4|11351|ES, KIAA1147|82046|AP, PPP2R5D|76200|ES, LOH12CR1|20507|ES, CDKN3|27569|AP, UBA52|48486|AD, CADPS|65499|AT, SRSF7| 53276|RI, and WEE1|14328|AP) was constructed and significantly related to STAD overall survival, immune cells, and cancer-related pathways. The differentially expressed immune-related genes between the high- and low-risk score groups were significantly enriched in cancer-related pathways. CONCLUSION: This study provided an AS-related prognostic model, potential mechanisms for AS, and alterations in the immune microenvironment (immune cells, genes, and pathways) for future research in STAD.


Assuntos
Adenocarcinoma , Processamento Alternativo , Adenocarcinoma/genética , Antígenos de Neoplasias , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Nucleares , Proteína Fosfatase 2 , Estômago , Microambiente Tumoral
8.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070107

RESUMO

T cell acute lymphoblastic leukemia (T-ALL) is a biologically and genetically heterogeneous disease with a poor prognosis overall and several subtypes. The neoplastic transformation takes place through the accumulation of numerous genetic and epigenetic abnormalities. There are only a few prognostic factors in comparison to B cell precursor acute lymphoblastic leukemia, which is characterized by a lower variability and more homogeneous course. The microarray and next-generation sequencing (NGS) technologies exploring the coding and non-coding part of the genome allow us to reveal the complexity of the genomic and transcriptomic background of T-ALL. miRNAs are a class of non-coding RNAs that are involved in the regulation of cellular functions: cell proliferations, apoptosis, migrations, and many other processes. No miRNA has become a significant prognostic and diagnostic factor in T-ALL to date; therefore, this topic of investigation is extremely important, and T-ALL is the subject of intensive research among scientists. The altered expression of many genes in T-ALL might also be caused by wide miRNA dysregulation. The following review focuses on summarizing and characterizing the microRNAs of pediatric patients with T-ALL diagnosis and their potential future use as predictive factors.


Assuntos
Biomarcadores Tumorais/genética , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Biomarcadores Tumorais/classificação , Biomarcadores Tumorais/metabolismo , Criança , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Humanos , MicroRNAs/classificação , MicroRNAs/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Prognóstico , Falha de Tratamento
9.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070203

RESUMO

Alternative transcript cleavage and polyadenylation is linked to cancer cell transformation, proliferation and outcome. This has led researchers to develop methods to detect and bioinformatically analyse alternative polyadenylation as potential cancer biomarkers. If incorporated into standard prognostic measures such as gene expression and clinical parameters, these could advance cancer prognostic testing and possibly guide therapy. In this review, we focus on the existing methodologies, both experimental and computational, that have been applied to support the use of alternative polyadenylation as cancer biomarkers.


Assuntos
Regiões 3' não Traduzidas , Biomarcadores Tumorais/genética , Processamento Alternativo , Biomarcadores Tumorais/metabolismo , Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/metabolismo , Poliadenilação , Sítios de Splice de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA-Seq , Análise de Célula Única
10.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070214

RESUMO

During tubo-ovarian high-grade serous carcinoma (HGSC) progression, tumoral cells undergo phenotypic changes in their epithelial marker profiles, which are essential for dissemination processes. Here, we set out to determine whether standard epithelial markers can predict HGSC patient prognosis. Levels of E-CADH, KRT7, KRT18, KRT19 were quantified in 18 HGSC cell lines by Western blot and in a Discovery cohort tissue microarray (TMA) (n = 101 patients) using immunofluorescence. E-CADH and KRT7 levels were subsequently analyzed in the TMA of the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158 patients) and in public datasets. Epithelial marker expression was highly variable in HGSC cell lines and tissues. In the Discovery cohort, high levels of KRT7 and KRT19 were associated with an unfavorable prognosis, whereas high E-CADH expression indicated a better outcome. Expression of KRT7 and E-CADH gave a robust combination to predict overall survival (OS, p = 0.004) and progression free survival (PFS, p = 5.5 × 10-4) by Kaplan-Meier analysis. In the COEUR cohort, the E-CADH-KRT7 signature was a strong independent prognostic biomarker (OS, HR = 1.6, p = 2.9 × 10-4; PFS, HR = 1.3, p = 0.008) and predicted a poor patient response to chemotherapy (p = 1.3 × 10-4). Our results identify a combination of two epithelial markers as highly significant indicators of HGSC patient prognosis and treatment response.


Assuntos
Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Neoplasias das Tubas Uterinas/metabolismo , Queratina-7/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Cistadenocarcinoma Seroso/mortalidade , Neoplasias das Tubas Uterinas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Queratina-19/metabolismo , Neoplasias Pulmonares/metabolismo , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Prognóstico , Intervalo Livre de Progressão , Neoplasias Gástricas/metabolismo , Vimentina/metabolismo
11.
Medicine (Baltimore) ; 100(22): e26194, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087888

RESUMO

BACKGROUND: Long noncoding RNAs (lncRNAs) can work as microRNA (miRNA) sponges through a competitive endogenous RNA (ceRNA) mechanism. LncRNAs and miRNAs are important components of competitive endogenous binding, and their expression imbalance in hepatocellular carcinoma (HCC) is closely related to tumor development, diagnosis, and prognosis. This study explored the potential impact of the ceRNA regulatory network in HCC on the prognosis of HCC patients. METHODS: We thoroughly researched the differential expression profiles of lncRNAs, miRNAs, and mRNAs from 2 HCC Gene Expression Omnibus datasets (GSE98269 and GSE60502). Then, a dysregulated ceRNA network was constructed by bioinformatics. In addition, hub genes in the ceRNA network were screened by Cytoscape, these hub genes functional analysis was performed by gene set enrichment analysis, and the expression of these hub genes in tumors and their correlation with patient prognosis were verified with Gene Expression Profiling Interactive Analysis. RESULTS: A ceRNA network was successfully constructed in this study including 4 differentially expressed (DE) lncRNAs, 7 DEmiRNAs, and 166 DEmRNAs. Importantly, 4 core genes (CCNA2, CHEK1, FOXM1, and MCM2) that were significantly associated with HCC prognosis were identified. CONCLUSIONS: Our study provides comprehensive and meaningful insights into HCC tumorigenesis and the underlying molecular mechanisms of ceRNA. Furthermore, the specific ceRNAs can be further used as potential therapeutic targets and prognostic biomarkers for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/genética , Adulto , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Carcinoma Hepatocelular/diagnóstico , Quinase 1 do Ponto de Checagem/genética , Ciclina A2/genética , Feminino , Proteína Forkhead Box M1/genética , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Componente 2 do Complexo de Manutenção de Minicromossomo/genética , Prognóstico , RNA Mensageiro/genética , Motivos de Ligação ao RNA/genética
12.
Hematol Oncol ; 39 Suppl 1: 39-45, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105815

RESUMO

The treatment of classical Hodgkin lymphoma in young patients is one of the success stories of modern medicine. The use of risk- and response-adapted approaches to guide treatment decisions has led to impressive cure rates while reducing the long-term toxicity associated with more intensive therapies. Tissue biomarkers have not yet proven more effective than clinical characteristics for risk stratification of patients at presentation, but functional imaging features such as metabolic tumor volume may be used to predict response, if early observations can be validated. The success of treatment in younger patients has unfortunately not been mirrored in those over 60, where complex decision-making is often required, with a paucity of data from clinical trials. The use of PD1 blocking antibodies and brentuximab vedotin in this cohort, either alone or in combination with chemotherapy, may provide attractive options. The incorporation of frailty assessment, quality-of-life outcomes, and specialist geriatric input is also important to ensure the best outcomes for this diverse group.


Assuntos
Biomarcadores Tumorais , Brentuximab Vedotin/uso terapêutico , Doença de Hodgkin , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Neoplasias , Medicina de Precisão , Receptor de Morte Celular Programada 1 , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo
13.
Molecules ; 26(10)2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065773

RESUMO

The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC50 values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells.


Assuntos
Antineoplásicos/síntese química , Compostos de Benzilideno/síntese química , Biomarcadores Tumorais/metabolismo , Neoplasias/metabolismo , Pirazóis/química , Pirimidinas/química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Biomarcadores Tumorais/química , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Concentração Inibidora 50 , Antígeno Ki-67/química , Antígeno Ki-67/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias/tratamento farmacológico
14.
Mol Biol Rep ; 48(4): 3541-3547, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33956301

RESUMO

Recent evidence reveals that miRNA sponges neutralize miRNAs activity by binding to miRNAs and sequester them from their relevant targets to regulate expression. The detailed mechanisms of sponge RNAs in colorectal cancer remain to be exactly determined. In this study DANCR, miR-145-5p, NRAS axis was evaluated and the diagnostic value of these targets was assessed in colorectal cancer patients. A case-control study was carried out on 40 samples of tumor tissues and 40 adjacent tissues. Total RNA was extracted, and then, the expression level of DANCR, miR-145-5p and NRAS was evaluated using qRT-PCR. In addition, the sensitivity and specificity of these markers were evaluated by receiver operating characteristic (ROC) curve analysis. Our results revealed that the expression level of DANCR was significantly upregulated in colorectal cancer tissues (p < 0.001). It was demonstrated that DANCR could regulate NRAS expression by sponging miR-145-5 in colorectal cancer patients. Furthermore, the mean expression of miR-145-5p (p < 0.001) and NRAS (p < 0.001) was significantly different between tumor and normal tissue. A significant correlation was observed between DANCR and miR-145-5p (p = 0.001), and also between miR-145-5p and NRAS (p < 0.001). Sensitivity and specificity value for DANCR, miR-145-5p and NRAS were (0.875 and 0.725), (0.875 and 0.745), and (0.877 and 0.694), respectively. According to the values of sensitivities and specificity of DANCR, miR-145-5p and NRAS, confirmed with ROC curve analysis, these biomarkers may be useful in the screening and differentiating between tumor and control sample in colorectal neoplasm.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/metabolismo , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , GTP Fosfo-Hidrolases/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , Regulação para Cima
15.
Gene ; 790: 145697, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-33964376

RESUMO

Human Mitoribosomal Small Subunit unit (MRPS) family of genes appears to have role in cancer. Gene expression analysis of select MRPS genes (n = 9) in 15 cancer cell lines showed altered expression in cancer cells. Protein levels of MRPS6, MRPS23 showed significant overexpression in breast cancer cells and tissues. Interestingly, their overexpression did not correlate with mitochondrial ribosome translated COX2 protein levels in breast cancer. Subcellular fractionation analysis showed a distinct presence of MRPS23 in the nuclear fraction. GST/MRP6 and GST/MRPS23 pulldown assays identified 32 novel protein-protein interactions (PPIs) and MRPS23-RIPK3 interaction was validated. Co-expression module identification tool (CEMi) analysis of breast cancer gene expression and MRPS6 and MRPS23 interactions revealed hub interactions in gene expression modules having functional roles in cancer-associated cellular processes. Based on PPI network analysis a novel interaction MRPS23-p53 was validated. Knockdown of MRPS6 and MRPS23 decreased proliferation, expression of select mesenchymal markers, oncogenes, and increased expression of tumor suppressor genes. Taken together present study has revealed that MRPS6 and MRPS23 genes have pro-tumorigenic functions in breast cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinogênese , Regulação Neoplásica da Expressão Gênica , Proteínas Mitocondriais/metabolismo , Ribossomos Mitocondriais/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Proteínas Mitocondriais/genética , Prognóstico , Células Tumorais Cultivadas
16.
Medicine (Baltimore) ; 100(21): e25993, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032716

RESUMO

ABSTRACT: Guanine nucleotide-binding protein-like-3-like (GNL3L) is required for processing ribosomal pre-rRNA and cell proliferation and is upregulated in many types of cancer. This study is aimed to investigate the clinical significance of GNL3L in esophageal cancer. The mRNA and protein expression levels of GNL3L were determined by using quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. GNL3L was localized in both cytoplasm and nucleus. The expression levels of GNL3L in esophageal cancer tissues were significantly higher than those in adjacent nonmalignant tissues. High GNL3L expression was associated with pathologic type and poor differentiation. Patients with high GNL3L expression had shorter overall survival (OS) than those with low GNL3L expression. Multivariate Cox regression analysis revealed that GNL3L expression was an independently predictive factor for the OS of patient with esophageal cancer. The Gene Expression Profiling Interactive Analysis (GEPIA) databases also showed that GNL3L was upregulated in esophageal cancer, which was closely associated with an unfavorable prognosis of patients with esophageal cancer. Taken together, our findings suggest that GNL3L is upregulated in esophageal cancer, which is linked to the progression of the disease. As a result, GNL3L could be used as a biomarker for esophageal cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/mortalidade , Proteínas de Ligação ao GTP/metabolismo , Proteínas Nucleares/metabolismo , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Núcleo Celular/patologia , Proliferação de Células , Quimioterapia Adjuvante/métodos , Citoplasma/patologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Esofagectomia , Esôfago/citologia , Esôfago/patologia , Esôfago/cirurgia , Feminino , Proteínas de Ligação ao GTP/análise , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/análise , Prognóstico , Regulação para Cima
17.
Medicine (Baltimore) ; 100(21): e26068, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032736

RESUMO

ABSTRACT: Some patients with advanced colon adenocarcinoma (COAD) are not sensitive to radiotherapy and chemotherapy, and as such, immunotherapy has become the most popular option for these patients. However, different patients respond differently to immunotherapy. Tumor mutational burden (TMB) has been used as a predictor of the response of advanced COAD patients to immunotherapy. A high TMB typically indicates that the patient's immune system will respond well to immunotherapy. In addition, while microRNAs (miRNA) have been shown to play an important role in treatment responses associated with the immune system, the relationship between miRNA expression levels and TMB has not been clarified in COAD.We downloaded miRNA data and mutational files of COAD from the Cancer Genome Atlas database. Differentially expressed miRNAs were screened in the training group, and miRNAs used to construct the model were further identified using the LASSO logistic regression method. After building the miRNA-based model, we explored the correlation between the model and TMB. The model was verified by a receiver operating characteristic curve, and the correlation between it and 3 widely used immune checkpoints (programmed death receptor-1, programmed death-ligand 1, and cytotoxic T-lymphocyte associated protein-4) was explored. Functional enrichment analysis of the selected miRNAs was performed, and these respective miRNA target genes were predicted using online tools.Our results showed that a total of 32 differentially expressed miRNAs were used in the construction of the model. The accuracies of the models of the 2 datasets (training and test sets) were 0.987 and 0.934, respectively. Correlation analysis showed that the correlation of the model with programmed death-ligand 1 and cytotoxic T-lymphocyte associated protein-4, as well as TMB, was high, but there was no correlation with programmed death receptor-1. The results of functional enrichment analysis indicated that these 32 miRNAs were involved in many immune-related biological processes and tumor-related pathways.Therefore, this study demonstrated that differentially expressed miRNAs can be used to predict the TMB level, which can help identify advanced COAD patients who will respond well to immunotherapy. The miRNA-based model may be used as a tool to predict the TMB level in patients with advanced COAD.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/genética , MicroRNAs/metabolismo , Modelos Genéticos , Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Logísticos , Masculino , MicroRNAs/análise , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Curva ROC , Tolerância a Radiação/genética
18.
Biomed Res Int ; 2021: 6650966, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33954190

RESUMO

New prevention strategies are needed to detect cervical intraepithelial neoplasia (CIN). The microRNA expression analysis has already been reported as molecular biomarkers in the early detection of cervical cancer (CC) through minimally invasive samples, such as liquid biopsy, obtained through collection using liquid-based cytology (LBC). In this study, we aimed to identify molecular signatures of microRNAs in cervical precursor lesions from LBC cervical and the molecular pathways potentially associated with the CC progression. We analyzed 31 LBC cervical samples from women who underwent colposcopy. These samples were divided into two groups: the first group was composed of samples without precursor lesions of CC, considering the control group, referred to as healthy female subjects (HFS; n = 11). The second group corresponded to women diagnosed with cervical interepithelial neoplasia grade 3 (CIN 3; n = 20). We performed microRNA and gene expression profiling using the nCounter® miRNA Expression Assays (NanoString Technology) and PanCancer Pathways (NanoString Technology), respectively. A microRNA target prediction was performed by mirDIP, and molecular pathway interaction was constructed using Cytoscape. Bidirectional in silico analyses and Pearson's correlation were performed for associated the relation between genes, and miRNAs differentially expressed related cervical cancer progression were performed. We found that the expression of nine microRNAs was significantly higher, two were downregulated (miR-381-3p and miR-4531), and seven miRNAs were upregulated (miR-205-5p, miR-130a-3p, miR-3136-3p, miR-128-2-5p, let-7f-5p, miR-202-3p, and miR-323a-5p) in CIN 3 (fold change ≥ 2 and p ≤ 0.05). The miRNA expression patterns were independent of hr-HPV infection. We identified four miRNAs (miR-205-5p, miR-130a-3p, miR-4531, and miR-381-3p) that could be used as biomarkers for CIN 3 in LBC samples through multiple logistic regression analyses. We found 16 genes differentially expressed between CIN 3 and HSF samples (fold change ≥ 2 and p ≤ 0.05). We found the correlation between miR-130a-3p and CCND1(R = -0.52; p = 0.0029), miR-205-5p and EGFR (R = 0.53; p = 0.0021), and miR-4531 and SMAD2 (R = -0.54; p = 0.0016). In addition, we demonstrated the most significant pathways of the targets associated with cervical cancer progression (FDR-corrected p < 0.001). This study demonstrated that miRNA biomarkers may distinguish healthy cervix and CIN 3 and regulate important molecular pathways of carcinogenesis.


Assuntos
Biomarcadores Tumorais/genética , Neoplasia Intraepitelial Cervical/genética , Neoplasia Intraepitelial Cervical/patologia , Colo do Útero/patologia , MicroRNAs/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais/metabolismo , Neoplasia Intraepitelial Cervical/virologia , Simulação por Computador , Regulação para Baixo/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Biópsia Líquida , Modelos Logísticos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Infecções por Papillomavirus/complicações , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Regulação para Cima/genética , Neoplasias do Colo do Útero/virologia , Adulto Jovem
19.
Nat Commun ; 12(1): 2474, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931648

RESUMO

As more clinically-relevant genomic features of myeloid malignancies are revealed, it has become clear that targeted clinical genetic testing is inadequate for risk stratification. Here, we develop and validate a clinical transcriptome-based assay for stratification of acute myeloid leukemia (AML). Comparison of ribonucleic acid sequencing (RNA-Seq) to whole genome and exome sequencing reveals that a standalone RNA-Seq assay offers the greatest diagnostic return, enabling identification of expressed gene fusions, single nucleotide and short insertion/deletion variants, and whole-transcriptome expression information. Expression data from 154 AML patients are used to develop a novel AML prognostic score, which is strongly associated with patient outcomes across 620 patients from three independent cohorts, and 42 patients from a prospective cohort. When combined with molecular risk guidelines, the risk score allows for the re-stratification of 22.1 to 25.3% of AML patients from three independent cohorts into correct risk groups. Within the adverse-risk subgroup, we identify a subset of patients characterized by dysregulated integrin signaling and RUNX1 or TP53 mutation. We show that these patients may benefit from therapy with inhibitors of focal adhesion kinase, encoded by PTK2, demonstrating additional utility of transcriptome-based testing for therapy selection in myeloid malignancy.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Estudos de Coortes , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Feminino , Fusão Gênica , Humanos , Mutação INDEL , Integrinas/genética , Integrinas/metabolismo , Leucemia Mieloide Aguda/genética , Masculino , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Prospectivos , RNA-Seq , Fatores de Risco , Transdução de Sinais/genética , Análise de Sobrevida , Transcriptoma , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
20.
Medicine (Baltimore) ; 100(18): e25545, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950928

RESUMO

BACKGROUND: Breast cancer is a common malignant tumor in women. In recent years, its incidence is increasing year by year, and its morbidity and mortality rank the first place among female malignant tumors. Some key enzymes and intermediates in glycolysis are closely related to tumor development. Pyruvate kinase M2 (PKM2) is an important rate-limiting enzyme in glycolysis pathway. Meanwhile, it is highly expressed in proliferative cells, especially in tumor cells, and plays an important role in the formation of Warburg effect and tumorigenesis. Previous studies have explored the effects of PKM2 expression on the prognosis and clinical significance of breast cancer patients, while the results are contradictory and uncertain. This study uses controversial data for meta-analysis to accurately evaluate the problem. We collected relevant Oncomine and The Cancer Genome Atlas (TCGA) data to further verify the results. Through bioinformatics analysis, the mechanism and related pathways of PKM2 in breast cancer are explored. METHODS: We searched Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, Embase, and Web of Science databases from inception to March 2021. The language restrictions are Chinese and English. The published literatures on PKM2 expression and prognosis or clinicopathological characteristics of breast cancer patients were statistically analyzed. Combined hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (95% CIs) were used to evaluate the effects of PKM2 on the prognosis and clinicopathological features of breast cancer. Stata 14.0 software was applied for meta-analysis. Oncomine and TCGA databases were used to meta-analyze the differences of PKM2 mRNA expression between breast cancer and normal breast tissues. The expression of PKM2 protein was verified by Human Protein Atlas (HPA) database. The relationship between the gene and the survival of breast cancer patients was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA). The relationship between PKM2 gene and clinicopathological characteristics was analyzed by using LinkedOmics, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis was performed by using Metascape. Protein-protein interaction (PPI) network was constructed by String website. RESULTS: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study provides high-quality medical evidence for the correlation between the expression of PKM2 and the prognosis and clinicopathological features of breast cancer. Through bioinformatics analysis, this study further deepens the understanding of the mechanism and related pathways of PKM2 in breast cancer. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also should not damage participants' rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/W52HB.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Mama/patologia , Carcinogênese/patologia , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Proteínas de Transporte/análise , Biologia Computacional , Intervalo Livre de Doença , Feminino , Humanos , Proteínas de Membrana/análise , Metanálise como Assunto , Prognóstico , Medição de Risco/métodos , Hormônios Tireóideos/análise , Efeito Warburg em Oncologia
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