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1.
Medicine (Baltimore) ; 100(35): e27162, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477172

RESUMO

ABSTRACT: Cancer-associated fibroblasts (CAFs) have been attracting attention in recent years, but their nature has not been fully elucidated. Although CAFs have been recognized as an important therapeutic target, therapeutic agents have not been developed to date. CAFs are characterized by their high migration rate and involvement in epithelial-to-mesenchymal transition with some displaying a dendritic morphology that is reminiscent of fascin expression.The present study was designed to immunohistochemically investigate fascin expression in lung adenocarcinoma including CAFs and compare the results with existing CAF markers.We immunohistochemically investigated fascin expression in not only cancer tissue but also CAFs from 26 autopsy cases of lung adenocarcinoma. Immunohistochemistry of α-smooth muscle actin and fibroblast activation protein was also performed.Fascin-positive staining in CAFs was observed in all cases, with a strong correlation observed with existing CAF markers α-smooth muscle actin and fibroblast activation protein (P < .001). In addition, the proportion of tumor cells showing fascin-positive staining was found to correlate with its expression in CAFs (P < .05).We propose that CAFs express fascin, and that fascin may mediate crosstalk between cancer tissue and CAFs. Fascin might be a novel therapeutic target for treatments that target the cancer stroma.


Assuntos
Adenocarcinoma/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas dos Microfilamentos/metabolismo , Actinas/metabolismo , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Endopeptidases/metabolismo , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade
2.
Medicine (Baltimore) ; 100(36): e27017, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516491

RESUMO

RATIONALE: Metastatic gastric cancer patients with poor eastern cooperative oncology group performance status (PS) (≥3) were lack of effective anti-tumor strategies. They always lived with poor PS, severe and multiple symptoms, and usually resulted in extremely limited survival time. Herein, we reported a patient diagnosed with gastric cancer metastasized to multiple bones, along with lymphangitis carcinomatosa in lungs, harboring Her-2 and c-MET amplification with poor PS, positively responded to combinational therapy with trastuzumab and crizotinib. PATIENT CONCERNS: The patient complained of persistent cough and fatigue for 2 months, otherwise, she denied smoking, alcohol history, or any other medical or family history. DIAGNOSIS: With the biopsy results from gastroscopy, as well as computer tomography for chest and abdomen, the patient was diagnosed as gastric adenocarcinoma, with metastasis on lungs, left adrenal gland, retroperitoneal lymph nodes, and multiple bones. INTERVENTIONS: Because of the poor PS (PS = 3), as well as Her-2 and c-MET amplification, the patient received combination treatment with trastuzumab and crizotinib as salvage strategy. OUTCOMES: After 2 months' exposure of trastuzumab and crizotinib, symptoms including persistent cough, and chest distress were alleviated significantly. Simultaneously, chest computer tomography showed significant dissipation of lymphangitis carcinomatosa, as well as apparent reduction of pleural effusion. No adverse reactions including nausea, vomiting, diarrhea, or hypertension was observed during the following 2 months. LESSONS: The present case suggested that combinational therapy with trastuzumab and crizotinib might be effective in metastatic gastric cancer patients harboring Her-2 and c-MET amplification, even with a poor PS. It was also implied that gene sequencing might be valuable, especially in patients with limited treatment strategies.


Assuntos
Adenocarcinoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica , Crizotinibe/administração & dosagem , Crizotinibe/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Trastuzumab/administração & dosagem , Trastuzumab/uso terapêutico
3.
Medicine (Baltimore) ; 100(32): e25909, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397867

RESUMO

ABSTRACT: Colorectal cancer is currently the third most common cancer around the world. In this study, we chose a bioinformatics analysis method based on network analysis to dig out the pathological mechanism and key prognostic targets of rectal adenocarcinoma (READ).In this study, we downloaded the clinical information data and transcriptome data from the Cancer Genome Atlas database. Differentially expressed genes analysis was used to identify the differential expressed genes in READ. Community discovery algorithm analysis and Correlation analysis between gene modules and clinical data were performed to mine the key modules related to tumor proliferation, metastasis, and invasion. Genetic significance (GS) analysis and PageRank algorithm analysis were applied for find key genes in the key module. Finally, the importance of these genes was confirmed by survival analysis.Transcriptome datasets of 165 cancer tissue samples and 9 paracancerous tissue samples were selected. Gene coexpression networks were constructed, multilevel algorithm was used to divide the gene coexpression network into 11 modules. From GO enrichment analysis, module 11 significantly associated with clinical characteristic N, T, and event, mainly involved in 2 types of biological processes which were highly related to tumor metastasis, invasion, and tumor microenvironment regulation: cell development and differentiation; the development of vascular and nervous systems. Based on the results of survival analysis, 7 key genes were found negatively correlated to the survival rate of READ, such as MMP14, SDC2, LAMC1, ELN, ACTA2, ZNF532, and CYBRD1.Our study found that these key genes were predicted playing an important role in tumor invasion and metastasis, and being associated with the prognosis of READ. This may provide some new potential therapeutic targets and thoughts for the prognosis of READ.


Assuntos
Adenocarcinoma/genética , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Retais/genética , Transcriptoma/genética , Adenocarcinoma/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Prognóstico , Neoplasias Retais/metabolismo
4.
Medicine (Baltimore) ; 100(31): e26439, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397793

RESUMO

ABSTRACT: This study aimed to investigate the expression and clinical significance of aurora B kinase (AURKB) gene in lung adenocarcinoma (LUAD) by collecting relevant data in Oncomine database.Firstly, mRNA expression level of AURKB in LUAD was systematically analyzed using the ONCOMINE and the cancer genome atlas databases. Then, the association between AURKB expression and clinical parameters was investigated by UALCAN. The Kaplan-Meier Plotter was used to assess the prognostic significance of AURKB.Pooled analysis showed that AURKB was frequently up-regulated expression in LUAD. In addition, immunohistochemistry showed that AURKB was highly expressed in lung adenocarcinoma tissues, while it was weakly expressed in normal tissues. Subsequently, AURKB expression was identified to be negatively associated with Overall survival (P < 1e-16), post-progression survival (P = .017), first progression (P = 9.8e-09).This study confirms that increased expression of AURKB in LUAD is associated with poor prognosis, suggesting that AURKB might be used as a promising prognostic biomarker and novel therapeutic target for LUAD.


Assuntos
Adenocarcinoma/genética , Aurora Quinase B/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Idoso , Aurora Quinase B/metabolismo , Biologia Computacional , Mineração de Dados , Bases de Dados Genéticas , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/metabolismo , Taxa de Sobrevida , Regulação para Cima
5.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360883

RESUMO

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.


Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Suplementos Nutricionais , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Valeratos/farmacologia , Adenocarcinoma/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Humanos , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo
6.
Medicine (Baltimore) ; 100(33): e26951, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414959

RESUMO

ABSTRACT: An overexpression of S-phase kinase-associated protein 2 (SKP2) is frequently observed in human cancer progression and metastasis, and evidence suggests that SKP2 plays a proto-oncogenic role both in vitro and in vivo. However, the function of SKP2 in gastric adenocarcinoma remains largely obscure. We investigated SKP2 expression in human gastric carcinomas.Tissue samples were acquired from 182 cases of gastric adenocarcinoma that were surgically resected from 2006 to 2012. Immunohistochemical staining for SKP2, Beclin-1, and forkhead box protein P3 (FOXP3) was performed. Pearson chi-square test was used to evaluate the associations among clinicopathological variables. The Kaplan-Meier method, the log-rank test, and the Cox proportional-hazards model were used in the analysis of the overall survival (OS) and disease-free survival (DFS).As a result, SKP2 overexpression in gastric adenocarcinomas showed a significant correlation with several favorable clinical factors, including the tumor size, T category, N category, lymphatic invasion, vascular invasion, OS, and DFS. SKP2 expression was positively correlated with the tumoral FOXP3, Beclin-1 expression, and regulatory T cell (Treg) infiltration. The difference in DFS between the SKP2 positive and negative group was attenuated by FOXP3 high expression, Beclin-1 high expression, and Tregs infiltration. Attenuation of the difference in OS by FOXP3 high expression, Beclin-1 high expression, and Tregs infiltration was not significant. In multivariable analysis, SKP2 expression was not correlated with OS and DFS.Our study showed a complex interrelationship between SKP2 and Beclin-1 and FOXP3 expression in gastric adenocarcinoma. The antioncogenic effect of Beclin-1 and FOXP3 expression in gastric adenocarcinoma is related to SKP2 expression.


Assuntos
Adenocarcinoma/metabolismo , Proteína Beclina-1/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Análise Serial de Tecidos
7.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206240

RESUMO

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


Assuntos
Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Ácidos Graxos/metabolismo , Regulação Neoplásica da Expressão Gênica , Metabolismo dos Lipídeos , Fosfolipídeos/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Idoso , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Células Epiteliais/enzimologia , Células Epiteliais/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Humanos , Lipidômica , Lipogênese , Masculino , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
8.
Nat Commun ; 12(1): 4651, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330898

RESUMO

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.


Assuntos
Adenocarcinoma/metabolismo , Fosfatase 6 de Especificidade Dupla/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Feminino , Humanos , Indóis/farmacologia , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas p21(ras)/genética , Estresse Fisiológico/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
Anticancer Res ; 41(8): 3801-3808, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281839

RESUMO

BACKGROUND/AIM: Colorectal adenocarcinoma has a poor prognosis due to its propensity for metastasis. It has been experimentally demonstrated that the microRNA (miRNA) let-7a can effectively inhibit tumor proliferation and metastasis by regulating the transforming growth factor (TGF)-ß signaling pathway; however, limited research has been conducted in the area of on colorectal cancer. Herein, we aimed to clarify the role and regulation of let-7a in a colorectal adenocarcinoma cell line (LS-174T). MATERIALS AND METHODS: LS-174T cells were transfected to express let-7a. Let-7a miRNA expression was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Cell growth was assessed by methyl thiazolyl tetrazolium (MTT) assay; invasion and migration were examined by Matrigel invasion and wound healing assays. The expression levels of matrix metalloproteinase (MMP)-2, phosphorylated Drosophila mothers against decapentaplegic 2 (p-SMAD2), and TGF-ß1 were analyzed by western blotting. The mRNA expression levels of TGFB1 were also analyzed by RT-qPCR. RESULTS: Overexpression of let-7a resulted in significant inhibition of LS-174T cell proliferation in vitro. The invasion and migration abilities of the cells overexpressing let-7a were decreased, compared to the control group and miR-negative control group. Transfection of LS-174T cells with let-7a resulted in down-regulation of MMP-2, as well as of TGF-ß1 and p-SMAD2 protein expression. Moreover, TGF-ß1 mRNA levels were reduced following let-7a overexpression. CONCLUSION: Let-7a inhibited the growth and metastasis of colonic mucinous adenocarcinoma cells, at least partially, by regulating the TGF-ß/Smad signaling pathway.


Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , MicroRNAs/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Transdução de Sinais/genética , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética
10.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200314

RESUMO

The influence of PVT1 and MALAT1 variants on colorectal cancer (CRC) susceptibility and their impact on PVT1/miRNA-186/epithelial-mesenchymal transition (EMT) and MALAT1/miRNA-101/EMT axes in CRC are unknown. We investigated the influence of PVT1 rs13255292 and MALAT1 rs3200401 on the risk of CRC and adenomatous polyps (AP), their impact on the long noncoding RNAs PVT1 and MALAT1 expression and their target miRNA-186, miRNA-101/E-cadherin pathways, along with their potential as early CRC biomarkers. Overall, 280 individuals were recruited: 140 patients with CRC, 40 patients with AP, and 100 healthy volunteers. Genotyping and serum expression profiles were assessed using qPCR. The EMT biomarker, E-cadherin, was measured by ELISA. rs3200401 was associated with increased CRC risk, whereas rs13255292 was protective. Serum PVT1 and MALAT1 were upregulated in CRC and AP patients versus healthy controls, whereas, miRNA-186, miRNA-101 and E-cadherin were downregulated in CRC versus non-CRC groups. MALAT1 showed superior diagnostic potential for CRC and predicted CRC risk among non-CRC groups in the multivariate logistic analysis. PVT1, MALAT1, miRNA-186 and miRNA-101 levels were correlated with E-cadherin, tumor stage, lymph node and distant metastasis. E-cadherin was lost in metastatic vs. non-metastatic CRC. rs3200401CC genotype carriers showed higher E-cadherin levels than CC + CT carriers. rs3200401 was correlated with lymph node status. For the first time, rs13255292 and rs3200401 are potential genetic CRC predisposition markers, with rs3200401 possibly impacting the EMT process. Serum PVT1, MALAT1, miRNA-186 and miRNA-101 are novel non-invasive diagnostic biomarkers that could improve the clinical outcome of CRC.


Assuntos
Adenocarcinoma/secundário , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal , MicroRNAs/genética , RNA Longo não Codificante/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Transcriptoma , Células Tumorais Cultivadas , Adulto Jovem
11.
J Biochem Mol Toxicol ; 35(8): e22818, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34075659

RESUMO

Geraniol, a natural compound found in the essential oils of various aromatic plants, has attracted attention for its probable anticancer effects. The molecular mechanisms of the cell proliferation suppression and apoptosis induction via geraniol in gastric cancer cells (AGS), however, remain unclear. Gastric cancer cells were treated with geraniol, and it was found that the IC50 values were 25 µM/ml, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results showed that 20 and 25 µM geraniol-induced reactive oxygen species (ROS) production (2'-7'dichlorofluorescin diacetate staining) and decreased mitochondrial membrane potential (rhodamine 123 staining) in AGS cells. Then, it effectively inhibited cell growth and induced apoptosis, confirmed through acridine orange/ethidium bromide, 4',6-diamidino-2-phenylindole, and propidium iodide staining and molecular marker analysis in AGS cells. Also, geraniol potently diminished caspase-9, Bax, Bcl-2, and caspase-3 expression in AGS cells. We also evaluated the essential mechanism of the cytotoxic effect of geraniol. Moreover, the present study depicted that geraniol-induced cell death through mitochondrial ROS production and inhibited the phosphorylation form of mitogen-activated protein kinase (p38, MAPK, JNK, and ERK1/2) signaling pathway. Taken together, these results concluded that geraniol has a novel therapeutic property against human stomach cancer.


Assuntos
Monoterpenos Acíclicos/farmacologia , Adenocarcinoma , Proliferação de Células/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Humanos , MAP Quinase Quinase 4/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo
12.
Nat Commun ; 12(1): 3372, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099734

RESUMO

Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.


Assuntos
Adenocarcinoma/genética , Carcinoma Neuroendócrino/genética , Regulação Neoplásica da Expressão Gênica , Próstata/metabolismo , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Adenocarcinoma/metabolismo , Animais , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Técnicas de Cultura de Órgãos/métodos , Prognóstico , Próstata/patologia , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo
13.
Toxicol Appl Pharmacol ; 426: 115618, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126112

RESUMO

WHO suggests that colon cancer incidences are rising steadily, propelling researchers to search for novel chemotherapeutic options. Metal-based chemotherapy is a potential forte to explore ruthenium-based complexes, exhibiting the capability to influence a variety of cellular targets. We discovered the chemotherapeutic effects of ruthenium-rifampicin complex on HT-29 and HCT-116 human colorectal cell lines and on a chemically developed murine colorectal cancer model. Complex was synthesized and characterized by analytical techniques and evaluation of antioxidant potential along with DNA binding capabilities. The complex minimizes cellular propagation and initiates apoptotic events in the colon cancer cell lines of HT-29 and HCT-116. The results of the in vivo study suggest that the complex has been successful in minimizing the wide spectrum of aberrant crypt foci and hyperplastic lesions, as well as encouraging elevated amounts of CAT, SOD and glutathione. Along with that, p53 could be modulated by the ruthenium-rifampicin complex to interfere with apoptosis in colon carcinoma, initiated by the intrinsic apoptotic trail facilitated through Bcl2 and Bax, thus controlling the Akt/mTOR/VEGF pathway coupled through the WNT/ß-catenin trail. Ruthenium-rifampicin chemotherapy could interrupt, retract or interrupt the progression of colorectal cancer through modifying intrinsic apoptosis including the antiangiogenic pathway, thereby achieving the function of a potential contender in chemotherapy in the near future.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Rifampina/uso terapêutico , Compostos de Rutênio/uso terapêutico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Combinação de Medicamentos , Feminino , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Rifampina/farmacologia , Rifampina/toxicidade , Compostos de Rutênio/farmacologia , Compostos de Rutênio/toxicidade , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Life Sci ; 281: 119763, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34186050

RESUMO

AIMS: Beclin1(BECN1) is known as an autophagy-related protein and the expression is promoted by apelin in lung adenocarcinoma cells, suggesting that apelin activates autophagy in lung adenocarcinoma. However, the functions of apelin-induced autophagy in lung adenocarcinoma tumorigenesis and deterioration are still unknown. Thus, this study aims to investigate the effects of apelin-induced autophagy on lung adenocarcinoma tumorigenesis and deterioration. MAIN METHODS: Protein expression of exogenous genes were detected by Western blotting analysis. Lung adenocarcinoma cell migration was assessed with cell migration assays. Autophagy was measured with quantification of GFP-LC3 or RFP-GFP-LC3 puncta using fluorescence microscopy in cells by an observed blinded to experimental condition and by western blot analysis of LC3 and p62 in cell lysates as well as autophagy flux. Immunofluorescence staining was performed in human lung adenocarcinoma A549 cells with p-cofilin antibody. The proteins expression in cancer specimens were examined with immunohistochemistry. KEY FINDINGS: Here, we reveal that apelin induces autophagy activation in lung adenocarcinoma. Apelin/APJ regulates BECN1 transcription via HIF1A. Apelin/APJ-activated autophagy promotes lung adenocarcinoma cell migration. Moreover, treatment with autophagy inhibitors significantly decreases apelin/APJ-induced lung adenocarcinoma cell migration. Evaluation of patient samples of lung adenocarcinoma reveals an association between APJ with BECN1 expression and a poor prognosis. SIGNIFICANCE: Our studies demonstrate that apelin-induced autophagy promotes lung adenocarcinoma cell migration which suggests a potential therapeutic target for lung adenocarcinoma.


Assuntos
Adenocarcinoma/patologia , Receptores de Apelina/metabolismo , Apelina/metabolismo , Autofagia , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Transdução de Sinais , Células A549 , Fatores de Despolimerização de Actina/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Autofagia/genética , Proteína Beclina-1/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Fosforilação
15.
J Cancer Res Clin Oncol ; 147(8): 2199-2207, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34115239

RESUMO

Colorectal cancer is an important public health concern leading to significant cancer associate mortality. A vast majority of colon cancer arises from polyp which later follows adenoma, adenocarcinoma, and carcinoma sequence. This whole process takes several years to complete and recent genomic and proteomic technologies are identifying several targets involved in each step of polyp to carcinoma transformation in a large number of studies. Current text presents interaction network of targets involved in polyp to carcinoma transformation. In addition, important targets involved in each step according to network biological parameters are also presented. The functional overrepresentation analysis of each step targets and common top biological processes and pathways involved in carcinoma indicate several insights about this whole mechanism. Interaction networks indicate TP53, AKT1, GAPDH, INS, EGFR, and ALB as the most important targets commonly involved in polyp to carcinoma sequence. Though several important pathways are known to be involved in CRC, the central common involvement of PI3K-AKT indicates its potential for devising CRC management strategies. The common and central targets and pathways involved in polyp to carcinoma progression can shed light on its mechanism and potential management strategies. The data-driven approach aims to add valuable inputs to the mechanism of the years-long polyp-carcinoma sequence.


Assuntos
Carcinoma/prevenção & controle , Transformação Celular Neoplásica , Neoplasias do Colo/prevenção & controle , Pólipos do Colo/terapia , Terapia de Alvo Molecular/métodos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Adenoma/prevenção & controle , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/prevenção & controle , Antineoplásicos/uso terapêutico , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Pólipos do Colo/genética , Pólipos do Colo/metabolismo , Pólipos do Colo/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Genes de Troca/efeitos dos fármacos , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Proteômica , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
16.
Theranostics ; 11(14): 6950-6965, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093864

RESUMO

Rationale: Psychological stress has been linked to cancer development and resistance to therapy by many epidemiological and clinical studies. Stress-induced immunosuppressive microenvironment by stress hormones, in particular glucocorticoids, has been extensively studied. However, the impacts of other stress-related neurotransmitters, such as serotonin (5-hydroxytryptamine, 5-HT), on cancer development just start to be revealed. Here, we aimed to identify novel neurotransmitters involved in stress-induced growth and dissemination of ovarian cancer (OC) and reveal the major underlying signaling pathway and the therapeutic significance. Methods: Through a genome-wide CRISPR/Cas9 knockout screen in the murine orthotopic model of ovarian carcinoma (OC), we identified candidate genes regulating the peritoneal dissemination of OC. Among them, we picked out HTR1E, one member of 5-HT receptor family specifically expressed in the ovary and endometrium in addition to brain. The correlation of HTR1E expression with OC progression was analyzed in OC patient specimen by quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry (IHC). Gain-of-function and loss-of-function analyses were performed to explore the functions of 5-HT/HTR1E signaling in OC growth and dissemination in vitro and in vivo. In addition, we investigated the therapeutic values of HTR1E specific agonist and small molecular inhibitors against HTR1E downstream factor SRC in a stressed murine OC xenograft model. Results: In OC patients, the HTR1E expression is dramatically decreased in peritoneal disseminated OC cells, which correlates with poor clinical outcome. Silence of HTR1E in OC cells greatly promotes cell proliferation and epithelial mesenchymal transition (EMT) by the activation of SRC-mediated downstream signaling pathways. Furthermore, chronic stress results in significantly decreased serotonin in the ovary and the enhanced OC growth and peritoneal dissemination in mice, which can be strongly inhibited by specific HTR1E agonist or the SRC inhibitor. Conclusions: We discovered the essential role of serotonin/HTR1E signaling in preventing the chronic psychological stress-promoted progression of OC, suggesting the potential therapeutic value of the HTR1E specific agonist and the SRC inhibitor for OC patients who are suffering from psychological stress.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Ovarianas/metabolismo , Receptores 5-HT1 de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/farmacologia , Estresse Fisiológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Escala de Avaliação Comportamental , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/ética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Testes Genéticos , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Serotonina/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188579, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34139275

RESUMO

Colorectal cancer (CRC) exhibits complex pathogenesis via compromised intestinal mucosal barrier. It is accepted that goblet cells secrete mucin which line the intestinal mucosal barrier and offer wide range protection and maintain the gut integrity. The principal mucin in the small and large intestine which is Mucin2 (MUC2) is predominantly expressed in the goblet cells which play a pivotal role in intestinal homeostasis. Its disruption is associated with diverse diseases and carcinomas. MUC2 has lately been identified as a principal marker in various mechanisms and secretory cell lineage. While MUC2 expression is regulated by various modulators, alterations in its expression are associated with immunomodulation, differences in tumor immunity and also regulation of microbiota. In the light of current literature, the present review explicates the regulation, functional mechanisms and essential role of MUC2 in colorectal cancer and aids in providing deep understanding of pathogenesis of the disease and also specifies the importance of the MUC2 in gaining more insights about the subtypes of colorectal cancer and how it can succour in approximating the prognosis and survival of the patients.


Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Mucina-2/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Mucina-2/genética , Prognóstico , Transdução de Sinais
18.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074015

RESUMO

TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.


Assuntos
Adenocarcinoma/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Antineoplásicos/farmacologia , Apoptose/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Esofágicas/metabolismo , MicroRNAs/metabolismo , Estresse Oxidativo/genética , Proteína Supressora de Tumor p53/metabolismo , Adenocarcinoma/genética , Sistema y+ de Transporte de Aminoácidos/genética , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Neoplasias Esofágicas/genética , Estrogênios/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Técnicas de Inativação de Genes , Ontologia Genética , Glutationa/metabolismo , Humanos , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética
19.
Biomed Res Int ; 2021: 5573628, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34055982

RESUMO

Background: Pancreatic cancer is one of the most malignant tumors of the digestive system, and its treatment has rarely progressed for the last two decades. Studies on m6A regulators for the past few years have seemingly provided a novel approach for malignant tumor therapy. m6A-related factors may be potential biomarkers and therapeutic targets. This research is focused on the gene characteristics and clinical values of m6A regulators in predicting prognosis in pancreatic cancer. Methods: In our study, we obtained gene expression profiles with copy number variation (CNV) data and clinical characteristic data of 186 patients with pancreatic cancer from The Cancer Genome Atlas (TCGA) portal. Then, we determined the alteration of m6a regulators and their correlation with clinicopathological features using the log-rank tests, Cox regression model, and chi-square test. Additionally, we validated the prognostic value of m6A regulators in the International Cancer Genome Consortium (ICGC). Results: The results suggested that pancreatic cancer patients with ALKBH5 CNV were associated with worse overall survival and disease-free survival than those with diploid genes. Additionally, upregulation of the writer gene ALKBH5 had a positive correlation with the activation of AKT pathways in the TCGA database. Conclusion: Our study not only demonstrated genetic characteristic changes of m6A-related genes in pancreatic cancer and found a strong relationship between the changes of ALKBH5 and poor prognosis but also provided a novel therapeutic target for pancreatic cancer therapy.


Assuntos
Adenocarcinoma/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/genética , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Prognóstico
20.
Bull Cancer ; 108(7-8): 730-739, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34052032

RESUMO

Thrombotic Microangiopathies (TM) have been described since the 1960s. They are characterized by presence of mechanical haemolytic anemia associated with peripheral thrombocytopenia. TM in cancer can be related to several causes, whose cancer himself: cancer-related microangiopathic haemolytic anaemia (MAHA). Incidence of cancer related MAHA remains unknown. Cancer-related MAHA are mainly observed in mucin-producer adenocarcinomas, such as gastric (half of reported cases) and breast cancer. We conducted a review of all original published cases of TM reported in breast cancer, and we specifically investigated BC-MAHA cases. A Medline search identified 158 MAHA cases including 118 BC-MAHA, and 40 drug-related MAHA. Most of BC-MAHA occur in disseminated cancers, mainly with medullar involvement, and/or bone metastasis. Patients typically suffer from poor general state, bone pain, and/or dyspnea. Laboratory abnormalities such as myelemia or erythromyelemia in peripheral blood are frequently observed. Incidence of coagulation disorders is increased, compared to other MAHA causes. BC-MAHA prognosis is dramatically poor. Treatments classically used in other MAHA causes, such as plasmapheresis or immunoglobulins, are inefficient. Urgent anti-neoplastic therapy may be the only effective treatment, associated to symptomatic therapies (transfusions, blood pressure control).


Assuntos
Anemia Hemolítica/complicações , Neoplasias da Mama/complicações , Microangiopatias Trombóticas/etiologia , Adenocarcinoma/metabolismo , Anemia Hemolítica/epidemiologia , Anemia Hemolítica/mortalidade , Anemia Hemolítica/terapia , Transtornos da Coagulação Sanguínea/epidemiologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Feminino , Humanos , Incidência , Mucinas/biossíntese , Trombocitopenia/complicações , Microangiopatias Trombóticas/terapia
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