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1.
Med Sci Monit ; 25: 7853-7863, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31630150

RESUMO

BACKGROUND Laryngeal cancer is one of the most common malignant tumors of the head and neck. Natural compounds in traditional Chinese medicine provide many valuable potential compounds for tumor chemotherapy. Esculetin, a coumarin derivative from several herbs, inhibits proliferation of many types of cancer cells, but its anticancer effect in laryngeal cancer is still not clear. MATERIAL AND METHODS We performed in vitro proliferation assay, invasion assay, and migration assay to assess the effect of esculetin against LC, and in vivo nude mouse xenograft animal model was used as well. Flow cytometry was conducted to analyze the effect of esculetin on cell cycle of LC cells, and Western blot analysis was used to assess the effect esculetin on the JAK-STAT signaling pathway. RESULTS Esculetin remarkably inhibits proliferation, migration, and invasion of LC cells, and reduces in vivo xenograft tumor growth and tumor weight in a dose-dependent manner. Our molecular mechanism study demonstrated that esculetin significantly inhibits STAT3 phosphorylation and blocks translocation of STAT3 into the nucleus, and esculetin also blocks the cell cycle in G1/S phase. CONCLUSIONS In a summary, by inhibiting the STAT3 activation, esculetin shows potential anticancer effects against the laryngeal cancer.


Assuntos
Neoplasias Laríngeas/tratamento farmacológico , Umbeliferonas/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cumarínicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Janus Quinases/metabolismo , Neoplasias Laríngeas/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica/fisiopatologia , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Umbeliferonas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Med Sci Monit ; 25: 7864-7871, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31631173

RESUMO

BACKGROUND Lung cancer is one of the leading causes of cancer-related mortalities worldwide and majority of these deaths result from non-small cell lung cancer (NSCLC). The primary objective of this research was to determine the anticancer potential of carnosic acid, a plant derived abietane diterpene, against human lung cancer cells, as well as to determine its effects on cell migration and invasion, apoptosis, and the PI3K/AKT/m-TOR signaling pathway. MATERIAL AND METHODS Cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assay; fluorescence microscopy using acridine orange/ethidium bromide stain and Comet assay were used to study cellular apoptosis. In vitro wound healing assay was used to study effects on cell migration; Transwell assay was used to study cell invasion after drug treatment. Western blot assay was used to study effects of carnosic acid on the PI3K/AKT/m-TOR signaling pathway. RESULTS It was shown that carnosic acid could inhibit the growth of A-549 human non-small cell lung carcinoma cells dose-dependently showing an IC50 value of 12.5 µM. This growth inhibition of A-549 cells was mediated via apoptotic cell death as observed by fluorescence microscopy showing nuclear fragmentation and chromatin condensation. Carnosic acid, dose-dependently, also inhibited cell migration and invasion. Finally, western blot assay revealed that carnosic acid also led to inhibition of the PI3K/AKT/m-TOR signaling pathway. CONCLUSIONS In conclusion, our results showed that Carnosic acid has the potential to inhibit cancer cell growth in A-549 lung cancer cells by activating apoptotic death, inhibiting cell migration and invasion and suppressing PI3K/AKT/m-TOR signaling pathway.


Assuntos
/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , China , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Invasividade Neoplásica/fisiopatologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
3.
Biochemistry (Mosc) ; 84(7): 762-772, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31509727

RESUMO

Intravasation is a key step in cancer metastasis during which tumor cells penetrate the vessel wall and enter circulation, thereby becoming circulating tumor cells and potential metastatic seeds. Understanding the molecular mechanisms of intravasation is critically important for the development of therapeutic strategies to prevent metastasis. In this article, we review current data on the mechanisms of cancer cell intravasation into the blood and lymphatic vessels. The entry of mature thymocytes into the circulation and of dendritic cells into the regional lymph nodes is considered as example of intravasation under physiologically normal conditions. Intravasation in a pathophysiological state is illustrated by the reverse transendothelial migration of leukocytes into the bloodstream from the sites of inflammation mediated by the sphingosine 1-phosphate interaction with its receptors. Intravasation involves both invasion-dependent and independent mechanisms. In particular, mesenchymal and amoeboid cell invasion, as well as neoangiogenesis and vascular remodeling, are discussed to play a significant role in the entry of tumor cells to the circulation. Special attention is given to the contribution of macrophages to the intravasation via the CSF1/EGF (colony stimulating factor 1/epidermal growth factor) paracrine signaling pathway and the TMEM (tumor microenvironment of metastasis)-mediated mechanisms. Other mechanisms including intravasation of tumor cell clusters surrounded by the vessel wall elements, cooperative intravasation (entry of non-invasive tumor cells to the circulation following invasive tumor cells), and intravasation associated with the vasculogenic mimicry (formation of vascular channels by tumor cells) are also discussed. Novel intravasation-specific mechanisms that have not yet been described in the literature are suggested. The importance of targeted therapeutic strategies to prevent cancer intravasation is emphasized.


Assuntos
Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Migração Transendotelial e Transepitelial , Microambiente Tumoral , Permeabilidade Capilar , Fator de Crescimento Epidérmico/metabolismo , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Comunicação Parácrina , Remodelação Vascular
4.
Life Sci ; 235: 116831, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31487530

RESUMO

AIMS: TRAF6 is an intracellular signal adapter molecule plays a significant role in tumor development. However, the specific mechanism causes and promotes of colorectal cancer keep largely unknown. Therefore, we sought to investigate the roles and the molecular mechanisms of TRAF6 in regulation colorectal cancer. MATERIAL AND METHODS: The immunohistochemistry analyzed the expression of TRAF6 in colorectal cancer samples and analyzed the effects of expression of TRAF6 on the prognosis in colorectal cancer. The roles of TRAF6 in regulating colorectal cancer cell proliferation, colony formation, cell migration, cell wound healing and cell invasion were evaluated in vitro. Animal studies were performed to investigate the effects of TRAF6 on tumor growth. mRNA abundance of key genes was analyzed via qPCR. Protein level of TRAF6 and NF-κB/AP-1 signaling pathways was examined by Western blot. Luciferase reporter and Immunofluorescence assays were used to identify the activities NF-κB/AP-1 signaling pathways. KEY FINDINGS: TRAF6 high expression in colorectal cancer tissues. And colorectal cancer patients with high expression of TRAF6 had a poor survival rate. TRAF6 knockdown can inhibit proliferation, migration, and invasion of colorectal cancer cells in vitro and in vivo experiments. TRAF6 activates the TRAF6-NF-κB/AP-1 signaling pathway by entering the nucleus, causing biobehavioral changes in colorectal cancer cells. SIGNIFICANCE: TRAF6 plays a vital role in the progression of colorectal cancer. What's more, research elucidating the biological mechanisms of TRAF6 can treated as potential therapeutic target for colorectal cancer.


Assuntos
Neoplasias Colorretais/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Adulto , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Neoplasias Colorretais/fisiopatologia , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/fisiopatologia , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/fisiologia , Ensaio Tumoral de Célula-Tronco , Cicatrização/fisiologia
5.
Artigo em Chinês | MEDLINE | ID: mdl-31315361

RESUMO

Objective: To compare the carcinogenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells and to identify the mechanism underlying the action of miRNAs. Methods: Solid tumor-derived laryngeal carcinoma stem cells and Hep-2-derived laryngeal carcinoma stem cells were cultured, and CD133(+)CD44(+) laryngeal cancer stem cells were sorted by flow cytometry. Boden chamber invasion assay, cell migration assay and tumor formation assay were then performed to compare the invasion, migration and tumorigenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells. And then, miRNAs isolated from two laryngeal cancer stem cells were detected and analysed with miRNA chip. Results: (1)In Boyden chamber invasion assay, the cell invasion rate of CD133(+)CD44(+) laryngeal cancer stem cells was obviously higher (80.2%±2.3% vs. 63.9%±3.2%, t=5.011, P=0.027); (2)CD133(+)CD44(+) laryngeal cancer stem cells also had higher mobility in cell migration assay (82.9%±1.1% vs. 70.9%±0.6%, t=4.514, P=0.031); (3)In tumor formation assay, the tumor formation rate of CD133(+)CD44(+) laryngeal cancer stem cells was also higher (80% vs. 50%). What's more, we identified 15 miRNAs that were significantly upregulated in CD133(+)CD44(+) laryngeal cancer stem cells and 3 miRNAs that were significantly downregulated in CD133(+)CD44(+) laryngeal cancer stem cells, compared with normal laryngeal cancer stem cells. Conclusions: CD133(+)CD44(+) laryngeal cancer stem cells have stronger invasion, migration and tumorigenic abilities compared with normal laryngeal cancer stem cells, and the difference of miRNAs' expression is one of the possible causes.


Assuntos
Neoplasias Laríngeas/fisiopatologia , MicroRNAs/biossíntese , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Antígeno AC133/biossíntese , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Humanos , Receptores de Hialuronatos/biossíntese , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Laringe/metabolismo , Laringe/patologia , Laringe/fisiopatologia , Invasividade Neoplásica/fisiopatologia , Processos Neoplásicos
6.
BMC Cancer ; 19(1): 609, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226958

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer with high aggressiveness and poor prognosis. There is an urgent need for understanding the molecular mechanism underlying the development and progression of ESCC. METHODS: ESCC tissues and corresponding non-neoplastic tissues were collected. The expression and function of miR-124-3p and BCAT1 in two cell lines KYSE-150 and Eca109 were determined. RESULTS: We show downregulation of miR-124-3p expression in ESCC tissues, which is highly correlated with proliferation and migration of ESCC cell lines KYSE-150 and Eca109. miR-124-3p show high correlation with TNM stage and differentiation grade. Furthermore, miR-124-3p directly targets mRNA 3'UTR region of BCAT1, which results in upregulation of BCAT1 expression as observed in ESCC tissues and cell lines. Also, our data indicates that BCAT1 high expression is strongly linked to the disease-free survival, tumor size, pathologic stage, T classification and differentiation grade. On the other hand, we clarified the upstream mechanism regulating miR-124-3p expression in ESCC, which involves in the hypermethylation-silencing regulation mediated by DNA methyltransferase 1(DNMT1), which is of high expression in ESCC tissues and cell lines in the present study. In addition, DNMT1 knockdown or inhibition of DNMT1 function contributes to downregulation of miR-124-3p and BCAT1 expression. CONCLUSIONS: Our study thus clarifies a new mechanism that DNMT1/miR-124/BCAT1 axis regulates the development and progression of ESCC.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Transaminases/metabolismo , Regiões 3' não Traduzidas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica/fisiopatologia , Estadiamento de Neoplasias , Transaminases/genética , Transfecção
7.
Cell Physiol Biochem ; 52(6): 1503-1516, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31112017

RESUMO

BACKGROUND/AIMS: Zinc Finger Protein 281 (ZNF281) was recently identified as a novel oncogene in several human carcinomas. However, the clinical significance of ZNF281 in colorectal cancer (CRC) and the molecular mechanisms by which ZNF281 promotes the growth and metastasis of CRC remain unknown. METHODS: ZNF281 expression in CRC tissues was assessed, and the outcomes were analyzed to determine the clinical importance of ZNF281 expression. Cell Transwell assays and a wound healing assay were performed to assess the effects of ZNF281 on CRC cell migration and invasion in vitro. Western blotting was applied to analyze the potential mechanisms. RESULTS: ZNF281 mRNA and protein levels were significantly increased in CRC tissues compared with normal colon tissues, and high ZNF281 expression was associated with advanced T stage, N stage, TNM stage and differentiation. Therefore, ZNF281 expression might be an independent prognostic indicator in CRC patients. Moreover, knockdown of ZNF281 expression suppressed cell proliferation, migration and invasion by inhibiting the Wnt/ß-catenin pathway. CONCLUSION: Our study indicates that ZNF281 plays a critical role in the progression and metastasis of CRC and could represent a potential therapeutic target for CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Transativadores/metabolismo , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Neoplasias Colorretais/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , RNA Interferente Pequeno/genética , Transativadores/antagonistas & inibidores , Transativadores/genética , Regulação para Cima , Via de Sinalização Wnt , beta Catenina/metabolismo
8.
Mar Drugs ; 17(5)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137656

RESUMO

Actinomycin V, an analog of actinomycin D produced by the marine-derived actinomycete Streptomyces sp., possessing a 4-ketoproline instead of a 4-proline in actinomycin D. In this study, the involvement of snail/slug-mediated epithelial-mesenchymal transition (EMT) in the anti-migration and -invasion actions of actinomycin V was investigated in human breast cancer MDA-MB-231 cells in vitro. Cell proliferation effect was evaluated by 3-(4,5-Dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. Wound-healing and Transwell assay were performed to investigate the anti-migration and -invasion effects of actinomycin V. Western blotting was used to detect the expression levels of E-cadherin, N-cadherin, vimentin, snail, slug, zinc finger E-box binding homeobox 1 (ZEB1), and twist proteins and the mRNA levels were detected by rt-PCR. Actinomycin V showed stronger cytotoxic activity than that of actinomycin D. Actinomycin V up-regulated both of the protein and mRNA expression levels of E-cadherin and down-regulated that of N-cadherin and vimentin in the same cells. In this connection, actinomycin V decreased the snail and slug protein expression, and consequently inhibited cells EMT procession. Our results suggest that actinomycin V inhibits EMT-mediated migration and invasion via decreasing snail and slug expression, which exhibits therapeutic potential for the treatment of breast cancer and further toxicity investigation in vivo is needed.


Assuntos
Neoplasias da Mama/fisiopatologia , Movimento Celular/efeitos dos fármacos , Dactinomicina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fatores de Transcrição da Família Snail/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica/fisiopatologia
9.
Biosci Biotechnol Biochem ; 83(9): 1703-1708, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31094297

RESUMO

miR-655-3p functions as a tumor suppressor in tumor metastases; however, its role and mechanism in regulating cell migration and invasion of non-small cell lung cancer (NSCLC) remain unclear. Here, we found that miR-655-3p expression was markedly decreased in the NSCLC cell lines A549, NCI-H1650, PC14/b, NCI-H1299, and HPAEpiC compared to levels observed in normal human lung fibroblasts. miR-655-3p overexpression significantly inhibited migration and invasion of A549 and PC14/b cells, and pituitary tumor-transforming 1 (PTTG1) expression was up-regulated in the NSCLC cells. Luciferase reporter assays indicated that PTTG1 was a direct target of miR-655-3p. Additionally, PTTG1 overexpression alleviated the inhibitory effect of miR-655-3p on migration and invasion abilities in A549 and PC14/b cells. In conclusion, miR-655-3p inhibits NSCLC migration and invasion by targeting PTTG1, suggesting that miR-655-3p may serve as a therapeutic target to provide a new approach for the clinical treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/fisiologia , Neoplasias Pulmonares/patologia , MicroRNAs/fisiologia , Invasividade Neoplásica/fisiopatologia , Neoplasias Hipofisárias/metabolismo , Linhagem Celular Tumoral , Humanos
10.
Biomed Pharmacother ; 115: 108891, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31082772

RESUMO

Accumulating evidence has indicated the vital roles of long noncoding RNA (lncRNA) in the epithelial ovarian cancer (EOC). However, the function of lncRNA HAS2-AS1 in EOC is still unclear. This study aims to investigate the expression and role of HAS2-AS1 in EOC. In the cells and tissue of EOC, HAS2-AS1 expression was markedly up-regulated. Besides, the overexpression of HAS2-AS1 indicated the poor clinical outcome of EOC patients. Transcription factor CREB1 could bind with the promoter of HAS2-AS1 and activate its transcriptional expression. Functionally, HAS2-AS1 knockdown suppressed the proliferation, invasion and tumor growth of EOC cells in vitro and in vivo. Mechanical investigation found that HAS2-AS1 could relive the RUNX2 protein expression via sponging the miR-466, acting as miRNA sponge. In conclusion, this finding suggests the CREB1/HAS2-AS1/miR-466/RUNX2 axis in the in the EOC tumorigenesis, providing the novel insight for the molecular mechanism of EOC.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MicroRNAs/metabolismo , Invasividade Neoplásica/fisiopatologia , Neoplasias Ovarianas/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Linhagem Celular Tumoral , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Neoplasias Experimentais , RNA Longo não Codificante/genética , Organismos Livres de Patógenos Específicos , Transfecção
11.
Neurosci Lett ; 705: 80-86, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31005653

RESUMO

Glioma stem cells (GSC) were important for Glioblastoma (GBM) initiation and chemotherapy resistance. Centrosomal protein of 55 kDa (CEP55) was a biomarker for multiple cancers. However, roles and mechanism of CEP55 in glioma tumorigenesis and stemness maintains of stem like cells was still unclear. U251 cells which stable overexpression or downregulation of CEP55 was obtained by lentivirus mediated transduction. Roles and mechanism of CEP55 in stemness maintains of stem like cells and tumorigenesis was investigated. Our results implied that knockdown the expression of CEP55 inhibited the invasion and migration of U251 cells, while overexpression of CEP55 displayed opposite results. Moreover, overexpression of CEP55 promoted neurosphere formation of glioma stem-like cells, while CEP55 knockdown decreased the number and size of neurosphere. Mechanistically, overexpression of CEP55 enhanced the expression of Forkhead box protein M1 (FOXM1), Matrix metalloproteinases (MMPs) and activated the NF-κB pathway, while knockdown CEP55 displayed opposite results. In conclusion, our results indicated that CEP55 played an important role in promoting the invasion and migration of U251 cell and self-renewal of glioma stem like cells which might be a new therapeutic target for glioma.


Assuntos
Agregação Celular/fisiologia , Proteínas de Ciclo Celular/fisiologia , Movimento Celular/fisiologia , Invasividade Neoplásica/fisiopatologia , Células-Tronco Neoplásicas/fisiologia , Carcinogênese , Proteínas de Ciclo Celular/biossíntese , Linhagem Celular Tumoral , Proteína Forkhead Box M1/biossíntese , Técnicas de Silenciamento de Genes , Glioma , Humanos , Lentivirus , Metaloproteinases da Matriz/biossíntese , Transdução de Sinais/fisiologia , Transdução Genética
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(2): 121-127, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30975276

RESUMO

Objective To investigate the role of transforming growth factor ß1/nicinamide adenine dinucleotide phosphate oxidase/reactive oxygen species (TGF-ß1/NOX4/ROS) signaling pathway in the invasion and migration of cervical cancer cells. Methods The cultured SiHa, CaSki, HeLa, C4-I and C33A cervical cancer cells were treated with 5 ng/mL TGF-ß1 for 4 hours or 8 hours. ROS levels in these cervical cancer cells were detected using 2', 7'-dichlorofluorescein diacetate (DCFH-DA) staining combined with flow cytometry. After the transfection of NOX4 small interfering RNA (NOX4-siRNA) into HeLa cells or using of NOX4 signaling pathway inhibitor diphenylidene iodine chloride (DPI), NOX4 protein expression was measured by Western blotting, and the effect of TGF-ß1 on migration and invasion ability of cervical cancer cells were analyzed by TranswellTM assay. Results TGF-ß1 significantly up-regulated NOX4 protein expression, increased ROS production in HPV-positive cervical cancer cells (SiHa, CaSki, HeLa and C4-I) and promoted the migration and invasion abilities of cervical cancer cells. Silencing the NADPH oxidase gene or using the NOX4 pathway inhibitor DPI could reverse this effect. Conclusion TGF-ß1 can activate NOX4/ROS signaling pathway to enhance the invasion and migration abilities of cervical cancer cells.


Assuntos
NADPH Oxidase 4 , Espécies Reativas de Oxigênio , Fator de Crescimento Transformador beta1 , Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Movimento Celular , Ativação Enzimática/efeitos dos fármacos , Feminino , Células HeLa , Humanos , NADPH Oxidase 4/metabolismo , Invasividade Neoplásica/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
13.
J Neurooncol ; 143(1): 69-77, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30887242

RESUMO

INTRODUCTION: Glioblastoma (GBM) is the most common and aggressive human primary brain malignancy. The key properties of GBM, stemness and invasiveness, are known to be associated with a highly unfavorable prognosis. Notably, the process of epithelial-mesenchymal transition (EMT) is closely related to the progression of GBM. On the basis of reports that 2'-hydroxycinnamaldehyde (HCA) and its derivative, 2'-benzoyloxycinnamaldehyde (BCA), suppresses EMT in several human cancer cells, we sought to evaluate the therapeutic efficacy of HCA and BCA, alone and in combination with temozolomide (TMZ), on GBM tumorspheres (TSs). METHODS: Two human GBM TSs were treated with HCA, BCA, or TMZ. Therapeutic effects were evaluated by measuring ATP levels, neurosphere formation, 3D-invasion in collagen matrix, and viability. Protein expression profiles after drug treatment were evaluated by western blotting. In vivo anticancer efficacy of drugs was examined in a mouse orthotopic xenograft model. RESULTS: Combined treatment of GBM TSs with HCA or BCA and TMZ significantly reduced cell viability, stemness, and invasiveness. Expression levels of stemness-, invasiveness-, and mesenchymal transition-associated markers, Zeb1, N-cadherin, and ß-catenin, were also substantially decreased by the combined treatment. The combined treatment also reduced tumor growth in a mouse orthotopic xenograft model. CONCLUSION: Our findings suggest that HCA and BCA, combined with TMZ, are potential therapeutic agents in the treatment of GBM.


Assuntos
Antineoplásicos/farmacologia , Cinamatos/farmacologia , Glioblastoma/tratamento farmacológico , Invasividade Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Temozolomida/farmacologia , Acroleína/análogos & derivados , Acroleína/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Benzoatos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Quimioterapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , Glioblastoma/fisiopatologia , Humanos , Camundongos Nus , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/fisiologia , Tecidos Suporte
14.
Int J Gynaecol Obstet ; 145(2): 245-252, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30776091

RESUMO

Since the last update of the International Federation of Gynecology and Obstetrics (FIGO) staging for corpus uteri cancer in 2009, a number of new insights into pathology, molecular genetics, and prognostic factors that justify a revision have been made. We recommend incorporation of histotype and grade along with depth of myometrial invasion to define stage I endometrial cancer, a change from 3-tier grading to binary grading, and inclusion of lymph node status (negative vs not removed) in the definition of stage I disease. Elimination of cervical involvement to define stage II and inclusion of positive peritoneal cytology to upstage otherwise stage I cancers to stage IIA is also recommended. Extrauterine pelvic involvement should be classified as stage IIB disease, and stage III should be reclassified based exclusively on retroperitoneal pelvic and/or para-aortic lymph node involvement. If feasible, molecular staging by immunohistochemistry (mismatch repair proteins and p53) as well as POLE exonuclease sequencing may be carried out in order to assign one of the four categories from The Cancer Genome Atlas.


Assuntos
Neoplasias do Endométrio/patologia , Gradação de Tumores/métodos , Estadiamento de Neoplasias/métodos , Adulto , Idoso , Neoplasias do Endométrio/genética , Feminino , Humanos , Metástase Linfática/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica/fisiopatologia
15.
J Neurooncol ; 142(2): 241-251, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30701354

RESUMO

BACKGROUND: MicroRNAs (miRs) regulate many biological processes, such as invasion, angiogenesis, and metastasis. Glioblastoma (GBM) patients with metastasis/metastatic dissemination have a very poor prognosis; therefore, inhibiting metastasis/metastatic dissemination has become an important therapeutic strategy for GBM treatment. METHODS: Using 76 GBM tissues, we examined the expression levels of 23 GBM-related miRs and compared the miRs' expression levels between GBMs with metastasis/metastatic dissemination and GBMs without metastasis/metastatic dissemination. Using the bioinformatics web site, we searched the target genes of miRs. To analyze the function of target gene, several biological assays and survival analysis by the Kaplan-Meier method were performed. RESULTS: We found that eight miRs were significantly decreased in GBM with metastasis/metastatic dissemination. By the bioinformatics analysis, we identified stanniocalcin-1 (STC1) as the most probable target gene against the combination of these miRs. Four miRs (miR-29B, miR-34a, miR-101, and miR-137) have predictive binding sites in STC1 mRNA, and mRNA expression of STC1 was downregulated by mimics of these miRs. Also, mimics of these miRs and knockdown of STC1 by siRNA suppressed invasion in GBM cells. GBM with metastasis/metastatic dissemination had significantly higher levels of STC1 than GBM without metastasis/metastatic dissemination. Finally, Kaplan-Meier analysis demonstrated that GBMs with high STC1 level had significantly shorter survival than GBMs with low STC1 level. CONCLUSIONS: STC1 may be a novel metastasis/metastatic dissemination promoting factor regulated by several miRs in GBM. Because STC1 is a secreted glycoprotein and functions via the autocrine/paracrine signals, inhibiting STC1 signal may become a novel therapeutic strategy for GBM.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Glicoproteínas/metabolismo , MicroRNAs/metabolismo , Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Estudos de Coortes , Biologia Computacional , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , MicroRNAs/antagonistas & inibidores , Pessoa de Meia-Idade , Neoplasias da Medula Espinal/metabolismo , Neoplasias da Medula Espinal/mortalidade , Neoplasias da Medula Espinal/secundário , Adulto Jovem
16.
Cancer Lett ; 448: 52-60, 2019 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-30763716

RESUMO

Snail is an important transcription factor of epithelial-mesenchymal transition (EMT) and related to poor prognosis and distant metastasis of tumor patients. Snail is a liable protein and degraded by ubiquitin-proteasome system. There are various E3 ligases mediating its degradation, but the deubiquitinating enzyme reversed Snail degradation is not fully understood. In this study, we screened a DUB library and found USP26 is a potent deubiquitinase mediating Snail stabilization. We also identified that USP26 is a booster of esophageal squamous cell carcinoma (ESCC) cell migration and invasion, and it is highly expressed in ESCC samples. Our observation demonstrates that USP26 is a novel deubiquitinating enzyme of Snail and it provides a potential target for the therapy of esophageal cancer metastasis.


Assuntos
Cisteína Endopeptidases/fisiologia , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Metástase Neoplásica/fisiopatologia , Animais , Movimento Celular/fisiologia , Humanos , Camundongos , Invasividade Neoplásica/fisiopatologia , Fatores de Transcrição da Família Snail/metabolismo , Células Tumorais Cultivadas
17.
Int J Biol Sci ; 15(1): 183-194, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30662358

RESUMO

Growing evidence indicates that phosphoserine phosphatase (PSPH) is up-regulated and correlates with prognosis in multiple types of cancer. However, little is known about the roles of PSPH in NSCLC. Thus, the aim of the present study was to demonstrate the expression of PSPH in human NSCLC and reveal its biological functions and the underlying mechanisms. qRT-PCR, western blot and immunohistochemistry were used to assess the expression of NSCLC patient specimens and NSCLC cell lines. The functions of PSPH in migration and invasion were determined using trans-well and wound-healing assays. Cell proliferation capacity was performed by cell counting kit-8 (CCK-8), colony formation assays and cell cycle analysis. We demonstrated that PSPH was overexpressed in NSCLC specimens compared with the adjacent non-tumorous specimens, and high expression of PSPH was associated with clinical stage, metastasis and gender in NSCLC. Decreased expression of PSPH inhibited NSCLC cells migration, invasion and proliferation. Most importantly, further experiments demonstrated that PSPH might regulate NSCLC progress through MAPK signaling pathways. Lastly, immunohistochemistry (IHC) revealed that the PSPH expression level was positively correlated with the clinical stage in NSCLC patients. These results suggest that PSPH may act as a putative oncogene and a potential therapeutic target in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Monoéster Fosfórico Hidrolases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Feminino , Humanos , Imuno-Histoquímica , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/fisiopatologia , Monoéster Fosfórico Hidrolases/genética
18.
Acta Pharmacol Sin ; 40(8): 1067-1075, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30670815

RESUMO

Triple-negative breast cancer (TNBC) is a heterogeneous disease with a poor prognosis due to the lack of an effective targeted therapy. Histone lysine methyltransferases (KMTs) have emerged as attractive drug targets for cancer therapy. However, the function of the majority of KMTs in TNBC has remained largely unknown. In the current study, we found that KMT nuclear receptor binding SET domain protein 2 (NSD2) is overexpressed in TNBC tumors and that its overexpression is associated with poor survival of TNBC patients. NSD2 regulates TNBC cell survival and invasion and is required for tumorigenesis and tumor growth. Mechanistically, NSD2 directly controls the expression of EGFR and ADAM9, a member of the ADAM (a disintegrin and metalloproteinase) family that mediates the release of growth factors, such as HB-EGF. Through its methylase activity, NSD2 overexpression stimulates EGFR-AKT signaling and promotes TNBC cell resistance to the EGFR inhibitor gefitinib. Together, our results identify NSD2 as a major epigenetic regulator in TNBC and provide a rationale for targeting NSD2 alone or in combination with EGFR inhibitors as a targeted therapy for TNBC.


Assuntos
Proteínas ADAM/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/fisiologia , Neoplasias de Mama Triplo Negativas/fisiopatologia , Proteínas ADAM/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Técnicas de Silenciamento de Genes , Histona-Lisina N-Metiltransferase/genética , Humanos , Proteínas de Membrana/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/fisiopatologia , Proteínas Repressoras/genética , Neoplasias de Mama Triplo Negativas/patologia
19.
Oncogene ; 38(4): 596-608, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30171263

RESUMO

Pancreas cancer cells have a tendency to invade along nerves. Such cancerous nerve invasion (CNI) is associated with poor outcome; however, the exact mechanism that drives cancer cells to disseminate along nerves is unknown. Immunohistochemical analysis of human pancreatic ductal adenocarcinoma (PDAC) specimens showed overexpression of the L1 cell adhesion molecule (L1CAM) in cancer cells and in adjacent Schwann cells (SC) in invaded nerves. By modeling the neural microenvironment, we found that L1CAM secreted from SCs acts as a strong chemoattractant to cancer cells, through activation of MAP kinase signaling. L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation. Using a transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we show that treatment with anti-L1CAM Ab significantly reduces CNI in vivo. We provide evidence of a paracrine response between SCs and cancer cells in the neural niche, which promotes cancer invasion via L1CAM secretion.


Assuntos
Carcinoma Ductal Pancreático/patologia , Metaloproteases/biossíntese , Invasividade Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Molécula L1 de Adesão de Célula Nervosa/fisiologia , Neoplasias Pancreáticas/patologia , Animais , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/genética , Meios de Cultivo Condicionados , Indução Enzimática/efeitos dos fármacos , Humanos , Metaloproteases/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/imunologia , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Células de Schwann/fisiologia , Regulação para Cima
20.
Ann Otol Rhinol Laryngol ; 128(1): 36-43, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30360641

RESUMO

OBJECTIVES:: Laryngeal squamous cell carcinoma (LSCC) can involve different anatomic subunits with peculiar surgical and prognostic implications. Despite conflicting outcomes for the same stage of disease, the current staging system considers different lesions in a single cluster. The aim of this study was to critically discuss clinical and pathologic staging of primary and recurrent advanced LSCC in order to define current staging pitfalls that impede a precise and tailored treatment strategy. METHODS:: Thirty patients who underwent total laryngectomy in the past 3 years for primary and recurrent advanced squamous cell LSCC were analyzed, comparing endoscopic, imaging, and pathologic findings. Involvement of the different laryngeal subunits, vocal-fold motility, and spreading pattern of the tumor were blindly analyzed. The diagnostic accuracy and differences between clinicoradiologic and pathologic findings were studied with standard statistical analysis. RESULTS:: Discordant staging was performed in 10% of patients, and thyroid and arytenoid cartilage were the major diagnostic pitfalls. Microscopic arytenoid involvement was significantly more present in case of vocal-fold fixation ( P = .028). Upstaging was influenced by paraglottic and pre-epiglottic space cancer involvement, posterior commissure, subglottic region, arytenoid cartilage, and penetration of thyroid cartilage; on the contrary, involvement of the inner cortex or extralaryngeal spread tended to be down-staged. Radiation-failed tumors less frequently involved the posterior third of the paraglottic space ( P = .022) and showed a significantly worse pattern of invasion ( P < .001). CONCLUSIONS:: Even with the most recent technologies, 1 in 10 patients with advanced LSCC in this case series was differently staged on clinical examination, with cartilage involvement representing the main diagnostic pitfall.


Assuntos
Carcinoma de Células Escamosas , Quimiorradioterapia , Neoplasias Laríngeas , Laringectomia , Laringoscopia , Laringe , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Idoso , Biópsia/métodos , Biópsia/estatística & dados numéricos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Quimiorradioterapia/estatística & dados numéricos , Confiabilidade dos Dados , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Itália , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/terapia , Laringectomia/efeitos adversos , Laringectomia/métodos , Laringectomia/estatística & dados numéricos , Laringoscopia/métodos , Laringoscopia/estatística & dados numéricos , Laringe/diagnóstico por imagem , Laringe/patologia , Laringe/fisiopatologia , Masculino , Invasividade Neoplásica/diagnóstico por imagem , Invasividade Neoplásica/fisiopatologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias/métodos , Estadiamento de Neoplasias/normas , Prognóstico , Sensibilidade e Especificidade
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