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1.
Toxicol Lett ; 318: 22-29, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634547

RESUMO

An attempt has been made to delineate the role of natural and synthetic retinoid receptor ligands on vimentin expression in the human triple-negative breast cancer cells. The effects of currently synthesized triorganotin derivatives of the general formula R3SnX (R is butyl or phenyl, X is isothiocyanate), which are considered RXR ligands, were investigated in the human MDA-MB-231 breast cancer cell line. Studies were evaluated in the presence and absence of all-trans retinoic acid (ATRA), a natural RAR ligand. Vimentin represents the major protein associated with epithelial-mesenchymal transition (EMT), an essential process when the primary tumour transforms into a malignant one. mRNA and proteomic data obtained in this study, based on the PDQuest software protein evaluation and further quantification of proteins by iTRAQ analysis, suggest that vimentin was significantly reduced in the combination of RAR ligand and RXR ligand treatment. Both tested triorganotin compounds showed similarly reduced expression of vimentin, but tributyltin isothiocyanate (TBT-ITC) proved to be more effective than triphenyltin isothiocyanate (TPT-ITC). Furthermore, the effect of natural (9cRA) and synthetic RXR ligands, both chloride and isothiocyanate derivatives, on vimentin expression was compared.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteômica/métodos , Receptores X Retinoide/agonistas , Compostos de Trialquitina/farmacologia , Vimentina/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Regulação para Baixo , Eletroforese em Gel Bidimensional , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Compostos Orgânicos de Estanho/farmacologia , Receptores X Retinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem , Tretinoína/farmacologia
2.
Anticancer Res ; 39(11): 6307-6316, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704861

RESUMO

BACKGROUND/AIM: Oropharyngeal squamous cell carcinoma (OPSCC) could be clinically undetectable despite the relatively large size of lymph node metastases. Here, we aimed to elucidate the correlation of p16 expression with epithelial-to-mesenchymal transition (EMT) markers. PATIENTS AND METHODS: Radically resected 121 OPSCC and 270 non-OPSCC tissue samples were included in the analysis, and p16, Twist, and Snail/Slug immunohistochemistry was performed. RESULTS: Compared to non-OPSCCs, OPSCCs were significantly associated with lymphovascular invasion, lymph node metastasis, larger maximal diameter of metastatic foci in the lymph nodes, and p16 expression. In addition, p16 expression correlated with high Twist and Snail/Slug expression. CONCLUSION: Expression of EMT markers, such as Twist and Snail/Slug, is related to p16 expression in OPSCC. This might indicate that HPV infection in OPSCCs alters the expression of EMT markers and results in metastases.


Assuntos
Carcinoma de Células Escamosas/secundário , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Transição Epitelial-Mesenquimal , Linfonodos/patologia , Proteínas Nucleares/metabolismo , Neoplasias Orofaríngeas/patologia , Fatores de Transcrição da Família Snail/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/complicações , Intervalo Livre de Progressão , Carga Tumoral
3.
Zhonghua Yi Xue Za Zhi ; 99(42): 3303-3307, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31715665

RESUMO

Objective: To studythe effect of lentivirus-mediated inhibition of Med19 on cell migration andinvasion in the PC3 cells, and explore the mechanism of epithelial-mesenchymal transition transformation. Methods: The lentivirus vectors containing small interferingRNA(siRNA) targeting Medl9 gene were constructed and transfected to PC3 cells.Quantitative real-time PCR(qRT-PCR) and Western blot analysis were used to detect the Medl9 expression in the siRNA group(PC3-Med 19-siRNA cells)and the NC group(PC3-Med 19-sc cells) at 72h after the transfection.The cell mobility,migration and invasion ability of PC3 cells were respectively measured by Boyden migration and woun-healing assay. The expression of E-Cadherin, N-Cadherin, Vimentin, ZEB2, Snail-1, and Snail-2 mRNA were detected by using qRT-PCR. Results: The expression of Medl9 mRNA in PC3-Med 19-siRNA cells was lower than that in PC3-Med 19-scRNA cells(P<0.01). The number of migrated cells and invaded cells were significantly decreased in PC3-Med 19-siRNA cells(P<0.01). The expression of N-Cadherin, Vimentin, ZEB2, Snail-1, and Snail-2 mRNA were remarkablylower and E-Cadherin was higher in PC3-Med 19-siRNA cells. Conclusion: Med 19 inhibitioncouldreduce migration abilityof prostate cancer PC3 cells by epithelial-mesenchymal transition.


Assuntos
Transição Epitelial-Mesenquimal , Complexo Mediador/metabolismo , Neoplasias da Próstata , Caderinas , Movimento Celular , Humanos , Masculino , Complexo Mediador/genética , Invasividade Neoplásica , Células PC-3
4.
Biochemistry (Mosc) ; 84(11): 1424-1432, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760928

RESUMO

A large body of evidence suggests that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT), as well as expression and function of retinoid receptors, are pivotal features of tumor initiation, progression, and chemoresistance. This is also true for pancreatic ductal adenocarcinoma (PDAC), which represents a clinical challenge due to poor prognosis and increasing incidence. Understanding the above features of cancer cells could open new avenues for PDAC treatment strategies. The aim of this study was to investigate the relation between CSCs, EMT, and retinoid receptors in PDAC after treatment with the chemotherapeutic agents - gemcitabine and 5-fluorouracil. First, we demonstrated the difference in the expression levels of CSC and EMT markers and retinoid receptors in the untreated Mia PaCa-2 and Panc1 cells that also differed in the frequency of spontaneous apoptosis and distribution between the cell cycle phases. Chemotherapy reduced the number of cancer cells in the S phase. Gemcitabine and 5-fluorouracil modulated expression of CSC markers, E-cadherin, and RXRß in Panc1 but not in Mia PaCa-2 cells. We suggest that these effects could be attributed to the difference in the basal levels of expression of the investigated genes. The obtained data could be interesting in the context of future preclinical research.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptor X Retinoide beta/metabolismo , Apoptose/efeitos dos fármacos , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fluoruracila/farmacologia , Humanos , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Receptor X Retinoide beta/genética , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos
5.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(5): 654-659, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31762233

RESUMO

OBJECTIVE: To investigate the expression of ß-catenin in the skin lesions of patients with systemic scleroderma (SSc) and its effect on epithelial-mesenchymal transition (EMT) of human epidermal keratinocytes. METHODS: The expression of ß-catenin, Snail1 and E-cadherin in the skin lesions sample of 45 SSc patients and normal skin sample from 20 healthy adults was detected with SP immunohistochemistry. HaCaT, the human epidermal keratinocytes, were treated with different concentrations of Wnt10b (0 ng/mL (control), 2 ng/mL and 4 ng/mL) for 48 h. then detected the localization of ß-catenin in HaCaT cells by immunofluorescence assay, determined the mRNA levels of Snail1 and Snail2 in HaCaT cells by real-time fluorescent quantitative PCR, detected the proteins expression of ß-catenin, Vimentin, N-cadherin and E-cadherin in HaCaT cells by Western blot. RESULTS: The positive rates of ß-catenin, Snail1 and E-cadherin in skin lesions of SSc patients were 100%, 88.89% and 2.22% respectively, while in healthy adult skin, the corresponding positive rates were 0%, 10.00%, and 95.00%. The difference between the two groups was significant. Compared with control group, treatment with different concentrations of Wnt10b (2 ng/mL and 4 ng/mL) induced up-regulation of ß-catenin expression and promoted translocation of ß-catenin from cytoplasm to nucleus, increased the mRNA levels of Snail1 and Snail2 (P < 0.05), and up-regulated the proteins expression of Vimentin, N-cadherin, down-regulated the E-cadherin protein expression in HaCaT cells (P < 0.05). CONCLUSIONS: Abnormally activated Wnt/ß-catenin signaling pathway and abnormally expressed EMT-related proteins are observed in SSc lesions. Activation of Wnt/ß-catenin signaling pathway may promote EMT in HaCaT cells.


Assuntos
Transição Epitelial-Mesenquimal , Queratinócitos/metabolismo , Escleroderma Sistêmico/metabolismo , Pele/metabolismo , beta Catenina/metabolismo , Adulto , Antígenos CD/metabolismo , Caderinas/metabolismo , Humanos , Queratinócitos/citologia , Escleroderma Sistêmico/patologia , Pele/patologia , Fatores de Transcrição da Família Snail/metabolismo , Vimentina/metabolismo , Via de Sinalização Wnt
6.
Zhonghua Yi Xue Za Zhi ; 99(38): 3019-3023, 2019 Oct 15.
Artigo em Chinês | MEDLINE | ID: mdl-31607036

RESUMO

Objective: To detect the expression of micro RNA(miRNA, miR)-30bin pancreatic cancer stem cells (PCSCs) and to observe the regulatory effect of miR-30b on epithelial-mesenchymal transformation (EMT) process, migration and invasion of PCSCs. Methods: CD24, CD44 and EpCAM triple-positive PCSCs in pancreatic ductal adenocarcinoma(PDAC) cell line PANC-1 were sorted out by flow cytometry and the expression of Nanog and Oct4 were evaluated. The expression profile of miR-30 family in PCSCs and common cancer cells was analyzed, and the memberwith the most obvious differential expression was selected.miR-30b mimic was transfected into PCSCs and then RT-qPCR or Western Blot were performed to investigate the expression of EMT markers. The effect of miR-30b on the migration and invasion ability of PCSCs was detected by Transwell assay. Then, miR-30b agomir was transfected into PCSCs and inoculated in nude mice to study the effect of mir-30b on the tumorigenic ability. Results: PCSCs accounted for 4.52-8.09% of the total. The mRNA and protein levels of Oct4 and Nanog of PCSCswere significantly higher than those of PANC-1(P<0.001). The expression levels of miR-30b, c and d were significantly down-regulated, among which miR-30b was the most significant. After miR-30b overexpression in PCSCs, E-cadherin was significantly up-regulated (P<0.001), N-cadherin (P<0.001) and transcription factor Snail (P<0.001) were significantly down-regulated, while vimentin expression was not significantly changed. Transwell assay showed that both migration and invasiveness of PCSCs were significantly decreased after transfection (P<0.001). In vivo experiments, the tumor volume and weight of the nude mice injected with PCSCs overexpressing miR-30b were also significantly lower than those of the control group (P<0.01). Conclusions: CD24, CD44 and EpCAMtriple positive PCSCs in pancreatic cancer cells showed obvious stemness characteristics. miR-30b can reverse the EMT process of PCSCs, reduce their migration and invasion, and inhibit the tumorigenicity of PCSCs.


Assuntos
Neoplasias Pancreáticas , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Camundongos , Camundongos Nus , MicroRNAs , Células-Tronco Neoplásicas , Neoplasias Pancreáticas/genética
7.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(9): 1016-1022, 2019 Sep 28.
Artigo em Chinês | MEDLINE | ID: mdl-31645491

RESUMO

OBJECTIVE: To investigate the correlation between the number of peripheral blood circulating tumor cells (CTCs) and clinicopathological features of early breast cancer. 
 Methods: The clinical and pathological data from 100 patients with early breast cancer treated by a breast cancer treatment team in the Department of Breast Surgery, Second Xiangya Hospital, Central South University, were collected from January 2017 to December 2018. For these patients, their peripheral blood CTCs were detected, enumerated and typed by CanpatrolTM CTC assay.
 Results: The positive rate of CTCs was 90% in peripheral blood of patients with early breast cancer, and the majority of molecular phenotypes was hybrid CTCs (55.6%). The positive rate of CTCs was only related to the pathological type of tumor (P<0.05), but not to other clinicopathological features. No correlation between clinicopathological features and the total number of CTCs, the number of epithelial CTCs or the number of hybrid CTCs was found. However, the number of mesenchymal CTCs was significantly correlated with the expression of hormone receptors and Ki-67 (r=0.200, P<0.05), and there was a significant correlation between the proportion of mesenchymal CTCs and the expression level of Ki-67 (r=0.213, P<0.05).
 Conclusion: The number of CTCs is not correlated with all clinicopathological features, but patients with negative hormone receptor and high expression of Ki-67 probably have more hybrid CTCs.


Assuntos
Neoplasias da Mama , Células Neoplásicas Circulantes , Biomarcadores Tumorais , Transição Epitelial-Mesenquimal , Humanos
8.
Chem Biol Interact ; 314: 108846, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606474

RESUMO

Matrix metalloproteinases (MMPs) have been implicated in EMT but their role in the regulation of cigarette smoke-induced EMT in airway epithelium is not clear. We have therefore investigated the potential role of MMP-2 and -9 in cigarette smoke extract (CSE) induced EMT using A549 lung epithelial cells and human small airway epithelial cells (SAEC). The cells were treated with different concentration of CSE, and MTT and trypan blue assays, acridine orange-ethidium bromide assay, gelatin zymography, Western blotting, immunofluorescence studies, Boyden-chamber assay, wound healing assay and air-liquid interface (ALI) culture were used to assess different cellular and molecular changes associated with EMT. The results depict that CSE increased the cytotoxicity along with a concurrent increase in the expression and activity of MMP-2 and -9. CSE further altered EMT markers like E-cadherin, N-cadherin, vimentin, and the molecular modulators of EMT such as ß-catenin and pGSK-3ß. Further, CSE also upregulated EGFR, AKT, and ERK1/2 in airway epithelial cells. SB-3CT, a known inhibitor of MMP-2 and -9, altered and reversed the expression of markers of EMT and kinases, validating the role of MMP-2 and -9 in CSE-induced EMT. Fisetin, a plant-derived bioflavonoid, also reversed the expression of EMT markers and molecular regulators in a similar fashion as SB-3CT. In summary, this study highlights the role of MMP-2 and -9 in CSE-induced EMT and curate its molecular cascade through EGFR/AKT/ERK/ß-catenin axis, which could be restored by MMP-2 and -9 inhibitor and fisetin. Fisetin is hitherto unknown to modulate CSE-induced MMPs activity in airway epithelial cells, and our study suggests its potential role as a therapeutic approach in CSE-induced EMT in lung epithelial cells.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Flavonoides/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fumaça/efeitos adversos , Tabaco/química , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo
9.
Anticancer Res ; 39(10): 5393-5401, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570434

RESUMO

BACKGROUND/AIM: Local recurrence of hepatocellular carcinoma (HCC) after thermal coagulation therapy may be associated with an aggressive phenotypic change. This study focused on the thermal effects on HCC cells and evaluated the heat shock response and phenotypic changes after heat treatment. MATERIALS AND METHODS: HepG2 and HuH7 cells were used. After heat treatment at 37-50°C for 5-30 min, we assessed their survival rate, induction of heat shock protein (HSP)70 promoter, proliferation rate, induction of the epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related markers. RESULTS: Induction of HSP70 promoter per surviving cell was maximized after 10 min of heat treatment at 48°C. Induction of EMT and CSC-related markers was also observed. CONCLUSION: Sub-lethal heat treatment causes large heat shock response to surviving HCC cells and induce EMT-like and CSC-like phenotypic changes that might contribute to increased aggressiveness.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Resposta ao Choque Térmico/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Transição Epitelial-Mesenquimal/genética , Proteínas de Choque Térmico HSP70/genética , Células Hep G2 , Temperatura Alta , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Taxa de Sobrevida
10.
Anticancer Res ; 39(10): 5437-5448, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570438

RESUMO

BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) is a key multi-step process which enables cancer cells to detach from the epithelial primary tumor mass and allows them to metastasize to distant organs. We immunohistochemically analyzed the expression of the transcription factors (TWIST-1, SLUG, ZEB1, ZEB2) and components of the extracellular matrix (laminin-5, fibronectin) which influence the EMT. MATERIALS AND METHODS: Primary human breast (MDA-MB-231), colon (HT29, HCT116), ovarian (SKOV3, OVCAR3) and head and neck squamous cell carcinoma cell lines (UTSCC2, UTSCC24A) grown as xenografts were immunohistochemically analyzed in vitro and in vivo. RESULTS: A high SLUG expression was observed in every cancer entity both in vitro and in vivo. ZEB1 and ZEB2 showed a high in vivo expression especially in SKOV3 and in in vitro grown MDA-MB-231 cells. CONCLUSION: SLUG expression showed the highest expression in all cancer entities investigated. Hence, it presumably represents the master regulator of EMT in these metastatic tumor entities.


Assuntos
Biomarcadores Tumorais/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Células HCT116 , Células HT29 , Humanos , Imuno-Histoquímica/métodos , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
11.
Adv Exp Med Biol ; 1164: 3-10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576536

RESUMO

Pancreatic ductal adenocarcinoma is an overwhelming fatal disease that often presents with overt metastases and ultimately causes the majority of cancer-associated deaths. The mechanisms underlying the metastatic cascade are complex, and research in recent years has begun to provide insights into the underlying drivers of this phenomenon. It has become clear that cancer cells, in particular pancreatic cancer cells, possess properties of plasticity involving bidirectional transition between epithelial and mesenchymal identities. Furthermore, recent work has begun to establish that there are distinct hybrid states between purely epithelial and purely mesenchymal states that cancer cells may reside, in order to thrive at different stages of carcinogenesis. We discuss how this plasticity is important for different phases of the metastatic cascade, from delamination to colonization, and how different epithelial-mesenchymal states may affect metastatic organotropism. In this review, we summarize the current understanding of pancreatic cancer cell plasticity and metastasis, and highlight current model systems that can be used to study these phenomena.


Assuntos
Carcinoma Ductal Pancreático , Plasticidade Celular , Neoplasias Pancreáticas , Carcinogênese , Carcinoma Ductal Pancreático/fisiopatologia , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Neoplasias Pancreáticas/fisiopatologia
12.
Adv Exp Med Biol ; 1164: 35-46, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576538

RESUMO

We have characterized two highly tumorigenic and metastatic basal B TNBC cell lines, XtMCF and LmMCF, with the additional values of having the normal and early-stage counterparts of them. This model allows the study of the evolution of TNBC, and investigates molecular pathways at different stages of transformation and progression in a relatively constant genetic background. This constitutes an ideal model for developing targeted therapy in two important fields in cancer biology which are the epithelial mesenchymal transition (EMT) and cancer stem cells (CSC).


Assuntos
Linhagem Celular Tumoral , Modelos Biológicos , Neoplasias de Mama Triplo Negativas , Transição Epitelial-Mesenquimal , Humanos , Técnicas In Vitro , Células-Tronco Neoplásicas
13.
Int J Nanomedicine ; 14: 7237-7247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564876

RESUMO

Background: The health hazards of silica nanoparticle (SiNP) are raising worldwide concern as SiNPs has become the second largest manufactured nanomaterial in global markets. However, insufficient data for the adverse health effects and safety evaluation of SiNPs are remaining a big question. Purpose: We evaluated the effects and related mechanism of SiNPs on pulmonary inflammation and collagen production through repeated intravenous administration in mice in a 45-day observation period. Methods: Morphological and ultrastructural change, ultradistribution of SiNPs in lungs were observed in ICR mice through intravenous administration. Oxidative damage, pro-inflammatory cytokines, hydroxyproline content, the marker of fibroblasts and epithelial-mesenchymal transition (EMT), and JAK2/STAT3 and TGF-ß1/Smad3 signaling pathways were detected to explore the lung injuries and related mechanism. Results: The results showed repeated intravenous exposure of SiNPs increased the weight of lung tissues and destroyed pulmonary histomorphological structure. The increased MDA content, depletion of SOD and GSH-Px in lungs were observed in SiNP-treated mice. The protein expressions of JAK2/STAT3 pathway were upregulated in lungs, and the levels of inflammatory cytokines TNF-α, IL-1ß, and IL-6 in serum and lungs were also elevated in SiNPs treated group. The increased hydroxyproline content indicated collagen accumulation in lungs of SiNP-treated mice. Meanwhile, the protein expressions of the marker of myofibroblast (a-SMA), the regulators in connective tissue remodeling (CTGF), TGF-ß, and p-Smad3 were all upregulated in lungs. In addition, we found intravenous administration of SiNPs-induced ultrastructural changes in type II alveolar epithelial cells but without downregulation of the protein expression of the key markers of epithelial cells (E-Cadherin). Conclusion: Our results revealed that oxidative stress and inflammation contributed to the collagen accumulation through activation of JAK2/STAT3 and TGF-ß/Smad3 pathways. It suggests that pulmonary aberrant inflammation and collagen accumulation induced by nanoparticles should be seriously considered for the safety application in diagnostics or therapeutics.


Assuntos
Colágeno/metabolismo , Janus Quinase 2/metabolismo , Nanopartículas/administração & dosagem , Pneumonia/patologia , Transdução de Sinais , Dióxido de Silício/administração & dosagem , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Administração Intravenosa , Animais , Caderinas/metabolismo , Citocinas/metabolismo , Transição Epitelial-Mesenquimal , Fibroblastos/metabolismo , Pulmão/patologia , Pulmão/ultraestrutura , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos ICR , Modelos Biológicos , Miofibroblastos/metabolismo , Nanopartículas/ultraestrutura , Estresse Oxidativo , Fator de Transcrição STAT3/metabolismo
14.
J Cancer Res Clin Oncol ; 145(12): 2875-2889, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31630262

RESUMO

PURPOSE: Circular RNAs (circRNAs), a large class of non-coding RNAs with covalently closed-loop structures, are abundant, stable, conserved, and have tissue and developmental-stage specificities. The biological functions of circRNAs are varied. Moreover, circRNAs participate in various pathological processes, especially in multiple cancers. Lung cancer is the most frequent malignant tumor worldwide. Many studies have suggested that circRNAs are pivotal in non-small cell lung cancer. This article aims to provide a retrospective review of the latest research on the functions of circRNAs in non-small cell lung cancer. In particular, we focus our discussion on the role of circRNAs in cell-cycle regulation and the epithelial-mesenchymal transition, and also discuss the known regulatory molecular mechanisms of circRNAs in non-small cell lung cancer. METHODS: We reviewed the literature on circRNAs and non-small cell lung cancer from PubMed databases. Specifically, we focused on the roles and mechanisms of circRNAs in regulating the cell cycle and the epithelial-mesenchymal transition. RESULTS: Dysregulation of circRNAs is closely correlated with proliferation, migration, and invasion of non-small cell lung cancer, especially in terms of modulating cell-cycle regulation and the epithelial-mesenchymal transition. CONCLUSION: Taken together, circRNAs have potential as biomarkers for the diagnosis, prognosis, and treatment of non-small cell lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , RNA/genética , Animais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Transição Epitelial-Mesenquimal/genética , Humanos , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Prognóstico , Estudos Retrospectivos
15.
Neoplasma ; 66(6): 896-907, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607129

RESUMO

Malic enzyme 3 (ME3) aberrant expression contributes to the development of human malignancies. ME3 expression was higher in pancreatic cancer tissues than that in non-tumor tissues, and patients with higher ME3 levels had significantly shorter survival than those with lower levels analyzed by of Badea and TCGA databases. Further, the abilities of proliferation, migration and invasion in pancreatic cancer cells were inhibited by ME3 knockdown and were promoted by ME3 overexpression. Meanwhile, ME3 can promote EMT in pancreatic cancer cells possibly by regulation of TGF-ß/Smad2/3 signaling pathway. In conclusion, ME3 is extensively involved in carcinogenesis of pancreatic cancer and may become a new candidate target for diagnosis, treatment and prognosis of pancreatic cancer.


Assuntos
Transição Epitelial-Mesenquimal , Malato Desidrogenase (NADP+)/metabolismo , Neoplasias Pancreáticas/enzimologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Malato Desidrogenase (NADP+)/genética , Invasividade Neoplásica , Neoplasias Pancreáticas/patologia
16.
Neoplasma ; 66(6): 918-929, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607134

RESUMO

Protein arginine methyltransferase 1 (PRMT1) is dysregulated in a number of human cancers. Herein, we report that PRMT1 expression is directly associated with epithelial-mesenchymal transition (EMT) in hepatic carcinoma cells. Firstly, we find that PRMT1 expression is higher in hepatic carcinoma tissues than that in normal liver tissues at both mRNA and protein levels, and higher expression of PRMT1 correlates with poor survival in liver tumors. The data in vitro reveals that PRMT1 knockdown inhibits the abilities of proliferation, migration and invasion, while PRMT1 overexpression promotes the above behaviors in hepatic carcinoma cells. Further studies indicate that PRMT1 knockdown remarkably decreases the expression of mesenchymal markers including Vimentin, Snail and N-cadherin, and upregulates expression of epithelial markers E-cadherin. Conversely, PRMT1 overexpression results in the opposite effects. Additionally, we identified that PRMT1 knockdown resulted in downregulation of TGF-ß1, p-Smad2 and p-Smad3, while PRMT1 overexpression activated TGF-ß1, p-Smad2 and p-Smad3. These findings suggest that PRMT1 promotes EMT in hepatic carcinoma cells probably via TGF-ß1/Smad pathway, and might represent a novel anti-liver cancer strategy.


Assuntos
Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/patologia , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
17.
Toxicol Lett ; 317: 102-109, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31574306

RESUMO

BACKGROUND: Cigarette smoke is considered a risk factor for lung and colorectal cancer. A convincing link between epithelial-to-mesenchymal transition (EMT) with colorectal cancer progression and therapeutic resistance has emerged. Deregulated expression of E-Cadherin and Claudin-1 and increased miR-21 expression and invasiveness represent hallmarks of EMT. The effects of cigarette smoke exposure on EMT in colorectal adenocarcinoma cells are largely unknown. AIM: The aim of the study is to evaluate the effect of cigarette smoke extract (CSE) on miR-21, Claudin-1 and E-Cadherin, molecules associated to EMT in colorectal cancer cells. METHODS: A human colorectal adenocarcinoma cell line (Caco-2) was treated with CSE at different concentration (5% and 10%) and for different time points (3 h and 24 h). Metabolic activity (by MTS assay), cell necrosis/cell apoptosis (evaluating Propidium Iodide/Annexin V expression by flow cytometry), miR-21, Claudin-1 and E-Cadherin gene expression were evaluated by Real time PCR. Cell permeability, actin polymerization and cancer cell migration was assessed by Trans-Epitelial Electrical Resistance (TEER), Phalloidin expression and matrigel system, respectively. RESULTS: CSE at all the tested concentrations and at all time points reduced cell necrosis. CSE at 10% increased miR-21 and reduced the metabolic activity, cell necrosis, Claudin-1 and E-cadherin mRNA at 3 h. Cell permeability, actin polymerization and cancer cell migration were all increased upon CSE exposure. CONCLUSION: These results showed that CSE increasing miR-21, Claudin-1 and E-Cadherin and enhancing the aggressiveness of cancer cells, may concur to colorectal cancer progression.


Assuntos
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Movimento Celular , Fumar Cigarros/efeitos adversos , Claudina-1/metabolismo , Neoplasias Colorretais/metabolismo , MicroRNAs/metabolismo , Fumaça/efeitos adversos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Antígenos CD/genética , Células CACO-2 , Caderinas/genética , Claudina-1/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Invasividade Neoplásica , Transdução de Sinais
18.
Cell Physiol Biochem ; 53(4): 713-730, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31599538

RESUMO

BACKGROUND/AIMS: Renal injury related to hypertension is characterized by glomerular and tubulointerstitial damage. The overactivation of the renin-angiotensin system mainly by angiotensin II (AII) seems to be a main contributor to progressive renal fibrosis. Epithelial to mesenchymal transition (EMT) is a mechanism that promotes renal fibrosis. Owing to heat shock protein 70 (Hsp70) cytoprotective properties, the chaperone exhibits an important potential as a therapeutic target. We investigate the role of Hsp70 on Angiotensin II induced epithelial mesenchymal transition within the Losartan effect in proximal tubule cells (PTCs) from a genetic model of hypertension in rats (SHR). METHODS: Primary cell culture of PTCs from SHR and Wistar Kyoto (WKY) rats were stimulated with AII, treated with Losartan (L), (L+AII) or untreated (Cc). The functional Hsp70 role in Losartan effect, after silencing its expression by cell transfection, was determined by Immunofluorescence; Western blotting; Gelatin Zymography assays; Scratch wound assays; flow cytometry; and Live Cell Time-lapse microscopy. RESULTS: (L) and (L+AII) treatments induced highly organized actin filaments and increased cortical actin in SHR PTCs. However, SHR PTCs (Cc) and (AII) treated cells showed disorganized actin. After Hsp72 knockdown in SHR PTCs, (L) was unable to stabilize the actin cytoskeleton. We demonstrated that (L) and (L+AII) increased E-cadherin levels and decreased vinculin, α-SMA, vimentin, pERK, p38 and Smad2-3 activation compared to (AII) and (Cc) SHR PTCs. Moreover, (L) inhibited MMP-2 and MMP-9 secretion, reduced migration and cellular displacement, stabilizing intercellular junctions. Notably, (L) treatment in shHsp72 knockdown SHR PTCs showed results similar to SHR PTCs (Cc). CONCLUSION: Our results demonstrate that Losartan through Hsp70 inhibits the EMT induced by AII in proximal tubule cells derived from SHR.


Assuntos
Angiotensina II/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/metabolismo , Losartan/farmacologia , Citoesqueleto de Actina/efeitos dos fármacos , Animais , Caderinas/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Adesões Focais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/genética , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vinculina/metabolismo
19.
Med Oncol ; 36(11): 95, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31637536

RESUMO

Ovarian cancer is one of the most lethal gynecological cancers; owning to its late detection and chemoresistance, understanding the pathogenesis of this malignant tumor is much critical. Previous studies have reported that ubiquitin-specific peptidase 39 (USP39) is generally overexpressed in a variety of cancers, including hepatocellular carcinoma, gastric cancer and so forth. Furthermore, USP39 is proved to be associated with the proliferation of malignant tumors. However, the function and mechanism of USP39 in ovarian cancer have not been elucidated. In the present study, we observed that USP39 was frequently overexpressed in human ovarian cancer and was highly correlated with TNM stage. Suppression of USP39 markedly inhibited the growth and migration of ovarian cancer cell lines HO-8910 and SKOV3 and induced cell cycle G2/M arrest. Moreover, knockdown of USP39 inhibited ovarian tumor growth in a xenograft model. In addition, our findings indicated that cell cycle arrest induced by USP39 knockdown might be involved in p53/p21 signaling pathway. Furthermore, we found that the depletion of USP39 inhibited the migration of ovarian cancer cells via blocking epithelial-mesenchymal transition. Taken together, these results suggest that USP39 may play vital roles in the genesis and progression and may serve as a potential biomarker for diagnosis and therapeutic target of ovarian cancer.


Assuntos
Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Animais , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular , Técnicas de Silenciamento de Genes , Células HEK293 , Xenoenxertos , Humanos , Imuno-Histoquímica , Pontos de Checagem da Fase M do Ciclo Celular , Camundongos , Camundongos Nus , Estadiamento de Neoplasias , Neoplasias Ovarianas/enzimologia , Transdução de Sinais , Proteases Específicas de Ubiquitina/biossíntese , Proteases Específicas de Ubiquitina/genética
20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(8): 673-681, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31638563

RESUMO

Objective To investigate the impact of the macrophage-derived exosomes on transforming growth factor-ß1 (TGF-ß1)-induced epithelial-mesenchymal transition (EMT) of lung epithelial cells in an inflammatory environment. Methods The morphology of exosomes derived from THP-1 macrophages was evaluated by transmission electron microscopy, and the biochemistry properties of exosomes were identified by accessing exosome-specific markers including tumor susceptibility gene 101 (TSG101), accessory protein ALG-2 interacting protein X (ALIX), CD81 and CD9 protein, and the calnexin, a negative control marker absent in exosomes, using an immunoblotting assay. The EMT of alveolar epithelial A549 cells was induced by TGF-ß1, and the impacts of exosomes on the EMT of A549 cells was ascertained by comparing cells treated with exsomes derived from LPS-primed THP-1 macrophages and naive THP-1 cells. Results We successfully established an A549 cell EMT model by TGF-ß1 induction and isolated exosomes derived from THP-1 macrophages. In comparison with the exosomes derived from untreated naive THP-1 macrophages, exosomes derived from LPS-primed THP-1 cells exhibited an ability to significantly promote TGF-ß-induced EMT of A549 cells, as determined by a significantly down-regulated E-cadherin, and an dramatically increased expression of proteins in EMT-related signaling including vimentin, alpha smooth muscle actin (α-SMA), TGF-ß1/Smad2/3 signaling proteins Smad2/3 protein and phosphorylated Smad2/3 (p-Smad2/3) and type 1 collagen (Col1). Conclusion Exosomes derived from LPS-stimulated macrophages are able to activate TGF-ß/Smad2/3 signaling, which in turn increase the expression of EMT-related proteins vimentin, α-SMA and Col1 in A549 cells, and subsequently promote EMT in A549 cells.


Assuntos
Transição Epitelial-Mesenquimal , Exossomos , Macrófagos , Fator de Crescimento Transformador beta1 , Células A549 , Transição Epitelial-Mesenquimal/fisiologia , Exossomos/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo
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