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1.
Medicine (Baltimore) ; 99(41): e22271, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031269

RESUMO

BACKGROUND: This study will summarize the clinical significance of E-Cadherin and ß-catenin in early gastric cancer (EGC). METHODS: Eligible case-control studies were searched from Cochrane Library, PUBMED, EMBASE, PsycINFO, Google Scholar, CBM, and CNKI from inception to the present. In addition, we will also search other sources to avoid missing potential studies. Two authors will independently carry out study selection, data collection, and study methodological quality. A fixed or random-effects model will be utilize to synthesize the data, and RevMan 5.3 software will be used for data analysis. RESULTS: This study will summarize all eligible studies to investigate the clinical significance of E-Cadherin and ß-catenin in EGC. CONCLUSION: The findings of this study may present a genuine understanding of perspective on the clinical significance of E-Cadherin and ß-catenin in EGC.


Assuntos
Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Projetos de Pesquisa , Neoplasias Gástricas/metabolismo , beta Catenina/metabolismo , Humanos , Revisões Sistemáticas como Assunto
2.
Nat Commun ; 11(1): 4477, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901019

RESUMO

Individual cells detach from cohesive ensembles during development and can inappropriately separate in disease. Although much is known about how cells separate from epithelia, it remains unclear how cells disperse from clusters lacking apical-basal polarity, a hallmark of advanced epithelial cancers. Here, using live imaging of the developmental migration program of Drosophila primordial germ cells (PGCs), we show that cluster dispersal is accomplished by stabilizing and orienting migratory forces. PGCs utilize a G protein coupled receptor (GPCR), Tre1, to guide front-back migratory polarity radially from the cluster toward the endoderm. Posteriorly positioned myosin-dependent contractile forces pull on cell-cell contacts until cells release. Tre1 mutant cells migrate randomly with transient enrichment of the force machinery but fail to separate, indicating a temporal contractile force threshold for detachment. E-cadherin is retained on the cell surface during cell separation and augmenting cell-cell adhesion does not impede detachment. Notably, coordinated migration improves cluster dispersal efficiency by stabilizing cell-cell interfaces and facilitating symmetric pulling. We demonstrate that guidance of inherent migratory forces is sufficient to disperse cell clusters under physiological settings and present a paradigm for how such events could occur across development and disease.


Assuntos
Drosophila melanogaster/embriologia , Células Germinativas Embrionárias/fisiologia , Animais , Animais Geneticamente Modificados , Fenômenos Biomecânicos , Padronização Corporal/fisiologia , Caderinas/metabolismo , Adesão Celular/fisiologia , Movimento Celular/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/fisiologia , Células Germinativas Embrionárias/citologia , Microscopia de Fluorescência por Excitação Multifotônica , Miosina Tipo II/metabolismo , Transdução de Sinais , Análise de Célula Única , Proteínas rho de Ligação ao GTP/metabolismo
4.
Nat Commun ; 11(1): 3987, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778678

RESUMO

Aneuploidy, the presence of an abnormal number of chromosomes, is a major cause of early pregnancy loss in humans. Yet, the developmental consequences of specific aneuploidies remain unexplored. Here, we determine the extent of post-implantation development of human embryos bearing common aneuploidies using a recently established culture platform. We show that while trisomy 15 and trisomy 21 embryos develop similarly to euploid embryos, monosomy 21 embryos exhibit high rates of developmental arrest, and trisomy 16 embryos display a hypo-proliferation of the trophoblast, the tissue that forms the placenta. Using human trophoblast stem cells, we show that this phenotype can be mechanistically ascribed to increased levels of the cell adhesion protein E-CADHERIN, which lead to premature differentiation and cell cycle arrest. We identify three cases of mosaicism in embryos diagnosed as full aneuploid by pre-implantation genetic testing. Our results present the first detailed analysis of post-implantation development of aneuploid human embryos.


Assuntos
Aneuploidia , Implantação do Embrião/genética , Embrião de Mamíferos , Desenvolvimento Embrionário , Antígenos CD/genética , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Pontos de Checagem do Ciclo Celular , Linhagem da Célula , Segregação de Cromossomos , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 21 , Feminino , Genes erbB-1/genética , Testes Genéticos , Humanos , Monossomia , Mosaicismo , Gravidez , Células-Tronco , Trissomia
5.
Medicine (Baltimore) ; 99(34): e21821, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846824

RESUMO

BACKGROUND: Traditional Chinese medicine Tongxinluo (TXL) has been widely used to treat coronary artery disease in China, since it could reduce myocardial infarct size and ischemia/reperfusion injury in both non-diabetic and diabetic conditions. It has been shown that TXL could regulate peroxisome proliferator activated receptor-α (PPAR-α), a positive modulator of angiopoietin-like 4 (Angptl4), in diabetic rats. Endothelial junction substructure components, such as VE-cadherin, are involved in the protection of reperfusion injury. Thus, we hypothesized cell-intrinsic and endothelial-specific Angptl4 mediated the protection of TXL on endothelial barrier under high glucose condition against ischemia/reperfusion-injury via PPAR-α pathway. METHODS: Incubated with high glucose medium, the human cardiac microvascular endothelial cells (HCMECs) were then exposed to oxygen-glucose-serum deprivation (2 hours) and restoration (2 hours) stimulation, with or without TXL, insulin, or rhAngptl4 pretreatment. RESULTS: TXL, insulin, and rhAngptl4 had similar protective effects on the endothelial barrier. TXL treatment reversed the endothelial barrier breakdown in HCMECs significantly as identified by decreasing endothelial permeability, upregulating the expression of JAM-A, VE-cadherin, and integrin-α5 and increasing the membrane location of VE-cadherin and integrin-α5, and these effects of TXL were as effective as insulin and rhAngptl4. However, Angptl4 knock-down with small interfering RNA (siRNA) interference and PPAR-α inhibitor MK886 partially abrogated these beneficial effects of TXL. Western blotting also revealed that similar with insulin, TXL upregulated the expression of Angptl4 in HCMECs, which could be inhibited by Angptl4 siRNA or MK886 exposure. TXL treatment increased PPAR-α activity, which could be diminished by MK886 but not by Angptl4 siRNA. CONCLUSION: These data suggest cell-intrinsic and endothelial-specific Angptl4 mediates the protection of TXL against endothelial barrier breakdown during oxygen-glucose-serum deprivation and restoration under high glucose condition partly via the PPAR-α/Angptl4 pathway.


Assuntos
Proteína 4 Semelhante a Angiopoietina/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/efeitos dos fármacos , Endotélio/efeitos dos fármacos , Endotélio/fisiopatologia , PPAR alfa/metabolismo , Proteína 4 Semelhante a Angiopoietina/genética , Proteína 4 Semelhante a Angiopoietina/farmacologia , Caderinas/metabolismo , Permeabilidade Capilar , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Vasos Coronários/citologia , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Glucose/farmacologia , Humanos , Indóis/farmacologia , Insulina/farmacologia , Integrina alfa5/metabolismo , Inibidores de Lipoxigenase/farmacologia , Microvasos/citologia , Oxigênio/metabolismo , Oxigênio/farmacologia , Receptores de Superfície Celular/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais
6.
Free Radic Res ; 54(7): 540-555, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32842802

RESUMO

Radiotherapy is an important treatment regime for lung cancer, worldwide. However, radiation-induced pneumonitis and fibrosis are the treatment-limiting toxicities among patients who have undergone radiotherapy. The epithelial cells via epithelial to mesenchymal transition [EMT] acquires mesenchymal phenotype, which ultimately leads to fibrosis. Many investigations are focussed on understanding the signalling pathways mediating in EMT, however, the role of histone methylation is less understood in radiation-induced lung EMT. In the present study, we analysed the effect of vanillin, an antioxidant, on histone methylation during radiation-induced EMT. The thoracic region of Wistar rats was irradiated with a fractionated dose of X-ray (3 Gy/day) for two weeks (total of 30 Gy). The irradiated animals were sacrificed at the 8th and 16th weeks and tissues were used for analyses. Our data showed that radiation decreased the level of antioxidant enzymes such as SOD, catalase and reduced glutathione that would ultimately enhance oxidative stress in the tissues. Histopathological analysis revealed that radiation increased the infiltration of inflammatory cells to the tissue injury site. Total global histone methylation was increased upon irradiation, which was effectively prevented by vanillin administration. Vanillin enhanced E-cadherin expression and decreased the mesenchymal markers N-cadherin and vimentin in the irradiated lung tissue. The ChIP-qPCR analysis suggested that snail expression in the nucleus might involve in the enrichment of suppressive marker H3K9me3 on the E-cadherin promoter. Finally, we suggested that vanillin administration decreased radiation-induced oxidative stress and EMT expression. Additionally, irradiation increased the H3K9 methylation status with nuclear translocation of snail during lung EMT.


Assuntos
Antígenos CD/metabolismo , Benzaldeídos/metabolismo , Caderinas/metabolismo , Histonas/metabolismo , Pulmão/efeitos da radiação , Células A549 , Animais , Antígenos CD/genética , Caderinas/genética , Transição Epitelial-Mesenquimal , Feminino , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia , Metilação/efeitos da radiação , Estresse Oxidativo/efeitos da radiação , Regiões Promotoras Genéticas , Ratos , Ratos Wistar
7.
Anticancer Res ; 40(7): 3751-3757, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620614

RESUMO

BACKGROUND/AIM: Colorectal cancer is frequently associated with metabolic diseases. Adiponectin (APN) is an insulin-sensitizing adipokine circulating as low molecular weight (LMW), medium molecular weight (MMW) and high molecular weight (HMW) oligomers; the latter are the most bio-active oligomers. APN, through AdipoR1, AdipoR2 and T-cadherin receptors, regulates inflammation, and proliferation. Considering the anti-proliferative and anti-inflammatory properties of APN, we investigated the involvement of the "APN system" in colorectal cancer. MATERIALS AND METHODS: A total of 44 colorectal cancer patients and 51 healthy controls were recruited. We analysed APN and HMW oligomers in sera, AdipoR1, AdipoR2 and T-cadherin expression in non-cancerous and cancerous colon tissues. RESULTS: we found statistically lower levels of APN in patients compared to controls, with a specific decrease of HMW oligomers. Importantly, APN correlated to cancer grade. AdipoR1 was found overexpressed in cancerous compared to non-cancerous tissues while AdipoR2 and T-cadherin were down-regulated. CONCLUSION: The deregulated expression of the "APN system" in colorectal cancer with a specific correlation to tumor grade suggests APN as a promising biomarker in colorectal cancer.


Assuntos
Adiponectina/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Estudos Transversais , Regulação para Baixo/fisiologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores/métodos
8.
J Cancer Res Clin Oncol ; 146(10): 2559-2574, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32681294

RESUMO

PURPOSE: Canonical Wnt/ ß-catenin pathway is one mechanism being activated in platinum-resistant epithelial ovarian cancer (EOC). Detecting potential targets for Wnt pathway modulation as a putative future therapeutic approach was the aim of this study. METHODS: Biological effects of different Wnt modulators (SB216763, XAV939 and triptolide) on the EOC cell lines A2780 and its platinum-resistant clone A2780cis were investigated via multiple functional tests. Immunohistochemistry (IHC) was carried out to compare the expression levels of Wnt marker proteins (ß-catenin, snail/ slug, E-cadherin) in patient specimens and to correlate them with lifetime data. RESULTS: We could show that activated Wnt signaling of the platinum-resistant EOC cell line A2780cis can be reversed by Wnt manipulators through SB216763 or XAV939. All Wnt manipulators tested consecutively decreased cell proliferation and cell viability. Apoptosis of A2780 and A2780cis was enhanced by triptolide in a dose-dependent manner, whereas cell migration was inhibited by SB216763 and triptolide. IHC analyses elucidated significantly different expression patterns for Wnt markers in the serous subtype. Herein, higher plasmatic snail/ slug expression is associated with improved progression-free (PFS) and overall survival (OS). CONCLUSION: According to the described effects on EOC biology, all three Wnt manipulators seem to have the potential to augment the impact of a platinum-based chemotherapy in EOC. This is promising as a dominance of this pathway was confirmed in serous histology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Antígenos CD/biossíntese , Antígenos CD/metabolismo , Caderinas/biossíntese , Caderinas/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Diterpenos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Compostos de Epóxi/farmacologia , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Indóis/farmacologia , Maleimidas/farmacologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Neoplasias Ovarianas/patologia , Fenantrenos/farmacologia , beta Catenina/biossíntese , beta Catenina/metabolismo
9.
PLoS Negl Trop Dis ; 14(7): e0007960, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32687500

RESUMO

Intracerebral microhemorrhages (CMHs) are small foci of hemorrhages in the cerebrum. Acute infections induced by some intracellular pathogens, including rickettsia, can result in CMHs. Annexin a2 (ANXA2) has been documented to play a functional role during intracellular bacterial adhesion. Here we report that ANXA2-knockout (KO) mice are more susceptible to CMHs in response to rickettsia and Ebola virus infections, suggesting an essential role of ANXA2 in protecting vascular integrity during these intracellular pathogen infections. Proteomic analysis via mass spectrometry of whole brain lysates and brain-derived endosomes from ANXA2-KO and wild-type (WT) mice post-infection with R. australis revealed that a variety of significant proteins were differentially expressed, and the follow-up function enrichment analysis had identified several relevant cell-cell junction functions. Immunohistology study confirmed that both infected WT and infected ANXA2-KO mice were subjected to adherens junctional protein (VE-cadherin) damages. However, key blood-brain barrier (BBB) components, tight junctional proteins ZO-1 and occludin, were disorganized in the brains from R. australis-infected ANXA2-KO mice, but not those of infected WT mice. Similar ANXA2-KO dependent CMHs and fragments of ZO-1 and occludin were also observed in Ebola virus-infected ANXA2-KO mice, but not found in infected WT mice. Overall, our study revealed a novel role of ANXA2 in the formation of CMHs during R. australis and Ebola virus infections; and the underlying mechanism is relevant to the role of ANXA2-regulated tight junctions and its role in stabilizing the BBB in these deadly infections.


Assuntos
Anexina A2/metabolismo , Hemorragia Cerebral/metabolismo , Ebolavirus/fisiologia , Doença pelo Vírus Ebola/metabolismo , Infecções por Rickettsia/metabolismo , Rickettsia/fisiologia , Animais , Anexina A2/genética , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Hemorragia Cerebral/genética , Hemorragia Cerebral/microbiologia , Hemorragia Cerebral/virologia , Endossomos/genética , Endossomos/metabolismo , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/virologia , Humanos , Camundongos , Camundongos Knockout , Rickettsia/genética , Infecções por Rickettsia/genética , Infecções por Rickettsia/microbiologia
10.
Anticancer Res ; 40(8): 4687-4694, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727793

RESUMO

BACKGROUND/AIM: The Japanese apricot "Prunus mume" is a traditional Japanese medicine. MK615, a compound extract from Prunus mume has been reported to have anti-tumor effects. Herein, we used 3D floating (3DF) culture to evaluate the anticancer effects of MK615 against human colorectal cancer (CRC) cells that contain mutant (mt) KRAS. MATERIALS AND METHODS: HKe3 cells exogenously expressing mtKRAS (HKe3-mtKRAS) were treated with MK615 in 3DF cultures. The protein levels of hypoxia-inducible factor 1 (HIF-1) and E-cadherin were quantified by western blotting. RESULTS: MtKRAS enhanced hypoxia tolerance via up-regulation of HIF-1. The expression of HIF-1 protein was suppressed by constitutive overexpression of E-cadherin in CRC HCT116 spheroids. MK615 increased the expression of E-cadherin and decreased the expression of HIF-1 in HKe3-mtKRAS. These results suggest that MK615 suppresses hypoxia tolerance by up-regulation of E-cadherin in CRC cells with mtKRAS. CONCLUSION: MK615 exhibits properties useful for the potential treatment of CRC patients with mtKRAS.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Hipóxia Celular/fisiologia , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Regulação para Cima/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Células HCT116 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prunus/química , Ativação Transcricional/efeitos dos fármacos
11.
Chem Biol Interact ; 329: 109202, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32717189

RESUMO

Triple-negative breast cancer (TNBC) is highly metastatic and lacks effective therapeutic targets among several subtypes of breast cancer. Cancer metastasis promotes the malignancy of TNBC and is closely related to the poor prognosis of the TNBC patients. We aim to explore novel agents that effectively inhibit cancer metastasis to treat TNBC. In our study, 2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ), a CA-4 analogue, could inhibit cell motility and invasion in MDA-MB-231 cells, and the mechanism is closely associated to the inhibition of epithelial-to-mesenchymal transition (EMT). Meanwhile, SQ significantly inhibited the expression and secretion of vascular endothelial growth factor (VEGF) in MDA-MB-231 cells. Moreover, the conditioned medium from SQ-treated MDA-MB-231 cells significantly inhibited the motility and invasion of human umbilical vein endothelial cells (HUVECs), which was correlated with the inhibition of EMT process in HUVECs. In addition, exogenous application of VEGF reversed the occurrence of EMT in HUVECs which stimulated by conditioned medium from SQ-treated cells. Furthermore, SQ inhibited vasculogenic mimicry (VM) formation in MDA-MB-231 cells, which was associated with VE-cadherin and EphA2 down-regulation. This study indicates that SQ inhibits MDA-MB-231 cell metastasis through suppressing EMT and VEGF, thereby implicating this compound might be a potential therapeutic agent against metastatic TNBC.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Fenóis/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Compostos Organosselênicos/química , Fenóis/química , Receptor EphA2/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Fator A de Crescimento do Endotélio Vascular/genética
12.
Proc Natl Acad Sci U S A ; 117(32): 19310-19320, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32727892

RESUMO

Fat, Fat-like, and Dachsous family cadherins are giant proteins that regulate planar cell polarity (PCP) and cell adhesion in bilaterians. Their evolutionary origin can be traced back to prebilaterian species, but their ancestral function(s) are unknown. We identified Fat-like and Dachsous cadherins in Hydra, a member of phylum Cnidaria a sister group of bilaterian. We found Hydra does not possess a true Fat homolog, but has homologs of Fat-like (HyFatl) and Dachsous (HyDs) that localize at the apical membrane of ectodermal epithelial cells and are planar polarized perpendicular to the oral-aboral axis of the animal. Using a knockdown approach we found that HyFatl is involved in local cell alignment and cell-cell adhesion, and that reduction of HyFatl leads to defects in tissue organization in the body column. Overexpression and knockdown experiments indicate that the intracellular domain (ICD) of HyFatl affects actin organization through proline-rich repeats. Thus, planar polarization of Fat-like and Dachsous cadherins has ancient, prebilaterian origins, and Fat-like cadherins have ancient roles in cell adhesion, spindle orientation, and tissue organization.


Assuntos
Caderinas/metabolismo , Polaridade Celular , Hydra/citologia , Animais , Caderinas/genética , Adesão Celular , Hydra/classificação , Hydra/genética , Hydra/metabolismo , Filogenia , Fuso Acromático/genética , Fuso Acromático/metabolismo
13.
Mol Immunol ; 125: 15-22, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32619930

RESUMO

PIM1 is serine/threonine protein kinase that is involved in numerous biological processes. Pulmonary fibrosis (PF) is a chronic pathological result of the dysfunctional repair of lung injury without effective therapeutic treatments. In the current study, we investigated whether PIM1 inhibition would improve bleomycin (BLM)-induced pulmonary fibrosis. In a BLM-induced pulmonary fibrosis model, PIM1 was persistently upregulated in fibrotic lung tissues. Furthermore, PIM1 inhibition by the PIM1-specific inhibitor SMI-4a showed protective effects against BLM-induced mortality. Furthermore, SMI-4a suppressed hydroxyproline deposition and reversed epithelial-mesenchymal transition (EMT) formation, which was characterized by E-cadherin and α-SMA expression in vivo. More importantly, the ZEB1/E-cadherin pathway was found to be closely associated with BLM-induced pulmonary fibrosis. After the in vitro treatment of A549 cells, PIM1 regulated E-cadherin expression by dependently modulating the activity of the transcription factor ZEB1. These findings were verified in vivo after SMI-4a administration. Finally, an shPIM1-expressing adeno-associated virus was delivered via intratracheal injection to induce a long-term PIM1 deficiency in the alveolar epithelium. AAV-mediated PIM1 knockdown in the lung tissues alleviated BLM-induced pulmonary fibrosis, as indicated by collagen accumulation reduction, pulmonary histopathological mitigation and EMT reversion. These findings enhance our understanding of the roles of PIM1 in BLM-induced pulmonary fibrosis and suggest PIM1 inhibition as a potential therapeutic strategy in chronic pulmonary injuries.


Assuntos
Células Epiteliais Alveolares/metabolismo , Caderinas/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fibrose Pulmonar/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Células A549 , Células Epiteliais Alveolares/patologia , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia
14.
PLoS Biol ; 18(6): e3000734, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502201

RESUMO

Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Loss-of-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions. We report here that microRNA-27a (miR-27a), a negative regulator of VE-cadherin, is elevated in ECs isolated from mouse brains developing early CCM lesions and in cultured ECs with CCM1 or CCM2 depletion. Furthermore, we show miR-27a acts downstream of kruppel-like factor (KLF)2 and KLF4, two known key transcription factors involved in CCM lesion development. Using CD5-2 (a target site blocker [TSB]) to prevent the miR-27a/VE-cadherin mRNA interaction, we present a potential therapy to increase VE-cadherin expression and thus rescue the abnormal vascular integrity. In CCM1- or CCM2-depleted ECs, CD5-2 reduces monolayer permeability, and in Ccm1 heterozygous mice, it restores dermal vessel barrier function. In a neonatal mouse model of CCM disease, CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. Furthermore, CD5-2 limits the accumulation of inflammatory cells in the lesion area. Our work has established that VE-cadherin is a potential therapeutic target for normalization of the vasculature and highlights that targeting miR-27a/VE-cadherin interaction by CD5-2 is a potential novel therapy for the devastating disease, CCM.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/genética , MicroRNAs/metabolismo , Animais , Regulação para Baixo/genética , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Rombencéfalo/irrigação sanguínea , Rombencéfalo/patologia , Regulação para Cima/genética , Proteína rhoA de Ligação ao GTP/metabolismo
15.
PLoS One ; 15(6): e0235337, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32589661

RESUMO

p120-catenin is considered to be a tumor suppressor because it stabilizes E-cadherin levels at the cell surface. p120-catenin phosphorylation is increased in several types of cancer, but the role of phosphorylation in cancer is unknown. The phosphorylation state of p120-catenin is important in controlling E-cadherin homophilic binding strength which maintains epithelial junctions. Because decreased cell-cell adhesion is associated with increased cancer metastasis we hypothesize that p120-catenin phosphorylation at specific Serine and Threonine residues alters the E-cadherin binding strength between tumor cells and thereby affect the ability of tumor cells to leave the primary tumor and metastasize to distant sites. In this study we show that expression of the p120-catenin phosphorylation dead mutant, by converting six Serine and Threonine sites to Alanine, leads to enhanced E-cadherin adhesive binding strength in tumor cells. We observed a decrease in the ability of tumor cells expressing the p120-catenin phosphorylation mutant to migrate and invade using in-vitro models of cancer progression. Further, tumor cells expressing the phosphorylation mutant form of p120-catenin demonstrated a decrease in ability to metastasize to the lungs using an in-vivo orthotopic mammary fat pad injection model of breast cancer development and metastasis. This suggests that regulation of p120-catenin phosphorylation at the cell surface is important in mediating cell-adhesion, thereby impacting cancer progression and metastasis.


Assuntos
Caderinas/metabolismo , Cateninas/metabolismo , Adesão Celular , Animais , Cateninas/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Camundongos , Mutação , Invasividade Neoplásica , Metástase Neoplásica , Fosforilação
16.
Cell Prolif ; 53(8): e12859, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32588946

RESUMO

OBJECTIVES: Bone mesenchymal stem cells (BMSCs) play critical roles in tumour microenvironment. However, molecular mechanisms of how BMSCs to be recruited and effect subsequent tumour progression are poorly understood in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The distribution of CXCL8 was detected by immunohistochemical staining in OSCC tissues. The chemotaxis of conditioned media from different epithelial cells to BMSCs was examined by trans-well assay. Real-time quantitative PCR (qPCR) and ELISA were used to detect the expression of related cytokines and chemokine receptors. The migration of BMSCs was observed in BALB/c nude mice. The roles of BMSCs in proliferation, migration and invasion of OSCC were detected by CCK-8, flow cytometry and trans-well assay. Epithelial-mesenchymal transition (EMT)-related markers were analysed by qPCR and Western blot in vitro, and growth was evaluated in BALB/c nude mice using subcutaneously implanted OSCC in nude mouse model in vivo. RESULTS: Using OSCC, we show CXCL8, secreted by OSCC, binds to exclusively CXCR2 in BMSCs to facilitate migration of BMSCs to OSCC. TGF-ß secreted by BMSCs subsequently induces EMT of OSCC to promote their proliferation, migration and infiltration. We also showed that the Ras/Raf/Erk axis plays a critical role in tumour progression. CONCLUSIONS: Our results provide the molecular basis for BMSC recruitment into tumours, and how this process leads to tumour progression and leads us to develop a novel OSCC treatment target.


Assuntos
Carcinoma de Células Escamosas/patologia , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica/genética , Células-Tronco Mesenquimais/citologia , Neoplasias Bucais/genética , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Animais , Caderinas/metabolismo , Carcinoma de Células Escamosas/genética , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Interleucina-8/metabolismo , Masculino , Camundongos Nus , Neoplasias Bucais/imunologia , Receptores de Interleucina-8B/metabolismo , Microambiente Tumoral/fisiologia
17.
Life Sci ; 256: 117968, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32544462

RESUMO

Osteosarcoma (OS) is the most common type of primary bone malignancy with high recurrence and metastasis. Peptidylarginine deiminase 4 (PADI4), as an important protein post-translational modification enzyme, has been identified as a potential regulator in the invasion and migration in several types of tumors. The role of PADI4 in osteosarcoma metastasis remains unknown. In this study, we revealed significant positive correlation between PADI4 and pulmonary metastasis of osteosarcoma. Wound-healing and transwell assay indicated that PADI4 induced invasion and migration of osteosarcoma cell in vitro while PADI4 inhibitor has repressive effect. PADI4 mutation with no deimination activity exhibited no significant effect on invasion and migration of osteosarcoma cells. Moreover, we evaluated the effect of PADI4 on expression of the markers of epithelial-mesenchymal transition and results showed that PADI4 promoted EMT while PADI4 inhibitor suppressed EMT in osteosarcoma cells. We also detected the expression of PADI4 and E-Cadherin in the tissues of osteosarcoma patients with or without pulmonary metastasis. Results showed positive relationship between the expression of PADI4 and osteosarcoma metastasis. In contrast, the expression of E-Cadherin exhibited negative correlation with PADI4 and osteosarcoma metastasis. Our research offered a novel link between PADI4 and osteosarcoma metastasis and demonstrated PADI4 as a promising target for treatment of osteosarcoma metastasis.


Assuntos
Movimento Celular , Regulação para Baixo , Transição Epitelial-Mesenquimal , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/secundário , Invasividade Neoplásica , Osteossarcoma/genética , Proteína-Arginina Desiminase do Tipo 4/genética
18.
Nat Commun ; 11(1): 3020, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541686

RESUMO

The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers. However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers. Here, we report that Epsin 3 (EPN3) is an oncogene with prognostic and therapeutic relevance in breast cancer. Mechanistically, EPN3 drives breast tumorigenesis by increasing E-cadherin endocytosis, followed by the activation of a ß-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGFß-dependent autocrine loop that sustains EMT. EPN3-induced partial EMT is instrumental for the transition from in situ to invasive breast carcinoma, and, accordingly, high EPN3 levels are detected at the invasive front of human breast cancers and independently predict metastatic rather than loco-regional recurrence. Thus, we uncover an endocytic-based mechanism able to generate TGFß-dependent regulatory loops conferring cellular plasticity and invasive behavior.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Neoplasias da Mama/fisiopatologia , Endocitose , Proteínas Adaptadoras de Transporte Vesicular/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caderinas/genética , Caderinas/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Transdução de Sinais , Fator de Transcrição 4/genética , Fator de Transcrição 4/metabolismo , Fator de Crescimento Transformador beta/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
19.
PLoS One ; 15(6): e0234407, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511276

RESUMO

Testisin (encoded by PRSS21) is a membrane anchored serine protease, which is tethered to the cell surface via a glycosylphosphatidylinositol (GPI)-anchor. While testisin is found in abundance in spermatozoa, it is also expressed in microvascular endothelial cells where its function is unknown. Here we identify testisin as a novel regulator of physiological hormone-induced angiogenesis and microvascular endothelial permeability. Using a murine model of rapid physiological angiogenesis during corpus luteal development in the ovary, we found that mice genetically deficient in testisin (Prss21-/-) show a substantially increased incidence of hemorrhages which are significantly more severe than in littermate control Prss21+/+ mice. This phenotype was associated with increased vascular leakiness, demonstrated by a greater accumulation of extravasated Evans blue dye in Prss21-/- ovaries. Live cell imaging of in vitro cultured microvascular endothelial cells depleted of testisin by siRNA knockdown revealed that loss of testisin markedly impaired reorganization and tubule-like formation on Matrigel basement membranes. Moreover testisin siRNA knockdown increased the paracellular permeability to FITC-albumin across endothelial cell monolayers, which was associated with decreased expression of the adherens junction protein VE-cadherin and increased levels of phospho(Tyr658)-VE-cadherin, without affecting the levels of the tight junction proteins occludin and claudin-5, or ZO-1. Decreased expression of VE-cadherin in the neovasculature of Prss21-/- ovaries was also observed without marked differences in endothelial cell content, vascular claudin-5 expression or pericyte recruitment. Together, these data identify testisin as a novel regulator of VE-cadherin adhesions during angiogenesis and indicate a potential new target for regulating neovascular integrity and associated pathologies.


Assuntos
Permeabilidade Capilar/fisiologia , Corpo Lúteo/irrigação sanguínea , Neovascularização Fisiológica , Serina Endopeptidases/deficiência , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Permeabilidade Capilar/genética , Células Cultivadas , Corpo Lúteo/patologia , Corpo Lúteo/fisiopatologia , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/fisiologia , Técnicas de Silenciamento de Genes , Hemorragia/etiologia , Hemorragia/genética , Hemorragia/fisiopatologia , Humanos , Luteinização/genética , Luteinização/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Fisiológica/genética , Fenótipo , Serina Endopeptidases/genética , Serina Endopeptidases/fisiologia
20.
Nat Commun ; 11(1): 3147, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561720

RESUMO

Transposons are known to participate in tissue aging, but their effects on aged stem cells remain unclear. Here, we report that in the Drosophila ovarian germline stem cell (GSC) niche, aging-related reductions in expression of Piwi (a transposon silencer) derepress retrotransposons and cause GSC loss. Suppression of Piwi expression in the young niche mimics the aged niche, causing retrotransposon depression and coincident activation of Toll-mediated signaling, which promotes Glycogen synthase kinase 3 activity to degrade ß-catenin. Disruption of ß-catenin-E-cadherin-mediated GSC anchorage then results in GSC loss. Knocking down gypsy (a highly active retrotransposon) or toll, or inhibiting reverse transcription in the piwi-deficient niche, suppresses GSK3 activity and ß-catenin degradation, restoring GSC-niche attachment. This retrotransposon-mediated impairment of aged stem cell maintenance may have relevance in many tissues, and could represent a viable therapeutic target for aging-related tissue degeneration.


Assuntos
Proteínas Argonauta/metabolismo , Senescência Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Células Germinativas/metabolismo , Animais , Proteínas Argonauta/genética , Caderinas/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Feminino , Inativação Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Ovário/citologia , Ovário/metabolismo , Retroelementos/genética , Transdução de Sinais , Nicho de Células-Tronco/fisiologia , Células-Tronco/metabolismo , Receptores Toll-Like/metabolismo , beta Catenina/metabolismo
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