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1.
Anticancer Res ; 41(9): 4497-4504, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475075

RESUMO

BACKGROUND/AIM: E-Cadherin has been implicated in cell-cell adhesion, and soluble E-cadherin is involved in angiogenesis and resistance to anti-angiogenic therapy in several cancer types. This study aimed to investigate the expression and clinical significance of soluble E-cadherin and other angiogenesis-related factors in plasma and malignant ascites of colorectal cancer (CRC) in patients with peritoneal carcinomatosis (PC). MATERIALS AND METHODS: Multiplex enzyme-linked immunosorbent assay was performed on 95 body fluid samples (57 plasma and 38 malignant ascites) from patients with CRC. The status of E-cadherin and angiopoietin-2 (AGNPT2) was retrospectively evaluated by immunohistochemistry in primary CRC and paired metastatic peritoneal tissues or cell blocks of malignant ascites of 30 patients with peritoneal metastases of CRC. RESULTS: The expression levels of soluble E-cadherin and ANGPT2 in plasma samples were significantly increased in patients with PC compared with those without. E-Cadherin concentration was significantly lower and ANGPT2 concentration was significantly higher in malignant ascites than plasma samples. Expression of E-cadherin was strongly positive, whilst that of ANGPT2 was negative in primary colorectal tissues, metastatic peritoneal tissues, and cell blocks of malignant ascites by immunohistochemistry. High levels of soluble E-cadherin or ANGPT2 in ascites were negatively associated with overall survival in patients with CRC with malignant ascites. CONCLUSION: Our findings suggest that soluble E-cadherin and ANGPT2 may be surrogate biomarkers for clinical outcome in patients with PC from CRC.


Assuntos
Angiopoietina-2/metabolismo , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/secundário , Neoplasias Peritoneais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Regulação para Cima
2.
Anticancer Res ; 41(9): 4365-4375, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475056

RESUMO

BACKGROUND/AIM: Ouabain has been shown to induce human cancer cell death via apoptosis. Still, its anti-metastatic effect on cell migration and invasion of human gastric cancer cells has not been addressed. MATERIALS AND METHODS: Cell proliferation and viability were measured by the MTT assay and flow cytometry, respectively. Cell motitlity was analysed by wound healing assay. Cell migration and invasion were analysed by the transwell system. Protein expression was assayed by western blotting. RESULTS: Ouabain decreased AGS cell proliferation, cell viability, and motility. In addition, ouabain inhibited AGS cell migration and invasion. Furthermore, ouabain decreased matrix metalloproteinase-2 (MMP-2) activity at 48 h. Ouabain reduced the levels of proteins associated with PI3K/AKT and p38/MAPK pathways. In addition, ouabain decreased the expressions of N-cadherin, tissue inhibitor of metalloproteinases-1 (TIMP-1), urokinase-type plasminogen activator (c-uPA), and MMP-2 at 48 h. CONCLUSION: Ouabain suppresses cell metastasis through multiple signaling pathways in AGS cells.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Ouabaína/farmacologia , Neoplasias Gástricas/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Inibidor Tecidual de Metaloproteinase-1/metabolismo
3.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360882

RESUMO

The human natural killer (HNK-1) carbohydrate plays important roles during nervous system development, regeneration after trauma and synaptic plasticity. Four proteins have been identified as receptors for HNK-1: the laminin adhesion molecule, high-mobility group box 1 and 2 (also called amphoterin) and cadherin 2 (also called N-cadherin). Because of HNK-1's importance, we asked whether additional receptors for HNK-1 exist and whether the four identified proteins share any similarity in their primary structures. A set of 40,000 sequences homologous to the known HNK-1 receptors was selected and used for large-scale sequence alignments and motif searches. Although there are conserved regions and highly conserved sites within each of these protein families, there was no sequence similarity or conserved sequence motifs found to be shared by all families. Since HNK-1 receptors have not been compared regarding binding constants and since it is not known whether the sulfated or non-sulfated part of HKN-1 represents the structurally crucial ligand, the receptors are more heterogeneous in primary structure than anticipated, possibly involving different receptor or ligand regions. We thus conclude that the primary protein structure may not be the sole determinant for a bona fide HNK-1 receptor, rendering receptor structure more complex than originally assumed.


Assuntos
Antígenos CD57/metabolismo , Caderinas/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB2/metabolismo , Laminina/metabolismo , Oligossacarídeos/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Antígenos CD57/química , Caderinas/química , Proteína HMGB1/química , Proteína HMGB2/química , Humanos , Laminina/química , Ligantes , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Oligossacarídeos/química , Ligação Proteica , Domínios Proteicos
4.
Gene ; 805: 145904, 2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-34418470

RESUMO

Breast cancer is the second most common cause of cancer-related mortality in women. Breast cancer metastasis which usually is observed at the last stage is the major cause of breast cancer-related death. Long non-coding RNAs (lncRNAs) are member of the non-coding RNA family. It is known that lncRNAs have important functions in the genes regulation of different processes and pathways such as EMT (Epithelial mesenchymal transition), metastasis and apoptosis. Therefore, it is inevitable that lncRNAs have potential contribution for the understanding of cancer pathogenesis. lncRNA-ZEB2NAT is the natural antisense transcript of ZEB2. Herein, we investigated the effects of lncRNA-ZEB2NAT on process of EMT, metastasis and apoptosis in MCF7 and MDA-MB-231 breast cancer cells. The effect of ZEB2NAT on the expression of important genes in EMT, metastasis and apoptosis, and some protein levels was determined by qRT-PCR and western blot analysis, respectively. The effects of ZEB2NAT on cell proliferation, apoptosis, invasion and colony formation were evaluated using XTT, annexin V, invasion and colony assays, respectively. The ZEB2NAT knockdown caused anti-metastatic and apoptotic effects. The ZEB2NAT knockdown resulted in a decrease in ZEB2 and N-cadherin but an increase in E-cadherin protein levels. In addition, it was determined that ZEB2NAT knockdown significantly decreased cell proliferation and stimulated apoptosis in both cells. It was found that ZEB2NAT knockdown significantly decreased invasion and colony formation in both cells. ZEB2NAT knockdown showed anti-metastatic and apoptotic effect by affecting the important genes in both cells. These results have suggested that ZEB2NAT has an important role in EMT, metastasis and apoptosis in breast cancer and ZEB2NAT knockdown caused significant anti-cancer activities.


Assuntos
Neoplasias da Mama/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Apoptose/genética , Neoplasias da Mama/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , RNA Longo não Codificante/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
5.
Nat Commun ; 12(1): 4906, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385456

RESUMO

Neoadjuvant chemotherapy (NAC) prior to surgery and immune checkpoint therapy (ICT) have revolutionized bladder cancer management. However, stratification of patients that would benefit most from these modalities remains a major clinical challenge. Here, we combine single nuclei RNA sequencing with spatial transcriptomics and single-cell resolution spatial proteomic analysis of human bladder cancer to identify an epithelial subpopulation with therapeutic response prediction ability. These cells express Cadherin 12 (CDH12, N-Cadherin 2), catenins, and other epithelial markers. CDH12-enriched tumors define patients with poor outcome following surgery with or without NAC. In contrast, CDH12-enriched tumors exhibit superior response to ICT. In all settings, patient stratification by tumor CDH12 enrichment offers better prediction of outcome than currently established bladder cancer subtypes. Molecularly, the CDH12 population resembles an undifferentiated state with inherently aggressive biology including chemoresistance, likely mediated through progenitor-like gene expression and fibroblast activation. CDH12-enriched cells express PD-L1 and PD-L2 and co-localize with exhausted T-cells, possibly mediated through CD49a (ITGA1), providing one explanation for ICT efficacy in these tumors. Altogether, this study describes a cancer cell population with an intriguing diametric response to major bladder cancer therapeutics. Importantly, it also provides a compelling framework for designing biomarker-guided clinical trials.


Assuntos
Caderinas/genética , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Neoplasias da Bexiga Urinária/terapia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Cateninas/genética , Cateninas/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Estimativa de Kaplan-Meier , Terapia Neoadjuvante/métodos , Avaliação de Resultados em Cuidados de Saúde , Proteômica/métodos , RNA-Seq/métodos , Linfócitos T/metabolismo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia
6.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299016

RESUMO

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial-mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Carcinoma/imunologia , Carcinoma/metabolismo , Transição Epitelial-Mesenquimal/imunologia , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Carcinoma/tratamento farmacológico , Carcinoma/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
7.
Genes (Basel) ; 12(6)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208174

RESUMO

There are many co-regulated genes in eukaryotic cells. The coordinated activation or repression of such genes occurs at specific stages of differentiation, or under the influence of external stimuli. As a rule, co-regulated genes are dispersed in the genome. However, there are also gene clusters, which contain paralogous genes that encode proteins with similar functions. In this aspect, they differ significantly from bacterial operons containing functionally linked genes that are not paralogs. In this review, we discuss the reasons for the existence of gene clusters in vertebrate cells and propose that clustering is necessary to ensure the possibility of selective activation of one of several similar genes.


Assuntos
Evolução Molecular , Família Multigênica , Animais , Caderinas/genética , Caderinas/metabolismo , Células Eritroides/metabolismo , Globinas/genética , Globinas/metabolismo , Humanos
8.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203800

RESUMO

Accumulating evidence support the cardioprotective properties of the nuclear receptor peroxisome proliferator activated receptor ß/δ (PPARß/δ); however, the underlying mechanisms are not yet fully elucidated. The aim of the study was to further investigate the mechanisms underlying PPARß/δ-mediated cardioprotection in the setting of myocardial ischemia/reperfusion (I/R). For this purpose, rats were treated with PPARß/δ agonist GW0742 and/or antagonist GSK0660 in vivo and hearts were subjected to ex vivo global ischemia followed by reperfusion. PPARß/δ activation improved left ventricular developed pressure recovery, reduced infarct size (IS) and incidence of reperfusion-induced ventricular arrhythmias while it also up-regulated superoxide dismutase 2, catalase and uncoupling protein 3 resulting in attenuation of oxidative stress as evidenced by the reduction in 4-hydroxy-2-nonenal protein adducts and protein carbonyl formation. PPARß/δ activation also increased both mRNA expression and enzymatic activity of aldehyde dehydrogenase 2 (ALDH2); inhibition of ALDH2 abrogated the IS limiting effect of PPARß/δ activation. Furthermore, upregulation of PGC-1α and isocitrate dehydrogenase 2 mRNA expression, increased citrate synthase activity as well as mitochondrial ATP content indicated improvement in mitochondrial content and energy production. These data provide new mechanistic insight into the cardioprotective properties of PPARß/δ in I/R pointing to ALDH2 as a direct downstream target and suggesting that PPARß/δ activation alleviates myocardial I/R injury through coordinated stimulation of the antioxidant defense of the heart and preservation of mitochondrial function.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Cardiotônicos/uso terapêutico , Metabolismo Energético , Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo , PPAR delta/metabolismo , PPAR beta/metabolismo , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Antioxidantes/metabolismo , Caderinas/metabolismo , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Catalase/metabolismo , Metabolismo Energético/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Modelos Biológicos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , PPAR delta/agonistas , PPAR beta/agonistas , Ratos Wistar , Superóxido Dismutase/metabolismo , Tiazóis/administração & dosagem , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Proteína Desacopladora 3/metabolismo , Regulação para Cima/efeitos dos fármacos
9.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203850

RESUMO

Steroid receptor coactivator-1 (SRC-1) is a transcription coactivator playing a pivotal role in mediating a wide range of signaling pathways by interacting with related transcription factors and nuclear receptors. Aberrantly elevated SRC-1 activity is associated with cancer metastasis and progression, and therefore, suppression of SRC-1 is emerging as a promising therapeutic strategy. In this study, we developed a novel SRC-1 degrader for targeted degradation of cellular SRC-1. This molecule consists of a selective ligand for SRC-1 and a bulky hydrophobic group. Since the hydrophobic moiety on the protein surface could mimic a partially denatured hydrophobic region of a protein, SRC-1 could be recognized as an unfolded protein and experience the chaperone-mediated degradation in the cells through the ubiquitin-proteasome system (UPS). Our results demonstrate that a hydrophobic-tagged chimeric molecule is shown to significantly reduce cellular levels of SRC-1 and suppress cancer cell migration and invasion. Together, these results highlight that our SRC-1 degrader represents a novel class of therapeutic candidates for targeting cancer metastasis. Moreover, we believe that the hydrophobic tagging strategy would be widely applicable to develop peptide-based protein degraders with enhanced cellular activity.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Coativador 1 de Receptor Nuclear/metabolismo , Proteólise , Transativadores/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Movimento Celular , Humanos , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Chaperonas Moleculares/metabolismo , Invasividade Neoplásica , Peptídeos/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199232

RESUMO

Non-muscle-invasive bladder cancer is the most common form of bladder cancer. The main problem in managing bladder tumors is the high recurrence after the transurethral resection of bladder tumors (TURBT). Our study aimed to examine the fate of intravesically applied cancer cells as the implantation of cancer cells after TURBT is thought to be a cause of tumor recurrence. We established an orthotopic mouse bladder tumor model with MB49-GFP cancer cells and traced them during the first three days to define their location and contacts with normal urothelial cells. Data were obtained by Western blot, immunolabeling, and light and electron microscopy. We showed that within the first two hours, applied cancer cells adhered to the traumatized epithelium by cell projections containing α3ß1 integrin on their tips. Cancer cells then migrated through the epithelium and on day 3, they reached the basal lamina or even penetrated it. In established bladder tumors, E-cadherin and desmoplakin 1/2 were shown as feasible immunohistochemical markers of tumor margins based on the immunolabeling of various junctional proteins. Altogether, these results for the first time illustrate cancer cell implantation in vivo mimicking cellular events of tumor recurrence in bladder cancer patients.


Assuntos
Epitélio/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Bexiga Urinária/patologia , Bexiga Urinária/patologia , Animais , Caderinas/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Modelos Animais de Doenças , Feminino , Integrina alfa3beta1/metabolismo , Junções Intercelulares/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Bexiga Urinária/ultraestrutura , Neoplasias da Bexiga Urinária/ultraestrutura , Urotélio/patologia , Urotélio/ultraestrutura
12.
Nanoscale ; 13(29): 12577-12586, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34259298

RESUMO

Nanomaterial induced endothelial cell leakiness (NanoEL) is caused because nanomaterials enter the interstitial space of the endothelial cells and disrupt the endothelial cell-cell interactions by interacting with vascular endothelial cadherin (VE-cad). Whereas the NanoEL effect could cause controllable leakiness in cancer therapy, the gaps created by the NanoEL effect can make the cancer cells cross the endothelial barrier and produce side effects induced by using nanomedicine. In this paper, a series of ultralow protein corona nanoparticle is reported that can penetrate the endothelial cell junction without obviously interacting with the VE-cad and phosphorylating the tyrosine 658 (Y658) and tyrosine 731 (Y731) residues on VE-cad, thus preventing the VE-cad from being activated by Src kinase, and this avoids inducing of the NanoEL effect and cancer cell migration, regardless of particle material, density and surface charge. These findings provide a new idea for the design of novel nanoparticles without side effects and can maximize their cancer-killing effect.


Assuntos
Células Endoteliais , Nanopartículas , Antígenos CD , Caderinas/metabolismo , Células Endoteliais/metabolismo , Nanopartículas/toxicidade , Fosforilação
13.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(6): 931-936, 2021 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-34238747

RESUMO

OBJECTIVE: To investigate the regulatory role of the long non-coding RNA (lncRNA) small nucleolar host gene 3 (SNHG3) in proliferation, migration and invasion of human cervical cancer cell line SiHa. OBJECTIVE: Array data were retrieved from GEO database to analyze the expression levels of SNHG3 in cervical cancer and adjacent normal tissues. SiHa cells were transfected with a small interfering RNA (siRNA) targeting SNHG3, and the changes in the transcriptional levels of lncRNA SNHG3 and the epithelial-mesenchymal transition (EMT) markers N-cadherin, Snail, vimentin and E-cadherin were detected using real-time quantitative PCR; the protein expressions of N-cadherin, Snail, vimentin and E-cadherin were determined using Western blotting. Cell counting kit-8 (CCK8) assay was utilized to assess the proliferation capacity of the transfected cells. Wound healing assay and Transwell assay were performed to evaluate the transversal and longitudinal migration and invasion abilities of the cells. OBJECTIVE: SNHG3 was over-expressed in cervical cancer tissues and SiHa cells. In SiHa cells, knocking down SNHG3 significantly inhibited the proliferation (P < 0.001), migration (P < 0.01) and invasion abilities (P < 0.001) of the cells, down-regulated the expression levels of N-cadherin, Snail and vimentin (P < 0.001) and up-regulated the expression of E-cadherin (P < 0.001). OBJECTIVE: SNHG3 may promote the proliferation, migration and invasion of SiHa cells by activating the EMT signaling pathway.


Assuntos
RNA Longo não Codificante , Neoplasias do Colo do Útero , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Longo não Codificante/genética , RNA Interferente Pequeno , Neoplasias do Colo do Útero/genética
14.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201472

RESUMO

The ubiquitously expressed transmembrane protein a disintegrin and metalloproteinase 10 (ADAM10) functions as a "molecular scissor", by cleaving the extracellular regions from its membrane protein substrates in a process termed ectodomain shedding. ADAM10 is known to have over 100 substrates including Notch, amyloid precursor protein, cadherins, and growth factors, and is important in health and implicated in diseases such as cancer and Alzheimer's. The tetraspanins are a superfamily of membrane proteins that interact with specific partner proteins to regulate their intracellular trafficking, lateral mobility, and clustering at the cell surface. We and others have shown that ADAM10 interacts with a subgroup of six tetraspanins, termed the TspanC8 subgroup, which are closely related by protein sequence and comprise Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33. Recent evidence suggests that different TspanC8/ADAM10 complexes have distinct substrates and that ADAM10 should not be regarded as a single scissor, but as six different TspanC8/ADAM10 scissor complexes. This review discusses the published evidence for this "six scissor" hypothesis and the therapeutic potential this offers.


Assuntos
Proteína ADAM10/fisiologia , Tetraspaninas/fisiologia , Secretases da Proteína Precursora do Amiloide/fisiologia , Animais , Caderinas/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Terapia de Alvo Molecular/métodos , Tetraspaninas/química
15.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199046

RESUMO

Hyperglycemia may contribute to the progression of carcinomas by triggering epithelial-to-mesenchymal transition (EMT). Some proteostasis systems are involved in metastasis; in this paper, we sought to explore the mechanism of Hsp70 chaperone in EMT. We showed that knockdown of Hsp70 reduced cell migration capacity concomitantly with levels of mRNA of the Slug, Snail, and Twist markers of EMT, in colon cancer cells incubated in high glucose medium. Conversely, treatment of cells with Hsp70 inducer U-133 were found to elevate cell motility, along with the other EMT markers. To prove that inhibiting Hsp70 may reduce EMT efficiency, we treated cells with a CL-43 inhibitor of the HSF1 transcription factor, which lowered Hsp70 and HSF1 content in the control and induced EMT in carcinoma cells. Importantly, CL-43 reduced migration capacity, EMT-linked transcription factors, and increased content of epithelial marker E-cadherin in colon cancer cells of three lines, including one derived from a clinical sample. To prove that Hsp70 chaperone should be targeted when inhibiting the EMT pathway, we treated cancer cells with 2-phenylethynesulfonamide (PES) and demonstrated that the compound inhibited substrate-binding capacity of Hsp70. Furthermore, PES suppressed EMT features, cell motility, and expression of specific transcription factors. In conclusion, the Hsp70 chaperone machine efficiently protects mechanisms of the EMT, and the safe inhibitors of the chaperone are needed to hamper metastasis at its initial stage.


Assuntos
Glicemia , Transição Epitelial-Mesenquimal , Glucose/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Biomarcadores , Caderinas/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucose/farmacologia , Humanos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Ligação Proteica , Fatores de Transcrição da Família Snail/metabolismo
16.
Theranostics ; 11(14): 6786-6799, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093853

RESUMO

Rationale: Bone marrow-derived mesenchymal stem cells (BM-MSCs) recruited into breast tumors regulate the behavior of tumor cells via various mechanisms and affect clinical outcomes. Although signaling molecules, such as transforming growth factor ß (TGF-ß), are known to transmit signals between BM-MSCs and breast tumor cells for recruiting BM-MSCs, it is unclear which specific intrinsic molecules involved in cell motility mediate the migration of BM-MSCs into breast tumor. It is also unclear as to how specific intrinsic molecules contribute to the migration. Methods: Conditioned medium (CM) from breast tumor cells (MCF-7 and MDA-MB-231) that simulates breast tumor secreting TGF-ß was used to examine the migration of BM-MSCs into breast tumors. A three-dimensional migration assay was performed to investigate the collective migration of BM-MSCs, maintaining cell-cell adhesion, toward breast tumor cells. Results: N-cadherin formed adherens junction-like structures on the intercellular borders of BM-MSCs, and TGF-ß increased the expression of N-cadherin on these borders. Knockdown of Smad4 impaired the TGF-ß-mediated increase in N-cadherin expression in BM-MSCs, but inhibitors of non-canonical TGF-ß pathways, such as extracellular signal-regulated kinases, Akt, and p38, did not affect it. siRNA-mediated knockdown of N-cadherin and Smad4 impaired the migration of BM-MSCs in response to TGF-ß. Conditioned medium from breast tumor cells also enhanced the expression of N-cadherin in BM-MSCs, but inactivation of TGF-ß type 1 receptor (TGFBR1) with SB505124 and TGFBR1 knockdown abolished the increase in N-cadherin expression. BM-MSCs collectively migrated toward CM from MDA-MB-231 in vitro while maintaining cell-cell adhesion through N-cadherin. Knockdown of N-cadherin abolished the migration of BM-MSCs toward the CM from breast tumor cells. Conclusion: In the present study, we identified N-cadherin, an intrinsic transmembrane molecule in adherens junction-like structures, on BM-MSCs as a mediator for the migration of these cells toward breast tumor. The expression of N-cadherin increases on the intercellular borders of BM-MSCs through the TGF-ß canonical signaling and they collectively migrate in response to breast tumor cells expressing TGF-ß via N-cadherin-dependent cell-cell adhesion. We, herein, introduce a novel promising strategy for controlling and re-engineering the breast tumor microenvironment.


Assuntos
Antígenos CD/metabolismo , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Fator de Crescimento Transformador beta/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Antígenos CD/genética , Benzodioxóis/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Feminino , Humanos , Imidazóis/farmacologia , Imuno-Histoquímica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Smad4/genética , Proteína Smad4/metabolismo , Microambiente Tumoral/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Life Sci ; 279: 119672, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34097971

RESUMO

AIMS: Intestinal nutrient absorption plays a vital role in developing obesity, and nutrient transporters expressed in the enterocytes facilitate this process. Moreover, previous studies have shown that specific foods and diets can affect their cell levels. Herein, we investigated the effects of pequi oil (PO), which is high in several bioactive compounds, on intestinal nutrient transporter levels as well as on intestinal morphology and metabolic biomarkers. MAIN METHODS: Groups of male C57BL/6 mice were fed either a standard (C) or a high-fat diet (HFD) and pequi oil (CP and HFDP with PO by gavage at 150 mg/day) for eight weeks. Food intake and body weight were monitored, serum metabolic biomarkers, intestinal transporter levels and histological analyses were performed. KEY FINDINGS: PO increased caloric intake without increasing body or fat mass regardless of diet. The HFD group treated with PO reduced fasting blood glucose and villus width. PO did not affect GLUT2, L-FABP, FATP4, NPC1L1, NHE3 or PEPT1 content in CP or HFDP groups. GLUT5 and FAT/CD36 levels were reduced in both CP and HFDP. SIGNIFICANCE: Our data suggest that PO attenuated monosaccharide and fatty acid absorption, contributing to lower fasting glycemia and higher food intake without affecting body weight or visceral fat of high-fat feed mice.


Assuntos
Glicemia/metabolismo , Antígenos CD36/metabolismo , Carotenoides/farmacologia , Transportador de Glucose Tipo 5/metabolismo , Hiperglicemia/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Óleos Vegetais/farmacologia , Animais , Biomarcadores/metabolismo , Caderinas/metabolismo , Dieta Hiperlipídica , Ingestão de Energia , Ericales/química , Ácidos Graxos/metabolismo , Controle Glicêmico , Hiperglicemia/etiologia , Hiperglicemia/patologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/complicações
18.
Nutrients ; 13(5)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069461

RESUMO

Investigating dietary polyphenolic compounds as antitumor agents are rising due to the growing evidence of the close association between immunity and cancer. Cancer cells elude immune surveillance for enhancing their progression and metastasis utilizing various mechanisms. These mechanisms include the upregulation of programmed death-ligand 1 (PD-L1) expression and Epithelial-to-Mesenchymal Transition (EMT) cell phenotype activation. In addition to its role in stimulating normal embryonic development, EMT has been identified as a critical driver in various aspects of cancer pathology, including carcinogenesis, metastasis, and drug resistance. Furthermore, EMT conversion to another phenotype, Mesenchymal-to-Epithelial Transition (MET), is crucial in developing cancer metastasis. A central mechanism in the upregulation of PD-L1 expression in various cancer types is EMT signaling activation. In breast cancer (BC) cells, the upregulated level of PD-L1 has become a critical target in cancer therapy. Various signal transduction pathways are involved in EMT-mediated PD-L1 checkpoint overexpression. Three main groups are considered potential targets in EMT development; the effectors (E-cadherin and Vimentin), the regulators (Zeb, Twist, and Snail), and the inducers that include members of the transforming growth factor-beta (TGF-ß). Meanwhile, the correlation between consuming flavonoid-rich food and the lower risk of cancers has been demonstrated. In BC, polyphenols were found to downregulate PD-L1 expression. This review highlights the effects of polyphenols on the EMT process by inhibiting mesenchymal proteins and upregulating the epithelial phenotype. This multifunctional mechanism could hold promises in the prevention and treating breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Polifenóis/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Antígenos CD , Antígeno B7-H1/metabolismo , Neoplasias da Mama/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Fator de Crescimento Transformador beta , Vimentina/metabolismo
19.
Nat Commun ; 12(1): 3624, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131132

RESUMO

The LIM and SH3 domain protein 1 (Lasp1) was originally cloned from metastatic breast cancer and characterised as an adaptor molecule associated with tumourigenesis and cancer cell invasion. However, the regulation of Lasp1 and its function in the aggressive transformation of cells is unclear. Here we use integrative epigenomic profiling of invasive fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and from mouse models of the disease, to identify Lasp1 as an epigenomically co-modified region in chronic inflammatory arthritis and a functionally important binding partner of the Cadherin-11/ß-Catenin complex in zipper-like cell-to-cell contacts. In vitro, loss or blocking of Lasp1 alters pathological tissue formation, migratory behaviour and platelet-derived growth factor response of arthritic FLS. In arthritic human TNF transgenic mice, deletion of Lasp1 reduces arthritic joint destruction. Therefore, we show a function of Lasp1 in cellular junction formation and inflammatory tissue remodelling and identify Lasp1 as a potential target for treating inflammatory joint disorders associated with aggressive cellular transformation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Junções Aderentes/metabolismo , Artrite/metabolismo , Transformação Celular Neoplásica/metabolismo , Proteínas do Citoesqueleto/metabolismo , Fibroblastos/metabolismo , Proteínas com Domínio LIM/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Artrite/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Caderinas/metabolismo , Proteínas do Citoesqueleto/genética , Feminino , Proteínas de Homeodomínio , Proteínas com Domínio LIM/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos , beta Catenina/metabolismo
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