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1.
Cancer Res ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580061

RESUMO

Tumor-initiating cells (TIC) are associated with tumor initiation, growth, metastasis, and recurrence. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a TIC marker in many cancers, including breast cancer. However the molecular mechanisms underlying ALDH1A1 functions in solid tumors remain largely unknown. Here we demonstrate that ALDH1A1 enzymatic activity facilitates breast tumor growth. Mechanistically, ALDH1A1 decreased the intracellular pH in breast cancer cells to promote phosphorylation of TAK1, activate NFκB signaling, and increase the secretion of granulocyte macrophage colony-stimulating factor (GM-CSF), which led to myeloid-derived suppressor cell (MDSC) expansion and immunosuppression. Furthermore, the ALDH1A1 inhibitor disulfiram and chemotherapeutic agent gemcitabine cooperatively inhibited breast tumor growth and tumorigenesis by purging ALDH+ TICs and activating T cell immunity. These findings elucidate how active ALDH1A1 modulates the immune system to promote tumor development, highlghting new therapeutic strategies for malignant breast cancer.

2.
Nat Commun ; 12(1): 4413, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285210

RESUMO

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Receptores de Superfície Celular/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Mama/patologia , Mama/cirurgia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Feminino , Humanos , Mastectomia , Camundongos , Proteínas dos Microfilamentos/antagonistas & inibidores , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Receptores de Superfície Celular/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nanoscale Res Lett ; 16(1): 107, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34128153

RESUMO

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the midbrain, and the stem cell transplantation method provides a promising strategy for the treatment. In these studies, tracking the biological behaviors of the transplanted cells in vivo is essential for a basic understanding of stem cell function and evaluation of clinical effectiveness. In the present study, we developed a novel ultrasmall superparamagnetic iron oxide nanoparticles coating with the polyacrylic acid (PAA) and methoxypolyethylene glycol amine (PEG) by thermal decomposition method and a two-step modification. The USPIO-PAA/PEG NPs have a uniform diameter of 10.07 ± 0.55 nm and proper absorption peak of the corresponding ligands, as showed by TEM and FTIR. MTT showed that the survival of cells incubated with USPIO-PAA/PEG NPs remained above 96%. The synthesized USPIO-PAA/PEG had a good relaxation rate of 84.65 s-1 Mm-1, indicating that they could be efficiently uptake and traced by MRI. Furthermore, the primary human adipose-derived stem cells (HADSCs) were characterized, labeled with USPIO-PAA/PEG and transplanted into the striatum of 6-hydroxydopamine (6-OHDA)-induced PD rat models. The labeled cells could be traced by MRI for up to 3 weeks after the transplantation surgery; moreover, transplantation with the labeled HADSCs significantly attenuated apomorphine-induced rotations in PD models and increased the number of the dopaminergic neurons in the substania nigra. Overall, the development of USPIO-PAA/PEG NPs provides a promising tool for in vivo tracing technique of cell therapy and identifies a novel strategy to track stem cells with therapeutic potential in PD.

4.
Environ Sci Pollut Res Int ; 28(36): 50286-50301, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33956322

RESUMO

A novel magnetic Fe3O4@SiO2@Bi2O2CO3/rGO composite comprising of uniform core-shell-structured Fe3O4@SiO2@Bi2O2CO3 microspheres mounted on reduced graphene oxide (rGO) sheets was successfully fabricated by using a facile hydrothermal method. The adsorption-desorption isotherm of Fe3O4@SiO2@Bi2O2CO3/rGO belonged to type IV with an H4-type hysteresis loop. The specific surface areas and magnetization saturation value (Ms) of Fe3O4@SiO2@Bi2O2CO3/rGO (x = 0.15 g) were 102.12 m2/g and 25.4 emu/g, respectively. Fe3O4@SiO2@Bi2O2CO3/rGO (x = 0.15 g) exhibited remarkable photocatalytic degradation activity and mineralization effect for MO and decolorization performance for the mixed solution of MO, Rh B, and MB. MO degradation by Fe3O4@SiO2@Bi2O2CO3/rGO conformed to a first-order kinetic reaction, and the corresponding kapp value was 0.05553 min-1. A suitable amount of rGO in Fe3O4@SiO2@Bi2O2CO3/rGO could decrease the energy band gap, inhibit the recombination of photo-induced electron/hole (e-/h+) pair, and broaden and enhance the response of the catalyst to visible light, thereby enhancing the visible-light catalytic degradation of organic dyes. The active species produced in the photocatalysis included •O2-, •OH, and h+, with •O2- being the dominant active species. The as-prepared photocatalyst also showed excellent magnetic separation performance and stability. Results show that the as-prepared Fe3O4@SiO2@Bi2O2CO3/rGO composite is a promising photocatalyst with considerable application potential in organic dyes removal.


Assuntos
Grafite , Dióxido de Silício , Corantes , Luz
5.
Wideochir Inne Tech Maloinwazyjne ; 16(1): 62-75, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33786118

RESUMO

Introduction: The landscape of surgical treatments for hepatobiliary disease was significantly changed after the advent of laparoscopy. Many kinds of complex laparoscopic procedures can be routinely performed at present, but radical resection of hilar cholangiocarcinoma (HC) by laparoscopy is still highly contentious. Aim: To describe our primary experience with laparoscopic radical resection for HC and determine the safety and feasibility of this procedure. Material and methods: Between December 2015 and November 2019, 32 patients planned to undergo curative-intent laparoscopic resection of HC in our department. The perioperative and long-term outcomes of these patients were retrospectively analyzed. Results: Laparoscopic surgery with radical resection was ultimately performed in 24 (75.0%) patients; 3 (9.3%) patients were found to be unresectable at the preliminary exploration stage, and 5 (15.7%) patients converted from laparoscopy to laparotomy. The operation time and blood loss were 476.95 ±133.89 min and 568.75 ±324.01 ml, respectively. A negative margin was achieved in 19 (79.1%) of the laparoscopy patients. Three (12.5%) patients were identified with microscopic positive margins, and 2 (8.4%) patients underwent macroscopic residual tumor resection (R2). The length of postoperative stay was 23.3 ±11.7 days. Severe morbidity occurred in 4 (16.6%) patients. The actuarial 3-year overall survival and disease-free survival for patients who underwent laparoscopic surgery were 49.1% and 47.0%, respectively. Conclusions: Laparoscopic radical resection for HC is safe and feasible in experienced hands for highly selected patients but is still in its initial stages. When adequate oncologic resection is performed, the laparoscopic approach does not adversely influence the prognosis of the patient.

6.
Cell Biol Toxicol ; 37(2): 277-291, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32472219

RESUMO

Uncoupling protein 1 (UCP1) has been implicated in ameliorating metabolic related disorders, of which most symptoms are risk factors for breast cancer. Here, we found that UCP1 was obviously downregulated in basal-like breast cancer (BLBC) and was positively correlated with improved survival. However, the underlying regulatory mechanisms remain largely unknown. Our studies showed that UCP1 inhibited tumor progression via suppressing aldehyde dehydrogenase (ALDH)-positive breast cancer stem cell (BCSC) population in BLBC. Furthermore, we found that UCP1 induced the upregulation of fructose bisphosphatase 1 (FBP1) which was previously blocked by Snail overexpression, and UCP1 decreased ALDH-positive BCSCs via FBP1-dependent metabolic rewiring, which could be reversed by Snail overexpression. In addition, breast cancer cells co-cultured with UCP1-deficient adipocytes had increased proportion of ALDH-positive BCSCs, indicating a potential protection role of UCP1 in tumor microenvironment. These results suggested that UCP1 suppressed BCSCs through inhibiting Snail-mediated repression of FBP1, and that upregulation of UCP1 might be a previously undescribed therapeutic strategy for combating breast cancer. Graphical abstract.

7.
Theranostics ; 10(5): 2405-2421, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104513

RESUMO

Rationale: NOTCH4 receptor has been implicated in triple-negative breast cancer (TNBC) development and breast cancer stem cell (BCSC) regulation. However, the potential of NOTCH4 as a BCSC marker and the underlying mechanisms remain unclear. Methods: In this study, we determined the expression and activation of NOTCH4 in breast cancer cell lines and tumor samples by qRT-PCR, western blotting and immunohistochemistry. Subsequently, in vitro and in vivo serial dilution experiments were performed to demonstrate the application of NOTCH4 as an efficient mesenchymal-like (ML)-BCSC marker in TNBC. Stable overexpression of activated NOTCH4 and knockdown cell lines were established using lentivirus. RNA-seq and qRT-PCR were employed to reveal the downstream effectors of NOTCH4, followed by dual-luciferase reporter and chromatin immunoprecipitation assays to identify the genuine binding sites of NOTCH4 on SLUG and GAS1 promoters. Transwell assay, mammosphere formation and chemoresistance experiments were performed to determine the effects of SLUG, GAS1 and NOTCH4 on the mesenchymal-like characteristics of TNBC cells. Survival analysis was used to study the relation of NOTCH4, SLUG and GAS1 with prognosis of breast cancer. Results: NOTCH4 is aberrantly highly expressed and activated in TNBC, which contributes to the maintenance of ML-BCSCs. Furthermore, NOTCH4 shows significantly higher efficiency in labeling ML-BCSCs than the currently commonly used CD24-CD44+ marker. Mechanistically, NOTCH4 transcriptionally upregulates SLUG and GAS1 to promote EMT and quiescence in TNBC, respectively. The effects of NOTCH4 can be mimicked by simultaneous overexpression of SLUG and GAS1. Moreover, SLUG is also involved in harnessing GAS1, a known tumor suppressor gene, via its anti-apoptotic function. Conclusions: Our findings reveal that the NOTCH4-SLUG-GAS1 circuit serves as a potential target for tumor intervention by overcoming stemness of ML-BCSCs and by conquering the lethal chemoresistance and metastasis of TNBC.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptor Notch4/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Células-Tronco Mesenquimais/metabolismo , Camundongos , Prognóstico , Receptor Notch4/genética , Fatores de Transcrição da Família Snail/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
8.
Adv Sci (Weinh) ; 7(1): 1901728, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31921558

RESUMO

Breast tumor initiating cells (BTICs) with ALDH+CD24-CD44+ phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin-1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse-free survival. High IL1R2 promotes BTIC self-renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1ß, as demonstrated by the fact that IL1ß induces the release of IL1R2 intracellular domain (icd-IL1R2) and icd-IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self-renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs.

9.
Cell Stem Cell ; 26(1): 17-26.e6, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31761724

RESUMO

Accumulating evidence indicates that patient-derived organoids (PDOs) can predict drug responses in the clinic, but the ability of PDOs to predict responses to chemoradiation in cancer patients remains an open question. Here we generate a living organoid biobank from patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (NACR) enrolled in a phase III clinical trial. Our co-clinical trial data confirm that rectal cancer organoids (RCOs) closely recapitulate the pathophysiology and genetic changes of corresponding tumors. Chemoradiation responses in patients are highly matched to RCO responses, with 84.43% accuracy, 78.01% sensitivity, and 91.97% specificity. These data imply that PDOs predict LARC patient responses in the clinic and may represent a companion diagnostic tool in rectal cancer treatment.


Assuntos
Organoides , Neoplasias Retais , Quimiorradioterapia , Humanos , Terapia Neoadjuvante , Neoplasias Retais/terapia
10.
J Cancer Res Clin Oncol ; 145(11): 2637-2647, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31598791

RESUMO

PURPOSE: Malignant ascites (MA) is a common manifestation in advanced gastric cancer with peritoneal carcinomatosis and usually indicates a poor prognosis. However, lack of in vitro models that can faithfully recapitulate the characteristics of tumour cells in ascites hinders related researches. Tumour organoids have emerged as a robust in vitro model for tumour research and drug screening. Hence, we aimed to generate a 3-D in vitro organoid cultures from malignant ascites of gastric cancer for disease modelling and drug screening. METHODS: Eleven MADOs were generated from the MA tumour cells of gastric cancer patients. We made comparisons between MADOs and original MA tumour cells in histopathology by immunohistochemistry and genomics by whole-exome sequencing. In order to evaluate MADOs as functional in vitro disease models, we tested whether MADOs could be used for drug sensitivity screens. RESULTS: Eleven MADO cultures from human gastric cancer were established. MADOs demonstrated divergent growth characteristics and morphologies. MADO cultures preserve the histological architecture, genomic landscape of the corresponding MA tumour cells. MADOs exhibited heterogeneous responses to standard-of-care chemotherapeutics. CONCLUSIONS: We generated MADOs modelling characteristics and mutated genes of MA tumour cells. A broad range of intrinsic MADO response to conventional chemotherapeutics suggests MADOs are amenable to drug screening.


Assuntos
Antineoplásicos/farmacologia , Ascite/patologia , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Técnicas de Cultura de Órgãos/métodos , Organoides/patologia , Neoplasias Gástricas/patologia , Humanos , Técnicas In Vitro , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Células Tumorais Cultivadas , Sequenciamento Completo do Exoma
11.
Front Immunol ; 10: 404, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941120

RESUMO

Background: Although myelin is composed of mostly lipids, the pathological role of myelin lipids in demyelinating diseases remains elusive. The principal lipid of the myelin sheath is ß-galactosylceramide (ß-Galcer). Its α-anomer (α-Galcer) has been demonstrated to be antigenically presented by macrophages via CD1d, a MHC class I-like molecule. Myelin, which is mostly composed of ß-Galcer, has been long considered as an immunologically-inert neuron insulator, because the antigen-binding cleft of CD1d is highly α-form-restricted. Results: Here, we report that CD1d-mediated antigenic presentation of myelin-derived galactosylceramide (Mye-GalCer) by macrophages contributed significantly to the progression of experimental autoimmune encephalomyelitis (EAE). Surprisingly, this presentation was recognizable by α-Galcer:CD1d-specific antibody (clone L363), but incapable of triggering expansion of iNKT cells and production of iNKT signature cytokines (IFNγ and IL-4). Likewise, a synthesized analog of Mye-Galcer, fluorinated α-C-GalCer (AA2), while being efficiently presented via CD1d on macrophages, failed to stimulate production of IFNγ and IL-4. However, AA2 significantly exacerbated EAE progression. Further analyses revealed that the antigenic presentations of both Mye-GalCer and its analog (AA2) in α-form via CD1d promoted IL-17 production from T cells, leading to elevated levels of IL-17 in EAE spinal cords and sera. The IL-17 neutralizing antibody significantly reduced the severity of EAE symptoms in AA2-treated mice. Furthermore, D-sphingosine, a lipid possessing the same hydrophobic base as ceramide but without a carbohydrate residue, efficiently blocked this glycolipid antigen presentation both in vitro and in spinal cords of EAE mice, and significantly decreased IL-17 and ameliorated the pathological symptoms. Conclusion: Our findings reveal a novel pathway from the presentation of Mye-GalCer to IL-17 production, and highlight the promising therapeutic potential of D-sphingosine for the human disorder of multiple sclerosis.


Assuntos
Apresentação do Antígeno/imunologia , Encefalomielite Autoimune Experimental/imunologia , Galactosilceramidas/imunologia , Macrófagos/imunologia , Bainha de Mielina/imunologia , Esfingosina/imunologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Autoantígenos/química , Autoantígenos/imunologia , Feminino , Glicolipídeos/imunologia , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/química , Esfingosina/farmacologia
12.
J Agric Food Chem ; 66(34): 9042-9051, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30096237

RESUMO

Chilling stress is the main constraint in tomato ( Solanum lycopersicum) production, as this is a chilling-sensitive horticultural crop. The highly conserved C-repeat binding factors (CBFs) are cold-response-system components found in many species. In this study, we generated slcbf1 mutants using the CRISPR-Cas9 system and investigated the role of SlCBF1 in tomato-plant chilling tolerances. The slcbf1 mutants exhibited more severe chilling-injury symptoms with higher electrolyte leakage and malondialdehyde levels than wild-type (WT) plants. Additionally, slcbf1 mutants showed lower proline and protein contents and higher hydrogen peroxide contents and activities of antioxidant enzymes than WT plants. Knockout of SlCBF1 significantly increased indole acetic acid contents but decreased methyl jasmonate, abscisic acid, and zeatin riboside contents. The reduced chilling tolerance of the slcbf1 mutants was further reflected by the down-regulation of CBF-related genes. These results contribute to a better understanding of the molecular basis underlying SlCBF1 mediation of tomato chilling sensitivity.


Assuntos
Lycopersicon esculentum/fisiologia , Proteínas de Plantas/genética , Estresse Fisiológico , Sistemas CRISPR-Cas , Temperatura Baixa , Técnicas de Inativação de Genes , Lycopersicon esculentum/genética , Mutagênese , Proteínas de Plantas/metabolismo
13.
PLoS Biol ; 16(7): e2005869, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30052635

RESUMO

Chemotherapeutic resistance in triple-negative breast cancer (TNBC) has brought great challenges to the improvement of patient survival. The mechanisms of taxane chemoresistance in TNBC have not been well investigated. Our results illustrated C-C motif chemokine ligand 20 (CCL20) was significantly elevated during taxane-containing chemotherapy in breast cancer patients with nonpathologic complete response. Furthermore, CCL20 promoted the self-renewal and maintenance of breast cancer stem cells (BCSCs) or breast cancer stem-like cells through protein kinase Cζ (PKCζ) or p38 mitogen-activated protein kinase (MAPK)-mediated activation of p65 nuclear factor kappa B (NF-κB) pathway, significantly increasing the frequency and taxane resistance of BCSCs. Moreover, CCL20-promoted NF-κB activation increased ATP-binding cassette subfamily B member 1 (ABCB1)/multidrug resistance 1 (MDR1) expression, leading to the extracellular efflux of taxane. These results suggested that chemotherapy-induced CCL20 mediated chemoresistance via up-regulating ABCB1. In addition, NF-κB activation increased CCL20 expression, forming a positive feedback loop between NF-κB and CCL20 pathways, which provides sustained impetus for chemoresistance in breast cancer cells. Our results suggest that CCL20 can be a novel predictive marker for taxane response, and the blockade of CCL20 or its downstream pathway might reverse the taxane resistance in breast cancer patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quimiocina CCL20/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Aldeído Desidrogenase/metabolismo , Animais , Neoplasias da Mama/genética , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , Proteína Quinase C/metabolismo , Indução de Remissão , Taxoides/farmacologia , Taxoides/uso terapêutico , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Chin J Nat Med ; 16(5): 330-338, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29860993

RESUMO

Fibroblast-like synoviocytes (FLS) play a pivotal role in Rheumatoid arthritis (RA) pathogenesis through aggressive migration and invasion. Madecassoside (Madec), a triterpenoid saponin present in Centella asiatica herbs, has a potent anti-inflammatory effect. In the present study, Madec exerted an obvious therapeutic effect in reversing the histological lesions in adjuvant-induced arthritis (AIA) rats. To recognize the anti-rheumatoid potentials of Madec, we further investigated whether Madec interfered with FLS invasion and metalloproteinase (MMP) expression. In cultures of primary FLS isolated from the AIA rats, Madec (10 and 30 µmol·L-1) was proven to considerably inhibit migration and invasion of FLS induced by interleukin 1ß (IL-1ß), but exhibiting no obvious effect on cell proliferation. Madec repressed IL-1ß-triggered FLS invasion by prohibiting the expression of MMP-13. Additionally, Madec suppressed MMP-13 transcription via inhibiting the MMP-13 promoter-binding activity of NF-κB. Our results further showed that Madec down-regulated the translocation and phosphorylation of NF-κB as demonstrated by Western blotting and immunofluorescence assays. In conclusion, our results suggest that Madec exerts anti-RA activity via inhibiting the NF-κB/MMP-13 pathway.


Assuntos
Artrite Experimental/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Metaloproteinase 13 da Matriz/genética , NF-kappa B/metabolismo , Sinoviócitos/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Antirreumáticos/química , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Células Cultivadas , Interleucina-1beta/farmacologia , NF-kappa B/genética , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Sinoviócitos/metabolismo , Ativação Transcricional/efeitos dos fármacos , Triterpenos/química , Triterpenos/uso terapêutico
15.
Cell Death Dis ; 9(2): 126, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29374148

RESUMO

Annexin A3 (ANXA3) is dysregulated and plays an important role in various cancers. However, the role of ANXA3 in breast cancer is still unclear. Here, we observed that the expression level of ANXA3 was significantly upregulated in breast cancer tissues. ANXA3 knockdown inhibited cell invasion but promoted cell proliferation in both in vitro and in vivo assays. Furthermore, we found that ANXA3 knockdown inhibited the NFκB pathway via upregulating IκBα, resulting in mesenchymal-epithelial transition (MET) and a heterogeneity change of breast cancer stem cells (BCSCs). In addition, we demonstrated that ANXA3 knockdown increased the sensitivity of breast cancer cells to doxorubicin by increasing the drug uptake. The combination of ANXA3 knockdown and doxorubicin treatment simultaneously inhibited tumor growth and metastasis in vivo. This study described the role and mechanisms of ANXA3 in regulating BCSCs and breast cancer growth and metastasis, indicating that downregulating ANXA3 together with chemotherapy might be a novel therapeutic strategy for treating breast cancer.


Assuntos
Anexina A3/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Animais , Anexina A3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Doxorrubicina/farmacologia , Transição Epitelial-Mesenquimal , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Análise de Sobrevida , Regulação para Cima/genética
16.
Cell Death Differ ; 25(2): 330-339, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29027990

RESUMO

Notch pathways have important roles in carcinogenesis including pathways involving the Notch1 and Notch2 oncogenes. Pan-Notch inhibitors, such as gamma secretase inhibitors (GSIs), have been used in the clinical trials, but the outcomes of these trials have been insufficient and have yielded unclear. In the present study, we demonstrated that GSIs, such as MK-0752 and RO4929097, inhibit breast tumor growth, but increase the breast cancer stem cell (BCSC) population in Notch3-expressing breast cancer cells, in a process that is coupled with IL6 induction and is blocked by the IL6R antagonist Tocilizumab (TCZ). IL6 induction results from inhibition of Notch3-Hey2 signaling through MK-0752. Furthermore, HIF1α upregulates Notch3 expression via direct binding to the Notch3 promoter and subsequently downregulates BCSCs by decreasing the IL6 levels in Notch3-expressing breast cancer cells. Utilizing both breast cancer cell line xenografts and patient-derived xenografts (PDX), we showed that the combination of MK-0752 and Tocilizumab significantly decreases BCSCs and inhibits tumor growth and thus might serve as a novel therapeutic strategy for treating women with Notch3-expressing breast cancers.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Interleucina-6/farmacologia , Receptor Notch3/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Benzazepinas/farmacologia , Derivados de Benzeno/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Propionatos/farmacologia , Receptor Notch3/metabolismo , Sulfonas/farmacologia , Células Tumorais Cultivadas
17.
Cell Signal ; 42: 97-105, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28958617

RESUMO

Stem cells of the small and large intestine are marked by expression of the Wnt target gene LGR5, a leucine-rich-repeat-containing G protein-coupled receptor. Previous studies reported increased expression of LGR5 in human colorectal cancer (CRC) compared to normal tissue either by immunohistochemistry or in situ hybridization (ISH). However, as these studies were semi-quantitative they did not provide a numerical estimate of the magnitude of this effect. While we confirm that LGR5+ cells are exclusively located at the base of normal human small and large intestinal crypts, representing approximately 6% of total crypt cells, we show this cell population is 10-fold expanded in all grades of CRC, representing as much as 70% of the cells of tumor crypt-like structures. This expansion of the LGR5 compartment coincides with maintenance of crypt-like glandular structure (adenomas, and well and moderately differentiated adenocarcinomas), and is reduced in poorly differentiated CRC, where crypt-like glandular architecture is lost, accompanied by reduced epithelial terminal differentiation. Altogether these results indicate that LGR5+ cell expansion is a hallmark of CRC tumorigenesis occurring during progression to adenoma, supporting CRC as a stem cell disease with implications for CRC therapy.


Assuntos
Adenocarcinoma/genética , Adenoma/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Receptores Acoplados a Proteínas G/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenoma/diagnóstico , Adenoma/metabolismo , Adenoma/patologia , Contagem de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Intestino Grosso/metabolismo , Intestino Grosso/patologia , Intestino Grosso/ultraestrutura , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Intestino Delgado/ultraestrutura , Análise em Microsséries , Gradação de Tumores , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Receptores Acoplados a Proteínas G/metabolismo
18.
Theranostics ; 8(21): 5801-5813, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30613263

RESUMO

Increasing evidence demonstrates the existence of two inter-convertible states of breast cancer stem cells (BCSCs) with distinct behaviors in proliferation and mobility, and the BCSC heterogeneity is accurately regulated by sophisticated mechanisms including microRNAs. The microRNA-200 family including miR-200c/141 cluster was reported to affect cancer cell invasion and metastasis by regulating epithelial to mesenchymal transition (EMT). However, the effect of miR-200 family on BCSC heterogeneity is uncertain. Thus, we investigated whether the miR-200c/141 cluster had different effects on breast tumor growth and metastasis by switching the two states of BCSC. Methods: The spontaneous mammary tumor mouse model with miR-200c/141 conditional knockout was utilized for analyzing the role of miR-200c/141 cluster in vivo. The effect of miR-200c/141 cluster on BCSCs was performed by CD24/CD29 staining and ALDEFLUOR assay. miR-200c/141 target expression and EMT-related marker expression were verified in tumor sections, primary cells and breast cancer cell lines by qRT-PCR or western blotting. Statistical analysis was determined using two-way ANOVA and Student's t-test. All values were presented as the mean ± s.e.m. Results: The deletion of miR-200c/141 cluster regulated BCSC heterogeneity and promoted the EMT-like BCSC generation, which resulted in increased tumor metastasis and inhibited tumor growth by directly upregulating the target gene homeodomain-interacting protein kinase 1 (HIPK1) and sequential ß-catenin activation. Conclusions: Our results indicated that miR-200c/141 played biphasic roles in breast tumor progression via affecting the BCSC heterogeneity, suggesting targeting BCSC heterogeneity to simultaneously restrict breast cancer initiation and metastasis could be a promising therapeutic strategy for breast cancer.


Assuntos
Proteínas de Transporte/metabolismo , Neoplasias Mamárias Animais/patologia , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/fisiologia , Mapas de Interação de Proteínas , Proteínas Quinases/metabolismo , beta Catenina/metabolismo , Animais , Western Blotting , Antígeno CD24/análise , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Integrina beta1/análise , Camundongos , MicroRNAs/genética , Células-Tronco Neoplásicas/química , Proteínas Serina-Treonina Quinases , Reação em Cadeia da Polimerase em Tempo Real
19.
Cancer Res ; 77(11): 2857-2868, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28416485

RESUMO

The tumor-promoting potential of CCL5 has been proposed but remains poorly understood. We demonstrate here that an autocrine CCL5-CCR5 axis is a major regulator of immunosuppressive myeloid cells (IMC) of both monocytic and granulocytic lineages. The absence of the autocrine CCL5 abrogated the generation of granulocytic myeloid-derived suppressor cells and tumor-associated macrophages. In parallel, enhanced maturation of intratumoral neutrophils and macrophages occurred in spite of tumor-derived CCL5. The refractory nature of ccl5-null myeloid precursors to tumor-derived CCL5 was attributable to their persistent lack of membrane-bound CCR5. The changes in the ccl5-null myeloid compartment subsequently resulted in increased tumor-infiltrating cytotoxic CD8+ T cells and decreased regulatory T cells in tumor-draining lymph nodes. An analysis of human triple-negative breast cancer specimens demonstrated an inverse correlation between "immune CCR5" levels and the maturation status of tumor-infiltrating neutrophils as well as 5-year-survival rates. Targeting the host CCL5 in bone marrow via nanoparticle-delivered expression silencing, in combination with the CCR5 inhibitor Maraviroc, resulted in strong reductions of IMC and robust antitumor immunities. Our study suggests that the myeloid CCL5-CCR5 axis is an excellent target for cancer immunotherapy. Cancer Res; 77(11); 2857-68. ©2017 AACR.


Assuntos
Quimiocina CCL5/imunologia , Imunossupressores/uso terapêutico , Células Mieloides/imunologia , Animais , Comunicação Autócrina , Neoplasias da Mama , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
20.
Carbohydr Res ; 443-444: 73-77, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28365448

RESUMO

The identification of immunoactive agents for clinical and mechanistic applications is a very active area of research. In this vein, analogues of the potent immunostimulant KRN 7000 with diverse cytokine profiles have attracted considerable attention. These compounds have been shown to activate iNKT cells via presentation by CD1d. Herein, we report on the synthesis and activity for four new C-glycosides of KRN 7000, 11-phenylundecanoyl and 11-p-fluorophenylundecanoyl derivatives of C-KRN 7000, 2,3-bis-epi-C-KRN 7000 and the reverse amide of C-KRN 7000. In mice, compared to C-KRN 7000, 2,3-bis-epi-C-KRN 7000 stimulated higher release of the anti-inflammatory cytokine IL-4 and lower release of the inflammatory cytokines IFN-γ and IL-12. The phenyl terminated alkanoyl and reverse amide analogues were inactive. These data suggest that structure activity effects for KRN 7000 are not necessarily additive and their use in the design of new analogues will require an improved understanding of how subtle structural changes impact on cytokine activity.


Assuntos
Adjuvantes Imunológicos/síntese química , Adjuvantes Imunológicos/farmacologia , Ceramidas/química , Galactosilceramidas/síntese química , Galactosilceramidas/farmacologia , Monossacarídeos/química , Adjuvantes Imunológicos/química , Animais , Técnicas de Química Sintética , Citocinas/biossíntese , Galactosilceramidas/química , Glicosídeos , Camundongos
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