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1.
Antioxidants (Basel) ; 10(10)2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34679723

RESUMO

Burmannic acid (BURA) is a new apocarotenoid bioactive compound derived from Indonesian cinnamon; however, its anticancer effect has rarely been investigated in oral cancer cells. In this investigation, the consequences of the antiproliferation of oral cancer cells effected by BURA were evaluated. BURA selectively suppressed cell proliferation of oral cancer cells (Ca9-22 and CAL 27) but showed little cytotoxicity to normal oral cells (HGF-1). In terms of mechanism, BURA perturbed cell cycle distribution, upregulated mitochondrial superoxide, induced mitochondrial depolarization, triggered γH2AX and 8-hydroxy-2-deoxyguanosine DNA damage, and induced apoptosis and caspase 3/8/9 activation in oral cancer cells. Application of N-acetylcysteine confirmed oxidative stress as the critical factor in promoting antiproliferation, apoptosis, and DNA damage in oral cancer cells.

2.
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.

3.
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
4.
Cells ; 10(5)2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946480

RESUMO

Cancer stem cells (CSCs) refer to a subpopulation of cancer cells responsible for tumorigenesis, metastasis, and drug resistance. Increasing evidence suggests that CSC-associated tumor neovascularization partially contributes to the failure of cancer treatment. In this review, we discuss the roles of CSCs on tumor-associated angiogenesis via trans-differentiation or forming the capillary-like vasculogenic mimicry, as well as the roles of CSCs on facilitating endothelial cell-involved angiogenesis to support tumor progression and metastasis. Furthermore, we discuss the underlying regulation mechanisms, including the intrinsic signals of CSCs and the extrinsic signals such as cytokines from the tumor microenvironment. Further research is required to identify and verify some novel targets to develop efficient therapeutic approaches for more efficient cancer treatment through interfering CSC-mediated neovascularization.

5.
Front Plant Sci ; 12: 640277, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959138

RESUMO

Pathogenic microorganisms deliver protein effectors into host cells to suppress host immune responses. Recent findings reveal that phytopathogens manipulate the function of plant cell-to-cell communication channels known as plasmodesmata (PD) to promote diseases. Several bacterial and filamentous pathogen effectors have been shown to regulate PD in their host cells. A few effectors of filamentous pathogens have been reported to move from the infected cells to neighboring plant cells through PD; however, it is unclear whether bacterial effectors can traffic through PD in plants. In this study, we determined the intercellular movement of Pseudomonas syringae pv. tomato (Pst) DC3000 effectors between adjoining plant cells in Nicotiana benthamiana. We observed that at least 16 Pst DC3000 effectors have the capacity to move from transformed cells to the surrounding plant cells. The movement of the effectors is largely dependent on their molecular weights. The expression of PD regulators, Arabidopsis PD-located protein PDLP5 and PDLP7, leads to PD closure and inhibits the PD-dependent movement of a bacterial effector in N. benthamiana. Similarly, a 22-amino acid peptide of bacterial flagellin (flg22) treatment induces PD closure and suppresses the movement of a bacterial effector in N. benthamiana. Among the mobile effectors, HopAF1 and HopA1 are localized to the plasma membrane (PM) in plant cells. Interestingly, the PM association of HopAF1 does not negatively affect the PD-dependent movement. Together, our findings demonstrate that bacterial effectors are able to move intercellularly through PD in plants.

6.
Cancer Immunol Res ; 9(6): 707-722, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33875483

RESUMO

EGFR-targeted chimeric antigen receptor (CAR) T cells are potent and specific in suppressing the growth of triple-negative breast cancer (TNBC) in vitro and in vivo. However, in this study, a subset of mice soon acquired resistance, which limits the potential use of EGFR CAR T cells. We aimed to find a way to overcome the observed resistance. Transcriptomic analysis results revealed that EGFR CAR T-cell treatment induced a set of immunosuppressive genes, presumably through IFNγ signaling, in EGFR CAR T-cell-resistant TNBC tumors. The EGFR CAR T-cell-induced immunosuppressive genes were associated with EGFR CAR T-cell-activated enhancers and were especially sensitive to THZ1, a CDK7 inhibitor we screened out of a panel of small molecules targeting epigenetic modulators. Accordingly, combination therapy with THZ1 and EGFR CAR T cells suppressed immune resistance, tumor growth, and metastasis in TNBC tumor models, including human MDA-MB-231 cell-derived and TNBC patient-derived xenografts, and mouse EMT6 cell-derived allografts. Taken together, we demonstrated that transcriptional modulation using epigenetic inhibitors could overcome CAR T-cell therapy-induced immune resistance, thus providing a therapeutic avenue for treating TNBC in the clinic.

7.
Semin Cancer Biol ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33737107

RESUMO

Tumors consist of heterogeneous cell populations, and tumor heterogeneity plays key roles in regulating tumorigenesis, metastasis, recurrence and resistance to anti-tumor therapies. More and more studies suggest that cancer stem cells (CSCs) promote tumorigenesis, metastasis, recurrence and drug resistance as well as are the major source for heterogeneity of cancer cells. CD24-CD44+ and ALDH+ are the most common markers for breast cancer stem cells (BCSCs). Previous studies showed that different BCSC markers label different BCSC populations, indicating the heterogeneity of BCSCs. Therefore, defining the regulation mechanisms of heterogeneous BCSCs is essential for precisely targeting BCSCs and treating breast cancer. In this review, we summarized the novel regulators existed in BCSCs and their niches for BCSC heterogeneity which has been discovered in recent years, and discussed their regulation mechanisms and the latest corresponding cancer treatments, which will extend our understanding on BCSC heterogeneity and plasticity, and provide better prognosis prediction and more efficient novel therapeutic strategies for breast cancer.

8.
Clin Exp Med ; 21(2): 331-340, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33417083

RESUMO

The objective of this study was to explore the association between transformation growth factor beta 1 (TGF-ß1) gene polymorphisms and different types of arthritis. PubMed, Medline, Web of Science, Cochrane Library, Biosis and four Chinese databases: China Biology Medicine, China National Knowledge Infrastructure, Wanfang and CQVIP, were searched. Studies that analyzed the association of the TGF-ß1 polymorphisms with different types of arthritis were included. OR, 95% confidence interval and P value were calculated in three models including allele, dominant and recessive models, using D + L method. The Newcastle-Ottawa Scale was used to assess the quality of the included studies. TGF-ß1 869T > C polymorphism was significantly associated with rheumatoid arthritis (RA) in allele and recessive models, but not in dominant model (allele model T vs. C: OR = 1.30, 95% CI = 1.13-1.49, P < 0.001; recessive model CC vs. TT + TC: OR = 0.57, 95% CI = 0.43-0.76, P < 0.001; dominant model TT vs. TC + CC: OR = 1.20, 95% CI = 0.99-1.45, P = 0.063). Additionally, allele and recessive models showed that TGF-ß1 -509C > T was significantly correlated with RA susceptibility, while dominant model revealed nonsignificant correlation (allele model: C vs. T: OR = 1.51; 95% CI = 1.00-2.28; P = 0.049; recessive model: TT vs. CC + TC: OR = 0.52, 95% CI = 0.37-0.72, P = 0.000; dominant model: CC vs. TT + TC: OR = 1.48; 95% CI = 0.79-2.76; P = 0.223). However, no significant association was found between TGF-ß1 polymorphisms and ankylosing spondylitis (AS) or osteoarthritis (OA) risk. This study demonstrated that 869T > C, -509 C > T polymorphisms of TGF-ß1 gene were associated with increased susceptibility of RA, while polymorphisms of TGF-ß1 gene were not associated with OA and AS. These findings suggest that studying TGF-ß1 genotype may be useful in the prevention and management of RA. However, more studies are needed to evaluate the association of TGF-ß1 gene polymorphisms with the susceptibility of OA and AS.

9.
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.

10.
Clin Rheumatol ; 40(1): 25-32, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32506313

RESUMO

Iguratimod (IGU) is a novel small molecule anti-rheumatic drug with the effect of non-steroidal anti-inflammatory drug and disease-modifying anti-rheumatic drug. IGU has various mechanisms of action, including inhibition of prostaglandin E2, tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17) production, inhibition of macrophage migration inhibitory factor (MIF)-induced proinflammatory effects, inhibition of osteoclastogenesis, and promotion of osteoblastic differentiation. Ankylosing spondylitis (AS) is the major subtype of spondyloarthritis that affects the axial skeleton, causing inflammatory back pain, which can lead to impairments in structure and function and a decrease in quality of life. Theories on pathogenesis of AS include misfolding of human leukocyte antigen-B27 during its assembly leading to endoplasmic reticulum stress and unfolded protein response (UPR). Activation of UPR genes results in release of TNF-α and IL-17, which have been shown to be important in the development of AS. In addition, current evidence suggests the importance of cyclooxygenase-2/prostaglandin E2 pathway and MIF in the pathogenesis of AS. Current drugs for the treatment of AS are limited and exploration of effective drugs is needed. IGU may be effective for the treatment of AS given that its mechanisms of action are closely related to the pathogenesis of AS. In fact, several small-scale clinical trials have shown the efficacy of IGU for the treatment of AS. This article reviews the molecular mechanisms of IGU that are related to the pathogenesis of AS and clinical trials of IGU for the treatment of AS, providing a reference for future clinical application of IGU for AS.


Assuntos
Espondilite Anquilosante , Cromonas , Humanos , Qualidade de Vida , Espondilite Anquilosante/tratamento farmacológico , Sulfonamidas
11.
Carbohydr Polym ; 251: 117018, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33142579

RESUMO

Deep eutectic solvents (DESs), as emerging green solvents, provide a new opportunity for the biorefinement of biomass, component extraction, and cellulose nanofibrillation. Herein, different carboxylic acid-based DESs were applied for preparation of cellulose nanofibers (CNFs) from cellulose raw materials accompanied by simultaneous esterification modifications of CNFs. The results showed that pretreatment of DESs combined with mechanical treatment can swell and esterify the cellulose materials, producing CNFs with widths less than 100 nm. The DES pretreatment temperature played important roles in the esterification modifications and nanofibrillation of cellulose. The esterification modifications of cellulose prevented the over-hydrolysis and dissolution of cellulose during the DES pretreatment, guaranteeing CNFs with high yields of 72 %-88 % and maintaining the cellulose I crystal structure. Moreover, the esterified CNFs were used as a reinforcement to prepare CNF-strengthened polylactic acid (PLA) composites. The surface esterification of the CNFs improved their dispersibility and interfacial compatibility with PLA, thereby achieving the mechanical enhancement of CNF/PLA composites.


Assuntos
Ácidos Carboxílicos/química , Celulose/química , Nanofibras/química , Madeira/química , Esterificação , Hidrólise , Poliésteres/química , Solventes/química
12.
Acta Clin Belg ; : 1-8, 2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32723037

RESUMO

BACKGROUND: To evaluate the performance of BACTEC FX, BacT/ALERT 3D, and VIRTUO systems using simulated blood culture (BC). METHODS: Two experimental designs based on 'with' or 'without' added trough antibiotic concentrations in bottles were implemented. RESULTS: For the experiment A, A shorter time to detection (TTD) was observed for most of organisms (17/22) in VIRTUO system. VIRTUO system was also faster than 3D and FX systems no matter in aerobic and anaerobic bottles. The anaerobic bottles had faster detection than aerobic bottles in 3D system (13.68 h vs 15.36 h, P < 0.001) and VIRTUO system (10.30 h vs 12.46 h, P = 0.001) but not in FX system (P = 0.38). When antibiotics were present, the bacterial recovery rate (RR) of FX, 3D and VIRTUO systems were 64.10% (50/78), 58.97% (46/78) and 43.59% (34/78), respectively (P = 0.027). the bacterial RR of various bottles were as follows: BPA vs. FA vs. SA [84.44%(38/45) vs. 55.56%(25/45) vs. 42.22(19/45), P < 0.001]; BFN vs. FN vs. SN [36.36%(12/33) vs. 63.64%(21/33) vs.45.45%(15/33), P = 0.078]. CONCLUSIONS: The VIRTUO system allowed faster growth detection for most of organisms compared with FX and 3D systems. When antibiotics were present, the bottles containing antibiotic-binding agent showed better bacterial RR, especially in BACTEC Plus Aerobic/F bottles.

13.
Nat Cell Biol ; 22(6): 716-727, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32367047

RESUMO

PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3-ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1ß restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1ß production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.


Assuntos
Antineoplásicos/farmacologia , Inflamassomos/imunologia , Interleucina-1beta/metabolismo , Macrófagos/imunologia , Células Mieloides/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , PTEN Fosfo-Hidrolase/fisiologia , Animais , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Fosforilação
14.
Sci Adv ; 6(8): eaaw9960, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32128390

RESUMO

Triple-negative breast cancer (TNBC) is life-threatening because of limited therapies and lack of effective therapeutic targets. Here, we found that moesin (MSN) was significantly overexpressed in TNBC compared with other subtypes of breast cancer and was positively correlated with poor overall survival. However, little is known about the regulatory mechanisms of MSN in TNBC. We found that MSN significantly stimulated breast cancer cell proliferation and invasion in vitro and tumor growth in vivo, requiring the phosphorylation of MSN and a nucleoprotein NONO-assisted nuclear localization of phosphorylated MSN with protein kinase C (PKC) and then the phosphorylation activation of CREB signaling by PKC. Our study also demonstrated that targeting MSN, NONO, or CREB significantly inhibited breast tumor growth in vivo. These results introduce a new understanding of MSN function in breast cancer and provide favorable evidence that MSN or its downstream molecules might serve as new targets for TNBC treatment.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas dos Microfilamentos/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Biomarcadores Tumorais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Progressão da Doença , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Modelos Biológicos , Fosforilação , Transporte Proteico , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/patologia
15.
Pharmacol Res ; 155: 104741, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32151679

RESUMO

Adipocyte account for the largest component in breast tissue. Dysfunctional adipocyte metabolism, such as metaflammation in metabolically abnormal obese patients, will cause hyperplasia and hypertrophy of its constituent adipocytes. Inflamed adipose tissue is one of the biggest risk factors causing breast cancer. Factors linking adipocyte metabolism to breast cancer include dysfunctional secretion of proinflammatory mediators, proangiogenic factors and estrogens. The accumulation of tumor supporting cells and systemic effects, such as insulin resistance, dyslipidemia and oxidative stress, which are caused by abnormal adipocyte metabolism, further contribute to a more aggressive tumor microenvironment and stimulate breast cancer stem cell to influence the development and progression of breast cancer. Here, in this review, we focus on the adipocyte metabolism in regulating breast cancer progression, and discuss the potential targets which can be used for breast cancer therapy.


Assuntos
Adipócitos/metabolismo , Neoplasias da Mama/metabolismo , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Progressão da Doença , Humanos , Microambiente Tumoral
16.
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
17.
Adv Exp Med Biol ; 1231: 53-65, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32060846

RESUMO

CCL20, as a chemokine, plays an important role in rheumatoid arthritis, psoriasis, and other diseases by binding to its receptor CCR6. Recent 10 years' research has demonstrated that CCL20 also contributes to the progression of many cancers, such as liver cancer, colon cancer, breast cancer, pancreatic cancer, and gastric cancer. This article reviews and discusses the previous studies on CCL20 roles in cancers from the aspects of its specific effects on various cancers, its remodeling on tumor microenvironment (TME), its synergistic effects with other cytokines in tumor microenvironment, and the specific mechanisms of CCL20 signal activation, illustrating CCL20 signaling in TME from multiple directions.


Assuntos
Quimiocina CCL20/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Microambiente Tumoral , Animais , Humanos , Receptores CCR6/metabolismo
18.
Int J Biol Sci ; 16(4): 611-619, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32025209

RESUMO

Triple-negative breast cancer (TNBC) is one of the most malignant breast cancers lacking targeted therapeutics currently. We recently reported that mifepristone (MIF), a drug regularly used for abortion, suppresses TNBC cell growth by inhibiting KLF5 expression via inducing miR-153. However, its anticancer efficacy is only modest at high dose. In order to enhance the anticancer activities, a focused compound library containing 17 compounds by altering the sensitive metabolic region of mifepristone has been designed and synthesized. We first tested the cell growth inhibitory effects of these compounds in TNBC cell lines. Among them, FZU-00,003 displayed the most potent efficiency. FZU-00,003 suppresses TNBC cell growth, cell cycle progression and induces apoptosis more effectively than MIF does. Consistently, FZU-00,003 induces miR-153 expression and suppressed KLF5 expression at much lower dosages than MIF does. Furthermore, FZU-00,003 inhibits tumor growth more potently than MIF does. Taken together, the MIF derivative, FZU-00,003 may serve as a better therapeutic compound for TNBC than MIF.


Assuntos
MicroRNAs/metabolismo , Mifepristona/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/genética , Neoplasias de Mama Triplo Negativas/genética
19.
Pharmacol Res ; 152: 104628, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31904506

RESUMO

Triple-negative breast cancers (TNBC) are more aggressive due to lacking receptors for hormone therapy and maintaining stemness features in cancer cells. Herein we found long non-coding RNA CCAT2 overexpressed specially in TNBC, and in breast cancer stem cells (BCSC) as well. Enforced overexpression and targeted knockdown demonstrated the oncogenic function of CCAT2 both in vitro and in vivo. CCAT2 promoted the expression of stemness markers including OCT4, Nanog and KLF4, increased mammosphere formation and induced ALDH+ cancer stem cell population in TNBC. A chromosomally adjacent gene OCT4-PG1, as a pseudogene of OCT4, was upregulated by CCAT2, and positively regulated the stemness features of TNBC cells. miR-205 was identified as a target gene of CCAT2 in TNBC. Point-mutation in CCAT2 impaired the sponge inhibition of miR-205. Overexpression of miR-205 rescued the oncogenic phenotypes induced by CCAT2. In addition, Notch2, as a target gene of miR-205, was downregulated by miR-205 and upregulated by CCAT2 in TNBC. Collectively, the current study revealed a novel function of CCAT2 in promoting tumor initiation and progression in TNBC through upregulating OCT4-PG1 expression and activating Notch signaling. These findings not only demonstrated a lncRNA-based therapeutic strategy in treatment of TNBC, but also added a node to the regulatory network of CCAT2 that controls aggressiveness of breast cancer stem cells.


Assuntos
Carcinogênese/genética , Neoplasias Mamárias Experimentais/genética , RNA Longo não Codificante , Neoplasias de Mama Triplo Negativas/genética , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Camundongos Nus , Células-Tronco Neoplásicas/fisiologia
20.
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.

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