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1.
Carcinogenesis ; 2021 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-34922339

RESUMO

Breast cancer is the most common malignancy among women worldwide. Functional studies have demonstrated that miRNA dysregulation in many cases of cancer, in which miRNAs acting as either oncogenes or tumor suppressor. Here we report that miR-345-3p is generally upregulated in breast cancer tissues and breast cancer cell lines. Overexpression and inhibition of miR-345-3p revealed its capacity in regulating proliferation and invasion of breast cancer cells. Further research identified protein phosphatase 2 catalytic subunit alpha (PPP2CA), a suppressor of AKT phosphorylation, as a candidate target of miR-345-3p. In vitro, miR-345-3p mimics promoted AKT phosphorylation by targeting its negative regulator, PPP2CA. Blocking miR-345-3p relieves its inhibition of PPP2CA, which attenuated PI3K-AKT signaling pathway. In vivo, inhibiting miR-345-3p with miR-345-3p-inhibition lentivirus suppressed tumor growth and invasiveness in mice. Together, the miR-345-3p/PPP2CA signaling axis exhibits tumor promoting functions by regulating proliferation and invasion of breast cancer cells. These data provide a clue to novel therapeutic approaches for breast cancer.

3.
Front Med (Lausanne) ; 8: 629828, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33693018

RESUMO

We reported that the complete genome sequence of SARS-Coronavirus-2 (SARS-CoV-2) was obtained from a cerebrospinal fluid (CSF) sample by ultrahigh-depth sequencing. Fourteen days after onset, seizures, maxillofacial convulsions, intractable hiccups and a significant increase in intracranial pressure developed in an adult coronavirus disease 2019 patient. The complete genome sequence of SARS-CoV-2 obtained from the cerebrospinal fluid indicates that SARS-CoV-2 can invade the central nervous system. In future, along with nervous system assessment, the pathogen genome detection and other indicators are needed for studying possible nervous system infection of SARS-CoV-2.

4.
ACS Med Chem Lett ; 12(2): 195-201, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33603965

RESUMO

In this study, a series of novel hydroxyamidine derivatives were identified as potent and selective IDO1 inhibitors by structure-based drug design. Among them, compounds 13-15 and 18 exhibited favorable enzymatic and cellular activities. Compound 18 showed improved bioavailability in mouse, rat, and dog (F% = 44%, 58.8%, 102.1%, respectively). With reasonable in vivo pharmacokinetic properties, compound 18 was further evaluated in a transgenic MC38 xenograft mouse model. The combination of compound 18 with PD-1 monoclonal antibody showed a synergistic antitumor effect. These data indicated that compound 18 as a potential cancer immunotherapy agent should warrant further investigation.

5.
Sci Adv ; 7(7)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33568480

RESUMO

Evidence that offspring traits can be shaped by parental life experiences in an epigenetically inherited manner paves a way for understanding the etiology of depression. Here, we show that F1 offspring born to F0 males of depression-like model are susceptible to depression-like symptoms at the molecular, neuronal, and behavioral levels. Sperm small RNAs, and microRNAs (miRNAs) in particular, exhibit distinct expression profiles in F0 males of depression-like model and recapitulate paternal depressive-like phenotypes in F1 offspring. Neutralization of the abnormal miRNAs in zygotes by antisense strands rescues the acquired depressive-like phenotypes in F1 offspring born to F0 males of depression-like model. Mechanistically, sperm miRNAs reshape early embryonic transcriptional profiles in the core neuronal circuits toward depression-like phenotypes. Overall, the findings reveal a causal role of sperm miRNAs in the inheritance of depression and provide insight into the mechanism underlying susceptibility to depression.

6.
J Exp Clin Cancer Res ; 40(1): 4, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33390170

RESUMO

BACKGROUND: Progranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. Here, we studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism. METHODS: The changes of macrophage phenotypes after PGRN treatment were detected by western blot, quantitative polymerase chain reaction (PCR) and flow cytometry. Western blot was used to study the signal molecular mechanism of PGRN regulating this process. The number and localization of immune cells in Wild-type (WT) and PGRN-/- breast cancer tissues were analyzed by immunohistochemical staining and immunofluorescence techniques. The activation and proliferation of CD8+ T cells were measured by flow cytometry. RESULTS: After being treated with PGRN, the expressions of M2 markers and programmed death ligand 1 (PD-L1) on macrophages increased significantly. Signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitor Stattic significantly inhibited the expression of PD-L1 and M2 related markers induced by PGRN. In WT group, CD8 were co-localized with macrophages and PD-L1, but not tumor cells. The number of immune cells in PGRN-/- breast cancer tissue increased, and their infiltration into tumor parenchyma was also enhanced. Moreover, in the co-culture system, WT peritoneal macrophages not only reduced the ratio of activated CD8+ T cells but also reduced the proportion of proliferating CD8+ T cells. The addition of programmed death receptor 1 (PD-1) and PD-L1 neutralizing antibodies effectively reversed this effect and restored the immune function of CD8+ T cells. CONCLUSION: These results demonstrate that PGRN promotes M2 polarization and PD-L1 expression by activating the STAT3 signaling pathway. Furthermore, through PD-1/PD-L1 interaction, PGRN can promote the breast tumor immune escape. Our research may provide new ideas and targets for clinical breast cancer immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Progranulinas/farmacologia , Macrófagos Associados a Tumor/metabolismo , Animais , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Regulação para Cima/efeitos dos fármacos
7.
Braz J Infect Dis ; 23(5): 343-351, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31542378

RESUMO

OBJECTIVE: The clinical significance of coexistence of HBsAg/anti-HBs in chronic hepatitis B (CHB) patients remains controversial. This study was aimed to assess the association of this serological pattern with hepatocellular carcinoma (HCC) in patients with CHB. METHODS: In this cross-section study, 206 CHB patients with coexistence of HBsAg/anti-HBs and 206 CHB patients with HBsAg alone were included to evaluate the risk of HCC development by logistic regression analysis. In addition, a retrospective cohort of 260 patients with CHB was recruited to estimate the cumulative incidence of HCC by Kaplan-Meier analysis. RESULTS: The serological pattern of coexistence of HBsAg/anti-HBs, with high levels of ("High") HBsAg/low levels of ("Low") anti-HBs, were considered as independent risk factors for HCC. In particular, patients with "High" HBsAg/"High" anti-HBs [odds ratio (OR), 4.295; 95% confidence interval (CI), 1.104-16.699; p = 0.035] and "Low" HBsAg/ "High" anti-HBs (OR, 3.207; 95%CI, 1.299-7.919; p = 0.012) exhibited significantly higher risk for HCC development. However, only "Low" HBsAg /"High" anti-HBs might increase risk of HCC in CHB patients with high HBV load (logrank p < 0.001) in our cohort study. CONCLUSION: The coexistence of "Low" HBsAg /"High" anti-HBs might increase the risk of HCC development in CHB patients with high HBV load, which reflected that the long-term interaction between immune response and virus might lead to the development of HCC. The identification of the patients with poor prognosis will help clinicians to refine the therapeutic decisions and individualize follow-up strategies.


Assuntos
Carcinoma Hepatocelular/virologia , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Neoplasias Hepáticas/virologia , Biomarcadores/sangue , Carcinoma Hepatocelular/sangue , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Carga Viral
8.
ACS Med Chem Lett ; 10(6): 949-953, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31223453

RESUMO

A novel series of imidazoisoindoles were identified as potent indoleamine-2,3-dioxygenase (IDO) inhibitors. Lead optimization toward improving potency and eliminating CYP inhibition resulted in the discovery of lead compound 25, a highly potent IDO inhibitor with favorable pharmacokinetic properties. In the MC38 xenograft model in hPD-1 transgenic mice, 25 in combination with the anti-PD-1 monoclonal antibody (SHR-1210) achieved a synergistic antitumor effect superior to each single agent.

9.
Int J Immunopathol Pharmacol ; 33: 2058738419857550, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31204533

RESUMO

Burn injury is a gigantic challenge in public health which brings multiple negative effects to patients both in physical and spiritual aspects. Inflammation plays vital roles in the progression of burn injury, and our study investigated whether notoginsenoside R1 (NGR1) alleviated lipopolysaccharide (LPS)-induced human keratinocyte HaCaT cell inflammatory injury. Inflammatory injury was induced by LPS in HaCaT cells. Stimulated cells were then treated by NGR1 in different concentrations. Cell viability and cell apoptosis were detected by Cell Counting Kit-8 and flow cytometry, respectively. The concentration of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay (ELISA). The accumulated levels of apoptosis-related proteins (caspase-3 and caspase-9), nuclear factor κB (NF-κB), p38 mitogen-activated protein kinase (p38MAPK) signal pathways-related proteins (p65, IκBα, and p38MAPK), and myeloid differentiation primary response 88 (MyD88) were examined by western blot. Transfection was used to alter the expression of MyD88. We found that LPS stimulated HaCaT cells and induced cell inflammation, evidenced by decreasing cell viability, increasing cell apoptosis, and elevating TNF-α and IL-6 expressions. Then, we found that NGR1 reversed the results by enhancing cell viability, inhibiting cell apoptosis, and reducing TNF-α and IL-6 expressions. In addition, NGR1 decreased the phosphorylation of p65, IκBα, and p38MAPK, which increased by LPS. Moreover, NGR1 negatively regulated the expression of MyD88, and transfection with pMyD88 led to the opposite results with what showed by NGR1 in LPS-stimulated HaCaT cells. To sum up, NGR1 alleviates LPS-induced HaCaT cell inflammatory injury by downregulation of MyD88, as well as inactivation of NF-κB and p38MAPK signal pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Ginsenosídeos/farmacologia , Queratinócitos/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-6/metabolismo , Queratinócitos/metabolismo , Lipopolissacarídeos , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Proc Natl Acad Sci U S A ; 116(13): 6162-6171, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30867286

RESUMO

Hepatic injury is often accompanied by pulmonary inflammation and tissue damage, but the underlying mechanism is not fully elucidated. Here we identify hepatic miR-122 as a mediator of pulmonary inflammation induced by various liver injuries. Analyses of acute and chronic liver injury mouse models confirm that liver dysfunction can cause pulmonary inflammation and tissue damage. Injured livers release large amounts of miR-122 in an exosome-independent manner into the circulation compared with normal livers. Circulating miR-122 is then preferentially transported to mouse lungs and taken up by alveolar macrophages, in which it binds Toll-like receptor 7 (TLR7) and activates inflammatory responses. Depleting miR-122 in mouse liver or plasma largely abolishes liver injury-induced pulmonary inflammation and tissue damage. Furthermore, alveolar macrophage activation by miR-122 is blocked by mutating the TLR7-binding GU-rich sequence on miR-122 or knocking out macrophage TLR7. Our findings reveal a causative role of hepatic miR-122 in liver injury-induced pulmonary dysfunction.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/complicações , Macrófagos Alveolares/metabolismo , MicroRNAs/metabolismo , Pneumonia/etiologia , Transdução de Sinais , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Pneumonia/metabolismo , Receptor 7 Toll-Like
11.
Medicine (Baltimore) ; 98(8): e14402, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813141

RESUMO

RATIONALE: Imatinib mesylate (imatinib) is a classic tyrosine kinase inhibitor used to treat chronic myeloid leukemia. Although it is well tolerated by most patients and helps in the achievement of complete remission, a few rare imatinib-associated adverse effects such as pulmonary interstitial fibrosis have been reported. Because of its rareity, the clinical features of imatinib-induced interstitial lung disease (ILD) remain unclear. PATIENT CONCERNS: A 49-year-old Chinese man with chronic myeloid leukemia received oral treatment with imatinib and initially exhibited a good response. However, he presented with cough and fever 9 months after treatment initiation. DIAGNOSES: Pulmonary computed tomography indicated diffuse interstitial fibrosis in both lungs. All tests for possible infectious pathologies provided negative results. INTERVENTIONS: The patient was diagnosed with interstitial pneumonia and treated with antibiotics; however, there was no improvement. On the basis of a suspicion of imatinib-induced ILD, imatinib was discontinued and prednisone treatment was initiated. OUTCOMES: The patient's symptoms ameliorated with treatment, and imatinib was reintroduced. However, he developed cough and dyspnea again, and his treatment was switched to nilotinib as a second-line regimen. He was regularly monitored, and although his clinical symptoms ameliorated, computed tomography performed 29 months after he was diagnosed with ILD showed irreversible pulmonary interstitial fibrosis without progression. LESSONS: Clinicians should consider the possibility of severe irreversible ILD and carefully monitor patients receiving imatinib treatment.


Assuntos
Mesilato de Imatinib/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Tomografia Computadorizada por Raios X
12.
Cancer Lett ; 440-441: 211-222, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30393198

RESUMO

Tumor cells switch metabolic profile from oxidative phosphorylation to glycolysis in a hypoxic environment for survival and proliferation. The mechanisms governing this metabolic switch, however, remain incompletely understood. Here, we show that three miRNAs in the miR-23a∼27a∼24 cluster, miR-23a, miR-27a and miR-24, are the most upregulated miRNA cluster in colorectal cancer (CRC) under hypoxia. Gain- and loss-of-function assays, a human glucose metabolism array and gene pathway analyses confirm that HIF-1α-induced miR-23a∼27a∼24 cluster collectively regulate glucose metabolic network through regulating various metabolic pathways and targeting multiple tricarboxylic acid cycle (TCA)-related genes. In specific, miR-24/VHL/HIF-1α in CRC form a double-negative feedback loop, which in turn, promotes the cellular transition to the 'high HIF-1α/miR-24 and low VHL' state and facilitates cell survival. Our findings reveal that the miR-23a∼27a∼24 cluster is critical regulator switching CRC metabolism from oxidative phosphorylation to glycolysis, and controlling their expression can suppress colorectal cancer progression.


Assuntos
Neoplasias Colorretais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/biossíntese , Animais , Células CACO-2 , Hipóxia Celular/fisiologia , Reprogramação Celular/fisiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Retroalimentação Fisiológica , Células HT29 , Xenoenxertos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , MicroRNAs/genética , Regulação para Cima
13.
Front Immunol ; 9: 2381, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30459760

RESUMO

Autoimmune diseases involve a complex dysregulation of immunity. Autoimmune diseases include many members [e.g., rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)], and most of them are classified according to what organs and tissues are targeted by the damaging immune response. Many studies have focused on finding specific biomarkers for single autoimmune diseases, but so far, there are no universal biomarkers for detecting almost all autoimmune diseases. Serum miRNAs have served as potential biomarkers for detecting various diseases. The purpose of this study was to find a universal biomarker for diagnosing autoimmune diseases. Regulatory T cells (Tregs) play a crucial role in protecting an individual from autoimmunity, and depletion of Tregs in mice is considered a representative animal model of autoimmune disease. Two mouse models for Treg depletion, in which Treg was depleted by CD25mAb (in C57 mice) or by diphtheria toxin (DT) (in Foxp3DTR mice), were investigated, and 381 miRNAs were identified in the serum of mice with Treg depletion. A distinctive circulating miRNA profile was identified in Treg-depleted mice and in patients with autoimmune disease. QRT-PCR confirmation and ROC curve analysis determined that six miRNAs (miR-551b, miR-448, miR-9, miR-124, miR-148, and miR-34c) in the Treg-depleted mouse models and three miRNAs [miR-551b (specificity 73.5%, sensitivity 88.4%), miR-448 (specificity 82.4%, sensitivity 91.3%), and miR-124 (specificity 76.5%, sensitivity 91.3%)] in patients with RA, SLE, Sjogren's syndrome (SS), and ulcerative colitis (UC) could serve as valuable specific biomarkers. These circulating miRNAs may represent potential universal biomarkers for autoimmune diseases diagnosis and prognosis.


Assuntos
Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Biomarcadores , MicroRNA Circulante , Estudos de Associação Genética , Predisposição Genética para Doença , MicroRNAs/genética , Animais , Doenças Autoimunes/sangue , Autoimunidade/genética , Biologia Computacional/métodos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Depleção Linfocítica , Masculino , Camundongos , MicroRNAs/sangue , Curva ROC , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transcriptoma
14.
J Nutr Sci Vitaminol (Tokyo) ; 64(2): 161-167, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29710034

RESUMO

This study was designed to determine whether there is a relationship between serum vitamin D levels and neurodevelopment and anthropometry in Chinese infants. A prospective cohort study with 160 women who gave birth to 160 healthy full-term infants and who were followed up for 6 mo was done. It included 80 pregnant women with vitamin D deficiency, and the other 80 pregnant women were enrolled matching the age and delivery method with a 25(OH)D level of more than 50 nmol/L. There was a signicant intergroup difference in length, weight or head circumference at birth (p<0.05). Meanwhile, there was a signicant intergroup difference in cognitive development and achievement at 6 mo (p<0.001). In multivariate analyses, maternal 25(OH)D levels less than 50 nmol/L were independently associated with a higher tendency for a low Bayley mental score (MDI) at 6 mo (OR=2.77, 95% CI: 1.44-5.35, p=0.002), as well as Bayley motor score (PDI) (OR=2.08, 95% CI: 1.07-4.04, p=0.032). Thus we observed that maternal vitamin D was associated with infant neurodevelopment and anthropometry.


Assuntos
Pesos e Medidas Corporais , Desenvolvimento Infantil , Cognição , Complicações na Gravidez/sangue , Fenômenos Fisiológicos da Nutrição Pré-Natal , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Adulto , Antropometria , Estatura , Peso Corporal , Estudos de Casos e Controles , China , Feminino , Cabeça , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Estudos Prospectivos , Vitamina D/sangue , Deficiência de Vitamina D/sangue
15.
Nucleic Acids Res ; 46(4): 2012-2029, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29253196

RESUMO

Hepatic miR-122 can serve as a pro-apoptotic factor to suppress tumorigenesis. The underlying mechanism, however, remains incompletely understood. Here we present the first evidence that miR-122 promotes hepatocellular carcinoma cell apoptosis through directly silencing the biogenesis of cell survival oncomiR miR-21 at posttranscriptional level. We find that miR-122 is strongly expressed in primary liver cell nucleus but its nuclear localization is markedly decreased in transformed cells particularly in chemoresistant tumor cells. MiRNA profiling and RT-qPCR confirm an inverse correlation between miR-122 and miR-21 in hepatocellular carcinoma tissues/cells, and increasing or decreasing nuclear level of miR-122 respectively reduces or increases miR-21 expression. Mechanistically, nuclear miR-122 suppresses miR-21 maturation via binding to a 19-nt UG-containing recognition element in the basal region of pri-miR-21 and preventing the Drosha-DGCR8 microprocessor's conversion of pri-miR-21 into pre-miR-21. Furthermore, both in vitro and in vivo studies demonstrate that nuclear miR-122 participates in the regulation of HCC cell apoptosis through modulating the miR-21-targeted programmed cell death 4 (PDCD4) signal pathway.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , Processamento Pós-Transcricional do RNA , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos SCID , MicroRNAs/química , Precursores de RNA/química , Precursores de RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo
16.
Sci Rep ; 7(1): 3089, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28596599

RESUMO

The Warburg effect is a metabolic hallmark of cancer. Tumor cells rapidly adjust their energy source to glycolysis in order to efficiently proliferate in a hypoxic environment, but the mechanism underlying this switch remains incompletely understood. Here, we show that hypoxia potently induces the down-regulation of miR-125a expression in hepatocellular carcinoma (HCC) cells and tumors. Furthermore, we demonstrate that miR-125a could decrease the production of lactate, the uptake of glucose, and the levels of ATP and reactive oxygen species (ROS) in HCC cells. We investigated the molecular mechanism through which miR-125a inhibits HCC glycolysis and identified hexokinase II (HK2) as a direct target gene of miR-125a. Finally, we revealed that the miR-125a/HK2 axis is functionally important for regulating glycolysis of HCC cell and progression of cancer in vitro and in vivo. In summary, our findings demonstrate for the first time that hypoxia-down-regulated miR-125a regulated HCC glycolysis and carcinogenesis by targeting hexokinase HK2, a key glycolytic enzyme for the Warburg effect, and add a new dimension to hypoxia-mediated regulation of cancer metabolism.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Metabolismo Energético , Regulação Neoplásica da Expressão Gênica , Hexoquinase/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , Adulto , Idoso , Animais , Apoptose/genética , Feminino , Glicólise , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo
17.
Cell Death Dis ; 8(1): e2540, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-28079894

RESUMO

Hepatocellular carcinoma (HCC) generally possesses a high resistance to chemotherapy. Given that autophagy is an important factor promoting tumor chemoresistance and HCC express low level of miR-26, we aim to investigate the functional role of miR-26 in autophagy-mediated chemoresistance of HCC. We found that chemotherapeutic drug doxorubicin (Dox) induced autophagy but decreased the level of miR-26a/b in HCC cells. Activating autophagy using rapamycin can directly downregulate the level of miR-26a/b in HCC cells. In turn, restoring the expression of miR-26a/b inhibited autophagy induced by Dox and promoted apoptosis in HCC cells. Further mechanistic study identified that miR-26a and miR-26b target ULK1, a critical initiator of autophagy, at post-transcriptional level. Results from 30 cases of patients with HCC also showed that tumor cellular levels of miR-26a and miR-26b are significantly downregulated as compared with the corresponding control tissues and negatively correlated with the protein level of ULK1 but are not correlated to the mRNA level of ULK1. Gain- and loss-of-function assay confirmed that miR-26a/b inhibited autophagic flux at the initial stage through targeting ULK1. Overexpression of miR-26a/b enhanced the sensitivity of HCC cells to Dox and promoted apoptosis via inhibiting autophagy in vitro. Using xenograft models in nude mice, we confirmed that miR-26a/b, via inhibiting autophagy, promoted apoptosis and sensitized hepatomas to Dox treatment in vivo. Our findings demonstrate for the first time that miR-26a/b can promote apoptosis and sensitize HCC to chemotherapy via suppressing the expression of autophagy initiator ULK1, and provide the reduction of miR-26a/b in HCC as a novel mechanism of tumor chemoresistance.


Assuntos
Apoptose/genética , Autofagia/genética , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/genética , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , MicroRNAs/biossíntese , RNA Mensageiro/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Nat Commun ; 8: 14041, 2017 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-28067230

RESUMO

Tumour cells secrete exosomes that are involved in the remodelling of the tumour-stromal environment and promoting malignancy. The mechanisms governing tumour exosome release, however, remain incompletely understood. Here we show that tumour cell exosomes secretion is controlled by pyruvate kinase type M2 (PKM2), which is upregulated and phosphorylated in tumours. During exosome secretion, phosphorylated PKM2 serves as a protein kinase to phosphorylate synaptosome-associated protein 23 (SNAP-23), which in turn enables the formation of the SNARE complex to allow exosomes release. Direct phosphorylation assay and mass spectrometry confirm that PKM2 phosphorylates SNAP-23 at Ser95. Ectopic expression of non-phosphorylated SNAP-23 mutant (Ser95→Ala95) significantly reduces PKM2-mediated exosomes release whereas expression of selective phosphomimetic SNAP-23 mutants (Ser95→Glu95 but not Ser20→Glu20) rescues the impaired exosomes release induced by PKM2 knockdown. Our findings reveal a non-metabolic function of PKM2, an enzyme associated with tumour cell reliance on aerobic glycolysis, in promoting tumour cell exosome release.


Assuntos
Proteínas de Transporte/genética , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/genética , Proteínas Qb-SNARE/genética , Proteínas Qc-SNARE/genética , Hormônios Tireóideos/genética , Células A549 , Animais , Sequência de Bases , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Células HeLa , Células Hep G2 , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Proteínas Qb-SNARE/antagonistas & inibidores , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/antagonistas & inibidores , Proteínas Qc-SNARE/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Hormônios Tireóideos/metabolismo
19.
Cell Death Differ ; 24(3): 421-432, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28009350

RESUMO

MicroRNAs (miRNAs) have emerged as a major regulator of the initiation and progression of human cancers, including breast cancer. However, the cooperative effects and transcriptional regulation of multiple miRNAs, especially miRNAs that are present in clusters, remain largely undiscovered. Here we showed that all members of the miR-23~27~24 clusters are upregulated and function as oncogenes in breast cancer and simultaneously target HIC1. Furthermore, we found that HIC1 functions as a transcriptional repressor to negatively control the expression of miR-23~27~24 clusters and forms a double-negative (overall positive) feedback loop. This feedback regulatory pathway is important because overexpression of miR-23~27~24 clusters can remarkably accelerate tumor growth, whereas restoration of HIC1 significantly blocks tumor growth in vivo. A mathematical model was created to quantitatively illustrate the regulatory circuit. Our finding highlights the cooperative effects of miRNAs in a cluster and adds another layer of complexity to the miRNA regulatory network. This study may also provide insight into the molecular mechanisms of breast cancer progression.


Assuntos
Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Aminopeptidases/genética , Animais , Apoptose , Sequência de Bases , Sítios de Ligação , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Efrina-A1/metabolismo , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/genética , Células MCF-7 , Camundongos , Camundongos SCID , MicroRNAs/química , Regiões Promotoras Genéticas , Interferência de RNA , Ratos , Alinhamento de Sequência , Sirtuína 1/metabolismo
20.
BMC Cancer ; 16(1): 826, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27842510

RESUMO

BACKGROUND: The origin and development of breast cancer remain complex and obscure. Recently, microRNA (miRNA) has been identified as an important regulator of the initiation and progression of breast cancer, and some studies have shown the essential role of miR-124-3p as a tumor suppressor in breast tumorigenesis. However, the detailed role of miR-124-3p in breast cancer remains poorly understood. METHODS: Quantitative RT-PCR and western blotting assays were used to measure miR-124-3p and CBL expression levels in breast cancer tissues, respectively. Luciferase reporter assay was employed to validate the direct targeting of CBL by miR-124-3p. Cell proliferation and invasion assays were performed to analyze the biological functions of miR-124-3p and CBL in breast cancer cells. RESULTS: In the present study, we found that miR-124-3p was consistently downregulated in breast cancer tissues. Moreover, we showed that miR-124-3p significantly suppressed the proliferation and invasion of breast cancer cells. In addition, we investigated the molecular mechanism through which miR-124-3p contributes to breast cancer tumorigenesis and identified CBL (Cbl proto-oncogene, E3 ubiquitin protein ligase) as a direct target gene of miR-124-3p. Moreover, we found that ectopic expression of CBL can attenuate the inhibitory effect of miR-124-3p on cell proliferation and invasion in breast cancer cells. CONCLUSIONS: This study identified a new regulatory axis in which miR-124-3p and CBL regulate the proliferation and invasion of breast cancer cells.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Interferência de RNA , Regiões 3' não Traduzidas , Pareamento de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Feminino , Técnicas de Silenciamento de Genes , Humanos , Reprodutibilidade dos Testes
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