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2.
Mol Cancer ; 20(1): 98, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34325714

RESUMO

BACKGROUND: Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. METHODS: Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. RESULTS: We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKß-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. CONCLUSION: We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.

3.
Front Oncol ; 11: 677678, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34127944

RESUMO

Avasimibe is a bioavailable acetyl-CoA acetyltransferase (ACAT) inhibitor and shows a good antitumor effect in various human solid tumors, but its therapeutic value in cholangiocarcinoma (CCA) and underlying mechanisms are largely unknown. In the study, we proved that avasimibe retard cell proliferation and tumor growth of CCAs and identified FoxM1/AKR1C1 axis as the potential novel targets of avasimibe. Aldo-keto reductase 1 family member C1 (AKR1C1) is gradually increased along with the disease progression and highly expressed in human CCAs. From survival analysis, AKR1C1 could be a vital predictor of tumor recurrence and prognostic factor. Enforced Forkhead box protein M1 (FoxM1) expression results in the upregulation of AKR1C1, whereas silencing FoxM1 do the opposite. FoxM1 directly binds to promoter of AKR1C1 and triggers its transcription, while FoxM1-binding site mutation decreases AKR1C1 promoter activity. Moreover, over-expressing exogenous FoxM1 reverses the growth retardation of CCA cells induced by avasimibe administration, while silencing AKR1C1 in FoxM1-overexpressing again retard cell growth. Furthermore, FoxM1 expression significantly correlates with the AKR1C1 expression in human CCA specimens. Our study demonstrates a novel positive regulatory between FoxM1 and AKR1C1 contributing cell growth and tumor progression of CCA and avasimibe may be an alternative therapeutic option for CCA by targeting this FoxM1/AKR1C1 signaling pathway.

4.
Zootaxa ; 4985(2): 294300, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34186649

RESUMO

Parapteronemobius contains 7 species or subspecies distributed in East Asia with only one species recorded from China. In this study, we reported the second species, P. chenggong He sp. nov., from Zhejiang. The new species differs from P. dibrachiatus in body size, male genitalia and COI gene. The phylogeny of this genus in subfamily Nemobiinae are discussed based on COI, 18S and 28S genes. The type specimens are deposited in the Museum of Biology, East China Normal University (ECNU).


Assuntos
Ortópteros/classificação , Animais , Tamanho Corporal , China , Genes Mitocondriais , Genitália Masculina , Masculino , Ortópteros/anatomia & histologia , RNA Ribossômico 18S , RNA Ribossômico 28S
5.
Cancer Res ; 81(14): 3835-3848, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34049973

RESUMO

Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer-initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission-mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment. SIGNIFICANCE: These findings show that TBX19/PRMT1 complex-mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.

6.
Adv Sci (Weinh) ; 8(4): 2001961, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33643786

RESUMO

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone-metastasis remain largely unknown. In the current study, HCC-secreted lectin galactoside-binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone-metastasis-free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal-related events by forming a bone pre-metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219-meidated α-catenin degradation prompts YAP1/ß-catenin complex-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone-metastasis.

7.
FEBS Lett ; 594(5): 823-840, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31693752

RESUMO

Selective autophagy for the elimination of aberrant mitochondria, termed mitophagy, can be regulated by the kinase PINK1 and the ubiquitin ligase Parkin. The lysosome-associated membrane protein 2 (LAMP-2) plays diverse functions in non-selective autophagy, chaperone-mediated autophagy and selective autophagy for the degradation of RNA/DNA. In the present study, we investigated whether LAMP-2 plays important roles during PINK1/Parkin-mediated mitophagy. The results obtained clearly show that knockdown of LAMP-2 does not cause defects in mitophagy in HeLa cells stably expressing Parkin, indicating that LAMP-2 is dispensable for PINK1/Parkin-mediated mitophagy. The present study is the first to determine the potential role of LAMP-2 in PINK1/Parkin-mediated mitophagy, thereby providing more insight into the sophisticated process of mitophagy.


Assuntos
Proteína 2 de Membrana Associada ao Lisossomo/genética , Mitocôndrias/metabolismo , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Carbonil Cianeto m-Clorofenil Hidrazona/efeitos adversos , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Mitofagia/efeitos dos fármacos , Proteínas Quinases/genética
8.
Life Sci ; 227: 114-121, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30890406

RESUMO

AIMS: Intraoperative blood salvage (IBS) is associated with shortened lifespan of red blood cells (RBCs). This study aims to examine how salvaged RBCs are compromised during IBS. MAIN METHODS: Thirty patients who underwent vertebra surgery with IBS were included in the study. To examine possible mechanisms of IBS-induced injury, both fresh and salvaged RBCs from each patient were mixed with plasma, the Ca2+ ionophore ionomycin or mannitol-adenine-phosphate (MAP) solution (n = 10 patients per condition). Binding of Fluo-3 and/or Annexin V by RBCs was measured. KEY FINDINGS: The percentage of Fluo-3-binding RBCs in salvaged samples was 2.83 ±â€¯0.76%, which increased to 15.34 ±â€¯5.99% after 48-h incubation in plasma. These percentages were significantly higher than those observed with fresh RBCs (P < 0.01). Ionomycin dose-dependently increased the percentage of Fluo-3-binding RBCs in salvaged samples, while MAP solution decreased it. Incubating salvaged RBCs in plasma for 48 h increased the percentage of Fluo-3-positive spherocytes from 0.8 ±â€¯0.6% to 11.35 ±â€¯3.96%, and this increase was blocked by MAP solution. Ionomycin increased the percentage of RBCs binding both Fluo-3 and Annexin V, while MAP decreased this percentage. The percentage of Annexin V-binding RBCs was also higher in salvaged samples than in fresh samples, but this percentage was unaffected by either ionomycin or MAP solution. SIGNIFICANCE: Our results suggest that IBS induces a postponed RBC damage by inducing spherocyte formation, which likely reflects Ca2+ entry induced by energy exhaustion, as well as by exposing phosphatidylserine on the RBC surface, which likely occurs via Ca2+ entry and via Ca2+-independent pathways.


Assuntos
Eritrócitos/efeitos dos fármacos , Eritrócitos/fisiologia , Recuperação de Sangue Operatório/métodos , Adenina/farmacologia , Adulto , Cálcio/metabolismo , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidilserinas/metabolismo , Estudos Prospectivos
9.
Medicine (Baltimore) ; 96(39): e8143, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28953650

RESUMO

BACKGROUND: Intraoperative blood salvage (IBS) recovers most lost blood, and is widely used in the clinic. It is unclear why IBS does not reduce long-term postoperative requirements for red blood cells (RBCs), and 1 possibility is that IBS affects RBC lifespan. METHODS: Prospectively enrolled patients who underwent spine, pelvic, or femur surgery not involving allogeneic RBC transfusion were grouped based on whether they received IBS or not. Volumes of blood lost and of RBCs salvaged during surgery were recorded. Total blood cell counts, levels of plasma-free hemoglobin, and CD235a-positive granulocytes were determined perioperatively. RESULTS: Although intraoperative blood loss was higher in the IBS group (n = 45) than in the non-IBS group (n = 52) (P < .001), hemoglobin levels were similar between groups (P = .125) at the end of surgery. Hemoglobin levels increased in non-IBS patients (4 ±â€Š11 g/L), but decreased in IBS patients (-7 ±â€Š12 g/L) over the first 3 postoperative days. Nadir hemoglobin levels after surgery were higher in the non-IBS group (107 ±â€Š12 g/L) than in the IBS group (91 ±â€Š12 g/L). Salvaged RBC volume correlated with hemoglobin decrease (r = 0.422, P = .004). In multivariate analysis, salvaged RBC volume was an independent risk factor for hemoglobin decrease (adjusted odds ratio 1.002, 95% confidence interval 1.001-1.004, P = .008). Flow cytometry showed the numbers of CD235a-positive granulocytes after surgery to be higher in the IBS group than in the non-IBS group (P < .05). CONCLUSION: IBS may shorten the lifespan of RBCs by triggering their engulfment upon re-infusion (China Clinical Trial Registry ChiCTR-OCH-14005140).


Assuntos
Anemia , Transfusão de Sangue Autóloga , Sobrevivência Celular/fisiologia , Eritrócitos/fisiologia , Recuperação de Sangue Operatório , Procedimentos Ortopédicos , Complicações Pós-Operatórias , Adulto , Anemia/diagnóstico , Anemia/etiologia , Anemia/fisiopatologia , Anemia/prevenção & controle , Perda Sanguínea Cirúrgica/prevenção & controle , Transfusão de Sangue Autóloga/efeitos adversos , Transfusão de Sangue Autóloga/métodos , Volume Sanguíneo/fisiologia , Contagem de Eritrócitos/métodos , Feminino , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Sangue Operatório/efeitos adversos , Recuperação de Sangue Operatório/métodos , Procedimentos Ortopédicos/efeitos adversos , Procedimentos Ortopédicos/métodos , Avaliação de Processos e Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/fisiopatologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Estatística como Assunto
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