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1.
Hepatology ; 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32298475

RESUMO

Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α (PGC1α) is a key regulator of mitochondrial biogenesis and respiration. PGC1α is involved in the carcinogenesis, progression, and metabolic state of cancer. However, its role in progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we observed that PGC1α was downregulated in human HCC. A clinical study showed that the low levels of PGC1α expression were correlated with poor survival, vascular invasion, and larger tumor size. PGC1α inhibited the migration and invasion of HCC cells both in vitro experiment and in vivo mouse model. Mechanistically, PGC1α suppressed Warburg effect through the downregulation of pyruvate dehydrogenase kinase isozyme 1 (PDK1) mediated by WNT/ß-catenin pathway, and the inhibition of WNT/ß-catenin pathway was induced by the activation of PPARγ. Conclusion: Low levels of PGC1α expression indicate a poor prognosis for HCC patients. PGC1α suppresses HCC metastasis by inhibiting aerobic glycolysis through regulating WNT/ß-catenin/PDK1 axis, which depends on PPARγ. PGC1α is a potential factor for predicting prognosis and therapeutic target for HCC patients.

2.
Cancer Med ; 9(7): 2551-2563, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32017451

RESUMO

Krüppel-like factor 4 (KLF4) has a tumor suppressor role in the progression of gastric cancer (GC), and inhibition or loss of KLF4 expression was identified in GC. The aim of this study was to explore the new molecular mechanism of KLF4 inactivation in gastric cancer. Herein, we report that Helicobacter pylori infection or Cag pathogenicity island protein A (CagA) gene transduction resulted in KLF4 expression downregulation and promoted gastric epithelial cell and gastric cancel cell proliferation, migration, and colony formation. Mechanistically, we found that CagA gene transduction led to DNA methylation of the KLF4 promoter, an effect that was relevant to the significant downregulation of TET1 expression. Causally, knockdown of TET1 expression decreased KLF4 expression, whereas overexpression of TET1 had the opposite effect. Clinically, we found that KLF4 expression and the 5-hmC levels were lower in GC cells with H pylori infection than in GC cells without H pylori infection. Thus, our study not only sheds new light on how H pylori infection promotes the progression of GC but also elucidates a novel mechanism of KLF4 inactivation in GC pathogenesis. During pathogenesis, an alteration in the H pylori/CagA-TET1-KLF4 signaling pathway plays a critical role, suggesting that this pathway may be a prospective target for gastric carcinoma intervention and therapy.

3.
Onco Targets Ther ; 12: 9435-9447, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31807022

RESUMO

Purpose: The aim of this study was to investigate the effects of gain-of-function (GOF) E76K-mutant Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) on the biological behaviors of glioblastoma (GBM) cells, and explore the molecular mechanisms of GBM progression. Methods: Firstly, a negative control vector and vectors overexpressing SHP2 and E76K-mutant SHP2 were transduced into GBM cells (U87 and A172) using a lentivirus. The effect of GOF-mutant SHP2 on proliferation was measured using the MTT assay, flow cytometry, colony formation assay, and soft agar assay. Moreover, the migration and invasion of GBM cells were determined through the transwell assay. Related proteins of the extracellular signal-regulated kinase/cAMP response element binding protein (ERK/CREB) pathway were detected by Western blotting analysis. A xenograft model was established to confirm the tumor-promoting effect of GOF-mutant SHP2 in vivo. Finally, ERK was inhibited using a mitogen-activated protein kinase/ERK kinase inhibitor (U0126) to further explore the molecular mechanism of GOF-mutant SHP2 affecting GBM cells. Results: After transduction, the expression of SHP2 in the SHP2-mutant and SHP2-overexpression groups was higher than that observed in the control and normal groups. Our data indicated that GOF-mutant SHP2 enhanced the abilities of GBM cells for proliferation, migration, and invasion in vitro, and promoted tumor growth in vivo. Mechanistically, the ERK/CREB pathway was activated, and the levels of relevant proteins were increased in the SHP2-mutant group. Furthermore, following inhibition of ERK in the GOF-SHP2 mutant group, the activation of CREB was also depressed, and the malignant biological behaviors were weakened accordingly. Conclusion: The GOF-mutant SHP2 promoted GBM cell proliferation, metastasis, and tumor growth through the ERK/CREB pathway, providing a promising target for the treatment of GBM.

4.
Medicine (Baltimore) ; 98(51): e18077, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860958

RESUMO

RATIONALE: Angelman syndrome (AS) is an uncommon genetic disease characterized as serious retarded mental development and ocular abnormality. PATIENT CONCERNS: This report aims to present the ophthalmological features, and identify the diagnosis and outcomes of strabismus surgery in AS patients. DIAGNOSIS: Three children with exotropia were diagnosed with AS based on their typical clinical features. INTERVENTIONS: All patients underwent multiplex ligation-dependent probe amplification (MLPA) analysis and accepted lateral rectus recession surgery with the assistance of intravenous combined inhalation anesthesia. OUTCOMES: The maternal heritage deletion of chromosome 15q11.2-q13 was verified in all patients by MLPA. All patients with strabismus could not cooperate during the vision test, and had astigmatism. The strabismus type of AS patients was horizontal exotropia, and no vertical strabismus was found. One of these patients was combined with high myopia. The hypopigmentation on the hair and iris was ubiquitous. However, retina pigmentation was normal. After different degrees of lateral rectus recession, the exotropia was significantly relieved, and the surgical effects were stable postoperatively. LESSONS: Horizontal exotropia is the major strabismus type. Severe intellectual disability, hyperactivity, and speech impairment are the common characteristics of AS children. Its examination and operation design remains challenging. Thus, repeated examinations and intelligence rehabilitation are essential.


Assuntos
Síndrome de Angelman/diagnóstico , Exotropia/diagnóstico , Exotropia/cirurgia , Movimentos Oculares/fisiologia , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Síndrome de Angelman/complicações , Criança , Pré-Escolar , China , Exotropia/complicações , Feminino , Humanos , Masculino , Músculos Oculomotores/fisiopatologia , Prognóstico , Doenças Raras , Recuperação de Função Fisiológica , Estrabismo/complicações , Estrabismo/diagnóstico , Estrabismo/cirurgia , Resultado do Tratamento , Testes Visuais
5.
ACS Appl Mater Interfaces ; 11(47): 43996-44006, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31682099

RESUMO

Liver cancer is a leading cause of cancer morbidity and mortality worldwide, especially in China. Sorafenib (SRF) is currently the most commonly used systemic agent against advanced hepatocellular carcinoma (HCC), which is the most common type of liver cancer. However, HCC patients have only limited benefit and suffer a serious side effect from SRF. Therefore, new approaches are urgently needed to improve the therapeutic effectiveness of SRF and reduce its side effect. In our current study, we developed a self-imaging and self-delivered nanodrug with SRF and indocyanine (ICG) to improve the therapeutic effect of sorafenib against HCC. With the π-π stacking effect between SRF and ICG, a one-step nanoprecipitation method was designed to obtain the SRF/ICG nanoparticles (SINP) via self-assembly. Pluronic F127 was used to shield the SINP to further improve the stability in an aqueous environment. The stability, photothermal effect, cell uptake, ROS production, cytotoxicity, tumor imaging, and tumor-targeting and tumor-killing efficacy of the SINP were evaluated in vitro and in vivo by using an HCC cell line Huh7 and its xenograft tumor model. We found that our designed SINP showed monodisperse stability and efficient photothermal effect both in vitro and in vivo. SINP could rapidly enter Huh7 cells and achieve potent cytotoxicity under near-infrared (NIR) laser irradiation partly by producing a great amount of reactive oxygen species (ROS). SINP had significantly improved stability and blood half-life, and could specifically target tumor via the enhanced permeability and retention (EPR) effect in vivo. In addition, SINP showed improved cytotoxicity in both subcutaneous and orthotopic HCC implantation models in vivo. Overall, this rationally designed sorafenib delivery system with a very high loading capacity (33%) has considerably improved antitumor efficiency in vitro and could completely eliminate subcutaneous tumors without any regrowth in vivo. In conclusion, our self-imaging and self-delivered nanodrug could improve the efficacy of SRF and might be a potential therapy for HCC patients.

6.
Dev Cogn Neurosci ; 40: 100721, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31704653

RESUMO

Fathers play a crucial role in their children's socio-emotional and cognitive development. A plausible intermediate phenotype underlying this association is father's impact on infant brain. However, research on the association between paternal caregiving and child brain biology is scarce, particularly during infancy. Thus, we used magnetic resonance imaging (MRI) to investigate the relationship between observed father-infant interactions, specifically paternal sensitivity, and regional brain volumes in a community sample of 3-to-6-month-old infants (N = 28). We controlled for maternal sensitivity and examined the moderating role of infant communication on this relationship. T2-weighted MR images were acquired from infants during natural sleep. Higher levels of paternal sensitivity were associated with smaller cerebellar volumes in infants with high communication levels. In contrast, paternal sensitivity was not associated with subcortical grey matter volumes in the whole sample, and this was similar in infants with both high and low communication levels. This preliminary study provides the first evidence for an association between father-child interactions and variation in infant brain anatomy.

7.
Sci Rep ; 9(1): 12938, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506514

RESUMO

Myelination is considered to be an important developmental process during human brain maturation and closely correlated with gestational age. Quantitative assessment of the myelination status requires dedicated imaging, but the conventional T2-weighted scans routinely acquired during clinical imaging of neonates carry signatures that are thought to be associated with myelination. In this work, we develop a quatitative marker of progressing myelination for assessment preterm neonatal brain maturation based on novel automatic segmentation method for myelin-like signals on T2-weighted magnetic resonance images. Firstly we define a segmentation protocol for myelin-like signals. We then develop an expectation-maximization framework to obtain the automatic segmentations of myelin-like signals with explicit class for partial volume voxels whose locations are configured in relation to the composing pure tissues via second-order Markov random fields. The proposed segmentation achieves high Dice overlaps of 0.83 with manual annotations. The automatic segmentations are then used to track volumes of myelinated tissues in the regions of the central brain structures and brainstem. Finally, we construct a spatio-temporal growth models for myelin-like signals, which allows us to predict gestational age at scan in preterm infants with root mean squared error 1.41 weeks.

8.
Hepatology ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31469428

RESUMO

BACKGROUND AND AIMS: Endoplasmic reticulum (ER) stress is associated with liver inflammation and hepatocellular carcinoma (HCC). However, how ER stress links inflammation and HCC remains obscure. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible secretion protein that inhibits inflammation by interacting with the key subunit of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) p65. We hypothesized that MANF may play a key role in linking ER stress and inflammation in HCC. APPROACH AND RESULTS: Here, we found that MANF mRNA and protein levels were lower in HCC tissues versus adjacent noncancer tissues. Patients with high levels of MANF had better relapse-free survival and overall survival rates than those with low levels. MANF levels were also associated with the status of liver cirrhosis, advanced tumor-node-metastasis (TNM) stage, and tumor size. In vitro experiments revealed that MANF suppressed the migration and invasion of hepatoma cells. Hepatocyte-specific deletion of MANF accelerated N-nitrosodiethylamine (DEN)-induced HCC by up-regulating Snail1+2 levels and promoting epithelial-mesenchymal transition (EMT). MANF appeared in the nuclei and was colocalized with p65 in HCC tissues and in tumor necrosis factor alpha (TNF-α)-treated hepatoma cells. The interaction of p65 and MANF was also confirmed by coimmunoprecipitation experiments. Consistently, knockdown of MANF up-regulated NF-κB downstream target genes TNF-α, interleukin (IL)-6 and IL-1α expression in vitro and in vivo. Finally, small ubiquitin-related modifier 1 (SUMO1) promoted MANF nuclear translocation and enhanced the interaction of MANF and p65. Mutation of p65 motifs for SUMOylation abolished the interaction of p65 and MANF. CONCLUSIONS: MANF plays an important role in linking ER stress and liver inflammation by inhibiting the NF-κB/Snail signal pathway in EMT and HCC progression. Therefore, MANF may be a cancer suppressor and a potential therapeutic target for HCC.

9.
Cancer Biol Ther ; 20(12): 1430-1442, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31441380

RESUMO

Hepatocellular carcinoma (HCC), characterized by a high rate of metastasis and recurrence after surgery, is caused by malignant proliferation of hepatocytes with epigenetic and/or genetic mutations. In particular, abnormal activation of the hepatocyte growth factor (HGF)-/c-mesenchymal-epithelial transition receptor (c-Met) axis is closely associated with HCC metastasis. Unfortunately, effective treatments or drugs that target the HGF/c-Met signaling pathway are still in the research pipeline. Here, a c-Met inhibitor named the C7 peptide, which can inhibit both HGF and c-Met, can significantly inhibit HGF-induced (but not EGF-induced) cell migration and suppress the phosphorylation of c-Met, Akt and Erk1/2. Moreover, the C7 peptide can also significantly suppress tumor metastasis in nude mice and the phosphorylation of c-Met. Together, our current findings, demonstrated that the C7 peptide can inhibit HGF-induced cancer cell migration and invasion through the inhibition of Akt and Erk1/2. Identification of a peptide that can block HGF/c-Met signaling provides new insight into the mechanism of HCC and future clinical treatments.

10.
Front Oncol ; 9: 535, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293973

RESUMO

Background: Inactivation of microRNA-100 (miR-100) is involved in hepatocellular carcinoma (HCC) and miR-100 behaves as a tumor suppressor. To understand miR-100 function in HCC genesis and development in vivo, we developed hepatocyte-specific miR-100 deficient mice. Methods: Mice homozygous for floxed miR-100 allele that carried the Alb-Cre transgene (miR-100flox/floxAlb -Cre+) were developed by mating miR-100flox/flox mice with Alb-Cre+/+mice. The mice tails DNA were genotyped using the primers for LoxP sites and Cre recombinase, respectively. The specific deletion of miR-100 in the livers was verified by quantitative Real-time PCR (qRT-PCR). HE-staining was performed for histology analysis. Liver function was assessed by transaminase activity. The metabolic profiles of the hepatocytes were detected using a Seahorse XFe24 extracellular flux analyzer. The direct targets of miR-100 (such as IGF1R-ß, mTOR and CDC25A) and HCC related protein (SHP-2) were detected by qRT-PCR and Western blot in liver tissues. Results: The resultant homozygous knockout mice with genotype of miR-100flox/flox-Alb-Cre+ showed an 80% decrease in hepatic miR-100 expression. In adult mice, miR-100 knockout has no effect on the liver function and morphology. In aged mice, HE staining showed that miR-100 knockout caused infiltration of inflammatory cells and expansion of hepatocellular nuclei. Consistently, liver function was impaired in miR-100 knockout aged mice as indicated by increased serum AST and ALT levels. The metabolic analysis demonstrated that the miR-100 knockout hepatocytes tend to adopt glycolysis. The expressions of the miR-100 target genes, such as IGF1R-ß, CDC25A and mTOR, were increased. In addition, the known HCC related protein, SHP-2 also was up-regulated in the knockout livers. Conclusions: We successfully generated a miR-100 hepatocyte-specific knock-out mouse model. The malignant transformation related to HCC were observed in aged mice. Therefore, this model is suitable for investigating the mechanism of miR-100 inactivation contributing to HCC genesis in vivo.

11.
Nat Commun ; 10(1): 3200, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324812

RESUMO

Circular RNAs (circRNAs) are identified as vital regulators in a variety of cancers. However, the role of circRNA in lung squamous cell carcinoma (LUSC) remains largely unknown. Herein, we explore the expression profiles of circRNA and mRNA in 5 paired samples of LUSC. By analyzing the co-expression network of differentially expressed circRNAs and dysregulated mRNAs, we identify that a cell cycle-related circRNA, circTP63, is upregulated in LUSC tissues and its upregulation is correlated with larger tumor size and higher TNM stage in LUSC patients. Elevated circTP63 promotes cell proliferation both in vitro and in vivo. Mechanistically, circTP63 shares miRNA response elements with FOXM1. circTP63 competitively binds to miR-873-3p and prevents miR-873-3p to decrease the level of FOXM1, which upregulates CENPA and CENPB, and finally facilitates cell cycle progression.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Progressão da Doença , Proteína Forkhead Box M1/metabolismo , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Animais , Carcinoma de Células Escamosas/genética , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células , Proteína Centromérica A/metabolismo , Proteína B de Centrômero/metabolismo , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs , Pessoa de Meia-Idade , Neoplasias Experimentais , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética , Transcriptoma , Proteínas Supressoras de Tumor/genética
12.
Mol Carcinog ; 58(8): 1427-1437, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31162747

RESUMO

The Helicobacter pylori (H. pylori) cytotoxin-associated gene A (CagA) and Krüppel-like transcription factor (KLF4) were both closely associated with the development and progression of gastric cancer (GC). However, the nature of the interactions between CagA and KLF4 in GC development has not been elucidated. Therefore, we focused on the CagA-mediated promotion of the malignant transformation of gastric epithelial cells. Herein, we first examined the expression of KLF4 in both human cancer and paracarcinoma tissues with or without H. pylori infection and found that KLF4 expression was significantly decreased in H. pylori-positive GC cells compared with the H. pylori-negative GC cells. Further functional studies revealed that the increased expression of CagA could suppress KLF4 expression and promote the malignant transformation of normal epithelial cells. Subsequently, we found that CagA could upregulate miR-155 and further restrict the expression of downstream KLF4. More importantly, the overexpression of miR-155 in GES-1 promoted epithelial-mesenchymal transition and eventually facilitated tumor growth in vivo. Overall, the identification of the CagA/miR-155/KLF4 signaling pathway provided a new insight into the development and treatment of GC.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Transformação Celular Neoplásica/patologia , Mucosa Gástrica/patologia , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Gástricas/patologia , Adulto , Animais , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transformação Celular Neoplásica/genética , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Feminino , Mucosa Gástrica/citologia , Células HEK293 , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , Transplante de Neoplasias , Transdução de Sinais , Estômago/patologia , Neoplasias Gástricas/genética , Transplante Heterólogo
13.
Cancer Med ; 8(6): 2930-2941, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31050207

RESUMO

Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma (mostly DLBCL). Richter syndrome is a rare complication with an aggressive clinical course, bearing an unfavorable prognosis. Currently, there is no effective treatment for it. As a novel cellular-based immune therapy, chimeric antigen receptor-modified T (CART) cells treatment is gradually used in treating hematological malignancies, especially in CD19+ B-cell malignancy. Therefore, CD19-directed chimeric antigen receptor-modified T cells (CART-19) treatment is promising to be used as a new method for RS patients. In our study, one RS patient expressing high level of CD19 molecule was enrolled in clinical trial; he has received a series of treatments but did not achieve a satisfactory therapeutic effect. The patient totally received 3.55 × 108 autologous CART-19 cells infusion. After CART-19 infusion, the mainly clinical side effect was repeated fever. The maximal duration period was 24 days and the highest temperature was 40.1°C. Pancytopenia and significantly serum cytokines level rise were observed, including IFN-γ, IL-6, and IL-10. Before discharge, the level of cytokines reduced to normal levels. In addition, we detected the serum biochemical indices as like K+ , Ca2+ , creatinine, and glutamic-pyruvic transaminase, all of these indices were normal. This showed that there was no tumor necrosis syndrome after treatment. The proportion of B cells in patient's peripheral blood decreased from 72% to 40.2% after infusion, co-occurring with reduction in lymph nodes and hematopoietic reconstitution. Based on the recent revolution in the therapeutic landscape for hematological malignancies including B-cell lymphomas, CART-CD19 cell therapy as a new therapeutic option for RS might be available in the coming years. It aims to reduce patient's tumor burden, prolong their survival time, and provide opportunities for other sequential therapy such as chemotherapy and bone marrow transplantation.

14.
Mol Med Rep ; 19(6): 4788-4796, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942420

RESUMO

The use of small molecule compounds to inhibit cell proliferation is one of the most promising approaches in cancer therapy. In the present study, a cell viability assay, flow cytometry analysis, western blotting and mouse xenograft models were used to investigate the anticancer activities of #2714 and its underlying mechanisms in lung cancer. The present in vitro results suggested that #2714 significantly inhibited the viability of the human non­small cell lung cancer line SPC­A1 in a concentration­ and time­dependent manner, with a half­maximal inhibitory concentration value of 5.54 µM after 48 h of treatment. Additionally, #2714 inhibited SPC­A1 cell proliferation via the Wnt/ß­catenin pathway and by impairing mitochondrial membrane potential. The protein expression levels of Wnt 3a, Wnt 5a/b, phosphorylated (p)­ß­catenin, p­glycogen synthase kinase 3ß, and p­mitogen­activated protein kinase 14 were downregulated following treatment with #2714. Furthermore, using a mouse xenograft model, #2714 was identified to significantly inhibit tumor growth and to decrease cancer cell proliferation in vivo. #2714 may represent a novel effective anticancer compound targeting lung cancer cells. Additionally, #2714 was able to induce apoptosis and decrease cell proliferation in SPC­A1 cells via the Wnt/ß­catenin pathway.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt-5a/metabolismo , Proteína Wnt3A/metabolismo , beta Catenina
15.
J Cancer ; 10(4): 918-926, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30854098

RESUMO

Alterations in cellular metabolism are one of the characteristics in cancer. They are not only the result of tumor progression but also the cause of cancer initiation. Pyruvate dehydrogenase kinase 4 (PDK4) is a key metabolic enzyme, which regulates cell metabolism by inhibiting pyruvate dehydrogenase (PDH). However, the function and regulating mechanism of PDK4 in HCC remain unclear. Here, we found that the expression of PDK4 was significantly decreased in HCC tissues, and its downregulation could predict poor prognosis of HCC patients. Silencing PDK4 significantly facilitated proliferation and migration of HCC cells. Knockdown of PDK4 didn't influence the oxidative phosphorylation and glycolysis capacity of HCC cells in vitro. However, knockdown of PDK4 increased expression of key lipogenic enzymes, fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD), which finally induced lipogenesis. These data suggest that PDK4 inhibits proliferation and migration of HCC cells probably via suppressing lipogenesis.

16.
Autism Res ; 12(4): 614-627, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30801993

RESUMO

Autism spectrum disorder (ASD) is a common neurodevelopmental condition, and infant siblings of children with ASD are at a higher risk of developing autistic traits or an ASD diagnosis, when compared to those with typically developing siblings. Reports of differences in brain anatomy and function in high-risk infants which predict later autistic behaviors are emerging, but although cerebellar and subcortical brain regions have been frequently implicated in ASD, no high-risk study has examined these regions. Therefore, in this study, we compared regional MRI volumes across the whole brain in 4-6-month-old infants with (high-risk, n = 24) and without (low-risk, n = 26) a sibling with ASD. Within the high-risk group, we also examined whether any regional differences observed were associated with autistic behaviors at 36 months. We found that high-risk infants had significantly larger cerebellar and subcortical volumes at 4-6-months of age, relative to low-risk infants; and that larger volumes in high-risk infants were linked to more repetitive behaviors at 36 months. Our preliminary observations require replication in longitudinal studies of larger samples. If correct, they suggest that the early subcortex and cerebellum volumes may be predictive biomarkers for childhood repetitive behaviors. Autism Res 2019, 12: 614-627. © 2019 The Authors. Autism Research published by International Society for Autism Research published byWiley Periodicals, Inc. LAY SUMMARY: Individuals with a family history of autism spectrum disorder (ASD) are at risk of ASD and related developmental difficulties. This study revealed that 4-6-month-old infants at high-risk of ASD have larger cerebellum and subcortical volumes than low-risk infants, and that larger volumes in high-risk infants are associated with more repetitive behaviors in childhood.

17.
Mol Carcinog ; 57(10): 1358-1370, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30295962

RESUMO

Hepatocellular Carcinoma (HCC) is a malignant tumor with high rate of relapse and metastasis. Ethanol is a well-known risk factor for HCC; it promotes the progression and aggressiveness of HCC. However, the underlying mechanism remains unclear. In clinic studies, we showed that alcohol consumption is positively correlated with TNM stage and vessel invasion; HCC patients with chronic drinking history had faster progression rate and poorer prognosis compared to non-drinkers. In experimental models, ethanol exposure enhanced the metastasis, and invasion of HCC cells. Ethanol exposure increased cancer stem cells (CSC) population and enhanced stemness of HCC cells in vitro and in vivo. Mechanically, we found that ethanol exposure induced epithelial to mesenchymal transition (EMT) through activating Wnt/ß-catenin signaling pathway in HCC cells. We further demonstrated that ß-catenin siRNA or salinomycin (an inhibitor of Wnt/ß-catenin pathway) partially rescued ethanol-induced EMT. In conclusion, this study suggested that ethanol exposure promotes the metastasis and stemness of HCC cells by inducing EMT.


Assuntos
Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Etanol/farmacologia , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Consumo de Bebidas Alcoólicas , Animais , Anti-Infecciosos Locais/farmacologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transplante Heterólogo
18.
Int J Nanomedicine ; 13: 5469-5483, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271141

RESUMO

Background: Honokiol is a bioactive lignanoid and has been utilized in traditional Chinese medicine for a long time. It exhibits several pharmacological properties, such as anticancer effects, anti-inflammatory effects, and antianxiety effects. However, the poor aqueous solubility of honokiol has impeded clinical applications. Materials and methods: In the present study, we adopted the liquid antisolvent precipitation (LAP) technique to prepare nanoparticles of honokiol for enhancement of solubility and bioavailability. Moreover, the honokiol nanoparticles obtained were investigated and evaluated in terms of morphology, physicochemical properties, saturation solubility, dissolution in vitro, bioavailability in vivo, toxicity, and the inhibitory effect on growth of HepG2 cells. Results: The obtained honokiol nanoparticles existed nearly in spherical shape and could be turned into amorphous structure by the LAP method. Moreover, the solubility of the honokiol nanoparticles was extremely higher than that of free honokiol, and the nanoparticle dissolution rate was also higher than that of free honokiol, which was about 20.41 times and 26.2 times than that of free honokiol in artificial gastric juice and in artificial intestinal juice. The area under the curve [AUC(0-t)] value of honokiol nanoparticles was about 6.52 times greater than that of free honokiol; therefore, the honokiol nanoparticles had a higher bioavailability than free honokiol but were innoxious to the organs of rats. Additionally, the honokiol nanoparticles exhibited a higher inhibition of HepG2 cells due to their lower IC50 compared to free honokiol. Conclusion: Honokiol nanoparticles have high solubility and bioavailability, and can become a new oral drug formulation and produce a better response for its clinical applications.


Assuntos
Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/farmacocinética , Precipitação Química , Lignanas/farmacologia , Lignanas/farmacocinética , Nanopartículas/química , Solventes/química , Administração Oral , Animais , Disponibilidade Biológica , Compostos de Bifenilo/sangue , Compostos de Bifenilo/química , Varredura Diferencial de Calorimetria , Feminino , Células Hep G2 , Humanos , Lignanas/sangue , Lignanas/química , Nanopartículas/ultraestrutura , Especificidade de Órgãos , Tamanho da Partícula , Ratos Sprague-Dawley , Solubilidade , Termogravimetria , Testes de Toxicidade , Difração de Raios X
19.
Biochim Biophys Acta Mol Basis Dis ; 1864(11): 3605-3617, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30251680

RESUMO

p38γ is a member of p38 MAPK family which contains four isoforms p38α, p38ß, p38γ, and p38δ. p38γ MAPK has unique function and is less investigated. Recent studies revealed that p38γ MAPK may be involved in tumorigenesis and cancer aggressiveness. However, the underlying cellular/molecular mechanisms remain unclear. Epithelial-mesenchymal transition (EMT) is a process that epithelial cancer cells transform to facilitate the loss of epithelial features and gain of mesenchymal phenotype. EMT promotes cancer cell progression and metastasis, and is involved in the regulation of cancer stem cells (CSCs) which have self-renewal capacity and are resistant to chemotherapy and target therapy. We showed that p38γ MAPK significantly increased EMT in breast cancer cells; over-expression of p38γ MAPK enhanced EMT while its down-regulation inhibited EMT. Meanwhile, p38γ MAPK augmented CSC population while knock down of p38γ MAPK decreased CSC ratio in breast cancer cells. MicroRNA-200b (miR-200b) was down-stream of p38γ MAPK and inhibited by p38γ MAPK; miR-200b mimics blocked p38γ MAPK-induced EMT while miR-200b inhibitors promoted EMT. p38γ MAPK regulated miR-200b through inhibiting GATA3. p38γ MAPK induced GATA3 ubiquitination, leading to its proteasome-dependent degradation. Suz12, a Polycomb group protein, was down-stream of miR-200b and involved in miR-200b regulation of EMT. Thus, our study established an important role of p38γ MAPK in EMT and identified a novel signaling pathway for p38γ MAPK-mediated tumor promotion.


Assuntos
Transição Epitelial-Mesenquimal , Fator de Transcrição GATA3/metabolismo , MicroRNAs/metabolismo , Proteína Quinase 12 Ativada por Mitógeno/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias da Mama/patologia , Carcinogênese/genética , Regulação para Baixo , Feminino , Fator de Transcrição GATA3/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Proteína Quinase 12 Ativada por Mitógeno/genética , Células-Tronco Neoplásicas/metabolismo , RNA Interferente Pequeno/metabolismo , Ubiquitinação
20.
Stem Cells Int ; 2018: 8351374, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29983715

RESUMO

Stem cells, including embryonic stem cells (ESCs) and adult stem cells, play a central role in mammal organism development and homeostasis. They have two unique properties: the capacity for self-renewal and the ability to differentiate into many specialized cell types. Src homology region 2- (SH2-) containing protein tyrosine phosphatase 2 (SHP-2), a nonreceptor protein tyrosine phosphatase encoded by protein tyrosine phosphatase nonreceptor type 11 gene (PTPN11), regulates multicellular differentiation, proliferation, and survival through numerous conserved signal pathways. Gain-of-function (GOF) or loss-of-function (LOF) SHP2 in various cells, especially for stem cells, disrupt organism self-balance and lead to a plethora of diseases, such as cancer, maldevelopment, and excessive hyperblastosis. However, the exact mechanisms of SHP2 dysfunction in stem cells remain unclear. In this review, we intended to raise the attention and clarify the framework of SHP2-mediated signal pathways in various stem cells. Establishment of integrated signal architecture, from ESCs to adult stem cells, will help us to understand the changes of dynamic, multilayered pathways in response to SHP2 dysfunction. Overall, better understanding the functions of SHP2 in stem cells provides a new avenue to treat SHP2-associated diseases.

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