RESUMO
Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation. Particularly, the expression of Cd44, a liver cancer stem marker, was regulated by AP-1 in a Kdm3a-dependent manner. We identified Cd44-positive hepatocytes with epithelial-mesenchymal transition-related expression profiles in the Pik3ca Tg liver and confirmed their in vivo tumorigenic capacity. Notably, the number and tumor-initiating capacity of Cd44-positive hepatocytes were governed by Kdm3a. As a mechanism in Kdm3a-dependent AP-1 transcription, Kdm3a recruited c-Jun to the AP-1 binding sites of Cd44, Mmp7 and Pdgfrb without affecting c-Jun expression. Moreover, Brg1, a component of the SWI/SNF chromatin remodeling complex, interacted with c-Jun in a Kdm3a-dependent manner and was bound to the AP-1 binding site of these genes. Finally, KDM3A and c-JUN were co-expressed in 33% of human premalignant lesions with PI3K activation. Our data suggest a critical role for KDM3A in the PI3K/AP-1 oncogenic axis and propose a novel strategy for inhibition of KDM3A against liver tumor development under PI3K pathway activation.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias Hepáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Carcinogênese , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Epigênese Genética , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Fosforilação , Transdução de SinaisRESUMO
Sharpin (Shank-associated RH domain-interacting protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-κB signaling activation and tumor suppressor gene inhibition. Sharpin is upregulated in various types of cancers, including hepatocellular carcinoma (HCC), and is implicated in tumor progression. However, the exact roles of Sharpin in tumorigenesis and tumor progression remain largely unknown. Here we report novel mechanisms of HCC progression through Sharpin overexpression. In our study, Sharpin was upregulated in human HCC tissues. Increased Sharpin expression enhanced hepatoma cell invasion, whereas decrease in Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that Versican, a chondroitin sulfate proteoglycan that plays crucial roles in tumor progression and invasion, was also upregulated in Sharpin-expressing stable cells. Versican expression increased in the majority of HCC tissues and knocking down of Versican greatly attenuated hepatoma cell invasion. Sharpin expression resulted in a significant induction of Versican transcription synergistically with Wnt/ß-catenin pathway activation. Furthermore, Sharpin-overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that Sharpin promotes Versican expression synergistically with the Wnt/ß-catenin pathway, potentially contributing to HCC development. A Sharpin/Versican axis could be an attractive therapeutic target for this currently untreatable cancer.
RESUMO
We report measurements of Bâχ(c1)γK and χ(c2)γK decays using 772×10(6) BB[over ¯] events collected at the Υ(4S) resonance with the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider. Evidence of a new resonance in the χ(c1)γ final state is found with a statistical significance of 3.8σ. This state has a mass of 3823.1±1.8(stat)±0.7(syst) MeV/c(2), a value that is consistent with theoretical expectations for the previously unseen 1(3)D(2) cc[over ¯] meson. We find no other narrow resonance and set upper limits on the branching fractions of the X(3872)âχ(c1)γ and χ(c2)γ decays.
Assuntos
Remoção de Dispositivo/métodos , Corpos Estranhos/cirurgia , Gastroscopia/métodos , Pâncreas/cirurgia , Stents , Doença Crônica , Falha de Equipamento , Feminino , Migração de Corpo Estranho/cirurgia , Gastroscopia/instrumentação , Humanos , Pessoa de Meia-Idade , Ductos Pancreáticos , Pancreatite Crônica/terapiaAssuntos
Carcinoma Hepatocelular/complicações , Doenças do Ducto Colédoco/diagnóstico , Cálculos Biliares/diagnóstico , Neoplasias Hepáticas/complicações , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Doenças do Ducto Colédoco/etiologia , Diagnóstico Diferencial , Óleo Etiodado/administração & dosagem , Humanos , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-IdadeAssuntos
Carcinoma Hepatocelular/patologia , Cateterismo , Neoplasias do Ducto Colédoco/patologia , Neoplasias do Ducto Colédoco/terapia , Neoplasias Hepáticas/patologia , Idoso , Carcinoma Hepatocelular/diagnóstico por imagem , Colangiopancreatografia Retrógrada Endoscópica , Neoplasias do Ducto Colédoco/diagnóstico por imagem , Feminino , Humanos , Invasividade NeoplásicaRESUMO
We present improved measurements of CP-violation parameters in B(0) --> phiK(0), eta(')K(0), KS(0)KS(0)KS(0) decays based on a sample of 535 x 10(6) BB pairs collected at the Upsilon(4S) resonance with the Belle detector at the KEKB energy-asymmetric e(+)e(-) collider. We obtain sin2phi1(eff)=+0.64+/-0.10(stat)+/-0.04(syst) for B(0) --> eta(')K(0), +0.50+/-0.21(stat)+/-0.06(syst) for B(0) --> phiK(0), and +0.30+/-0.32(stat)+/-0.08(syst) for B(0) --> KS(0)KS(0)KS(0) decays. We have observed CP violation in the B(0) --> eta(')K(0) decay with a significance of 5.6 standard deviations. We also perform an improved measurement of CP asymmetries in B(0) --> J/psiK(0) decays and obtain sin2phi1=+0.642+/-0.031(stat)+/-0.017(syst).
RESUMO
The microvasculature of porcine ovaries, with special regard to the follicles in the interstitial-stromal tissue, was studied by scanning electron microscopy (SEM) of vascular corrosion casts. Porcine ovaries displayed several coiled arteries in the hilus and many branches with small diameters and a tightly spiraling configuration in the cortical areas. However, small arterioles became straight before entering vascular complexes of follicles and finally divided into capillaries. Vascular baskets of various sizes (150-9,900 micro m in diameter) and architecture related to follicles in various developmental stages were observed in the ovarian cortex. Small follicles (150-300 micro m in diameter) began with a polygonal meshwork of a few large capillary meshes and developed to an obvious spherical microvascular network with a thin single layer of capillaries when reaching 500-700 micro m in diameter. The microvascular architecture of follicles 1,000-2,000 micro m in diameter developed further and had a three-layer vascular plexus. With a diameter of more than 2,000 micro m, the microvasculature of antral follicles was arranged as an inner vascular plexus of about 25 micro m, a middle plexus of about 100 micro m, and an outer capillary plexus of about 30 micro m in thickness. The present observations indicate that follicular vascular baskets of diverse sizes and architecture in various developmental stages support the gradual increase of follicular blood flow during follicle growth in the pig.
Assuntos
Folículo Ovariano/irrigação sanguínea , Sus scrofa/anatomia & histologia , Animais , Arteríolas/fisiologia , Arteríolas/ultraestrutura , Capilares/fisiologia , Capilares/ultraestrutura , Molde por Corrosão , Feminino , Microcirculação/fisiologia , Microcirculação/ultraestrutura , Microscopia Eletrônica de Varredura , Folículo Ovariano/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Sus scrofa/fisiologia , Vênulas/fisiologia , Vênulas/ultraestruturaRESUMO
Isopoly-L-ornithine derivatives of thymine, and thymidine were found to hardly interact with poly A. Conformational studies of the oligomers with CD and NMR revealed that stable intramolecular hydrogen bonding was formed between the thymine base and the ornithine unit.
Assuntos
Conformação de Ácido Nucleico , Peptídeos/química , Poli A/química , Conformação Proteica , Timidina , Timina , DNA/química , Ligação de Hidrogênio , Isomerismo , Modelos Moleculares , Modelos Estruturais , RNA/químicaRESUMO
Nucleic acid analogs, that consist of oligo-omega-amino acids as main chains were synthesized. At first, hydroxyl group of deoxy and ribonucleic acid was converted into amino or carboxylic acid group. Then, amino acid derivatives containing aminonucleoside or nucleoside-5'-carboxylic acid at alpha-position were synthesized. Amino acids used in this paper were L-glutamic acid, L-2-amino adipic acid (L-homo glutamic acid), L-ornithine, and L-lysine. These amino acid derivatives containing nucleoside were oligomerized by activated ester methods and Merrifield's solid phase synthesis. The properties of these analogs were studied and compared with oligo-alpha-amino acid derivatives containing nucleoside at omega-position.