RESUMO
BACKGROUND: Aberrant TAK1 (transforming growth factor ß-activated kinase 1) activity is known to be involved in a variety of malignancies, but the regulatory mechanisms of TAK1 remain poorly understood. GRAMD4 (glucosyltransferase Rab-like GTPase activator and myotubularin domain containing 4) is a newly discovered p53-independent proapoptotic protein with an unclear role in HCC (hepatocellular carcinoma). RESULTS: In this research, we found that GRAMD4 expression was lower in HCC samples, and its downregulation predicted worse prognosis for patients after surgical resection. Functionally, GRAMD4 inhibited HCC migration, invasion and metastasis. Mechanistically, GRAMD4 interacted with TAK1 to promote its protein degradation, thus, resulting in the inactivation of MAPK (Mitogen-activated protein kinase) and NF-κB pathways. Furthermore, GRAMD4 was proved to recruit ITCH (itchy E3 ubiquitin protein ligase) to promote the ubiquitination of TAK1. Moreover, high expression of TAK1 was correlated with low expression of GRAMD4 in HCC patients. CONCLUSIONS: GRAMD4 inhibits the migration and metastasis of HCC, mainly by recruiting ITCH to promote the degradation of TAK1, which leads to the inactivation of MAPK and NF-κB signalling pathways.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , MAP Quinase Quinase Quinases/antagonistas & inibidores , Proteínas Mitocondriais/farmacologia , Metástase Neoplásica/tratamento farmacológico , Carcinoma Hepatocelular/fisiopatologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/fisiopatologia , MAP Quinase Quinase Quinases/uso terapêutico , Proteínas Mitocondriais/uso terapêutico , Metástase Neoplásica/prevenção & controle , Proteínas Repressoras/farmacologia , Proteínas Repressoras/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ubiquitina-Proteína Ligases/farmacologia , Ubiquitina-Proteína Ligases/uso terapêuticoRESUMO
The specific mechanisms by which acupuncture affects the central nervous system are unclear. In the International Standard Scalp Acupuncture system, acupuncture needles are applied at the middle line of the vertex, anterior parietal-temporal oblique line, and the posterior parietal-temporal oblique line. We conducted a single-arm prospective clinical trial in which seven healthy elderly volunteers (three men and four women; 50-70 years old) received International Standard Scalp Acupuncture at MS5 (the mid-sagittal line between Baihui (DU20) and Qianding (DU21)), the left MS6 (line joining Sishencong (EX-HN1) and Xuanli (GB6)), and the left MS7 (line joining DU20 and Qubin (GB7)). After acupuncture, resting-state functional magnetic resonance imaging demonstrated changes in the fractional amplitude of low frequency fluctuations and regional homogeneity in various areas, showing remarkable enhancement of regional homogeneity in the bilateral anterior cingulate, left medial frontal gyrus, supramarginal gyrus, right middle frontal gyrus, and inferior frontal gyrus. Functional connectivity based on a seed region at the right middle frontal gyrus (42, 51, 9) decreased at the bilateral medial superior frontal gyrus. Our data preliminarily indicates that the international standard scalp acupuncture in healthy elderly participants specifcally enhances the correlation between the brain regions involved in cognition and implementation of the brain network regulation system and the surrounding adjacent brain regions. The study was approved by the Ethics Committee of the China-Japan Union Hospital at Jilin University, China, on July 18, 2016 (approval No. 2016ks043).
RESUMO
BACKGROUND: Increasing evidence indicates that aberrant micro (mi)RNA-448 expression plays a critical role in the progression of several human cancers. However, the function of miRNA-448 in hepatocellular carcinoma (HCC) has not been fully investigated. METHODS: miRNA-448 expression levels in HCC tissues, adjacent non-cancerous tissues (ANTs), and HCC cell lines were examined by quantitative real-time polymerase chain reaction (qRT-PCR). HCC cells were treated with a miRNA-448 mimic or inhibitor, followed by cell viability measurements with the CCK-8 assay. Venn diagram analysis predicted, and dual luciferase reporter assays verified, the target gene of miRNA-448. Expression of the target gene was detected by qRT-PCR and immunohistochemistry. Growth of miRNA-448- or target gene-expressing HCC xenograft tumors in nude mice was measured. RESULTS: miRNA-448 was expressed at a lower level in HCC tissues than ANTs, and correlated with a larger tumor size, incomplete tumor encapsulation, and advanced Barcelona Clinic Liver Cancer stage. miRNA-448 inhibited HCC cell growth. The downstream target of miRNA-448 was BCL-2, which was highly expressed in HCC tissues and its mRNA level was negatively correlated with miRNA-448 expression. In vivo, BCL-2 attenuated the tumor inhibiting effect of miRNA-448. CONCLUSION: miRNA-448 functions as a tumor suppressor by targeting BCL-2 in HCC.
Assuntos
Carcinoma Hepatocelular/patologia , Proliferação de Células , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-bcl-2/genéticaRESUMO
We present a study for the impact of exciton-phonon and exciton-plasmon interactions on bistable four-wave mixing (FWM) signals in a metal nanoparticle (MNP)-monolayer MoS2 nanoresonator hybrid system. Via tracing the FWM response we predict that, depending on the excitation conditions and the system parameters, such a system exhibits 'U-shaped' bistable FWM signals. We also map out bistability phase diagrams within the system's parameter space. Especially, we show that compared with the exciton-phonon interaction, a strong exciton-plasmon interaction plays a dominant role in the generation of optical bistability, and the bistable region will be greatly broadened by shortening the distance between the MNP and the monolayer MoS2 nanoresonator. In the weak exciton-plasmon coupling regime, the impact of exciton-phonon interaction on optical bistability will become obvious. The scheme proposed may be used for building optical switches and logic-gate devices for optical computing and quantum information processing.
RESUMO
The epithelial-mesenchymal transition (EMT) is the key process that drives tumor metastasis. Accumulating evidence suggests that the deregulation of some microRNAs (miRNAs), is implicated in this process. Here, we highlight the function and molecular mechanism of miR-630 and its potential clinical application in hepatocellular carcinoma (HCC). First, we identified the clinical relevance of miR-630 expression in a screen of 97 HCC patient tissues. Patients with low miR-630 expression had higher recurrence rates and shorter overall survival than those with high miR-630 expression. Functional studies demonstrated the overexpression of miR-630 in HCC cells attenuated the EMT phenotype in vitro. Conversely, inhibition of miR-630 promoted EMT in HCC cells. Mechanistically, our data revealed that miR-630 suppressed EMT by targeting Slug. Knockdown of Slug expression reversed miR-630 inhibitor-mediated EMT progression. Furthermore, we found that the TGF-ß-Erk/SP1 and JNK/c-Jun signaling pathways repressed miR-630 transcription through occupying transcription factor binding sites. Ectopic expression of miR-630 restored the TGF-ß-activated EMT process. Taken together, these findings demonstrate, in HCC cells, miR-630 exerts its tumor-suppressor functions through the TGF-ß-miR-630-Slug axis and provides a potential prognostic predictor for HCC patients.
Assuntos
Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Transição Epitelial-Mesenquimal/genética , Feminino , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
11beta-hydroxysteroid dehydrogenase type 1 (11ßHSD1), converting glucocorticoids from hormonally inactive cortisone to active cortisol, plays an essential role in glucose homeostasis. Accumulating evidence suggests that enhanced glycolytic activity is closely associated with postoperative recurrence and prognosis of hepatocellular carcinoma (HCC). Whether 11ßHSD1 contributes to HCC metastasis and recurrence remains unclear. Here we found that expression of 11ßHSD1 in human HCC (310 pairs) was frequently decreased compared to the adjacent non-neoplastic liver tissues (ANT), which correlated well with the intrahepatic-metastatic index, serum glycemia, and other malignant clinicopathological characteristics of HCC and predicted poor prognosis. Knockdown of 11ßHSD1 in BEL-7402 cells drastically reduced the pH of culture medium and induced cell death. Meanwhile, overexpression of 11ßHSD1 in SMMC-7721 HCC cells resulted in repression of cell migration, invasion, angiogenesis, and proliferation in vitro. When transferred into BALB/c nude mice, 11ßHSD1 overexpression resulted in decreased intrahepatic metastasis, angiogenesis, and tumor size. F-18-2-fluoro-2-deoxyglucose accumulation assay measured by positron emission tomography elucidated that 11ßHSD1 reduced glucose uptake and glycolysis in SMMC-7721 cells in vitro, and intrahepatic metastasis foci and subcutaneous tumor growth in vivo. We showed that 11ßHSD1 repressed cell metastasis, angiogenesis and proliferation of HCC by causing disruption of glycolysis via the HIF-1α and c-MYC pathways. In conclusion, 11ßHSD1 inhibits the intrahepatic metastasis of HCC via restriction of tumor glycolysis activity and may serve as a prognostic biomarker for patients.