No abstract

Hepatocellular carcinoma (HCC) is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. There is frequent down-regulation of miR-195 expression in HCC tissues. In this study, the role of miR-195 in HCC angiogenesis and metastasis was investigated with in vitro capillary tube formation and transwell assays, in vivo orthotopic xenograft mouse models, and human HCC specimens. Reduction of miR-195 in HCC tissues was significantly associated with increased angiogenesis, metastasis, and worse recurrence-free survival. Both gain-of-function and loss-of-function studies of in vitro models revealed that miR-195 not only suppressed the ability of HCC cells to promote the migration and capillary tube formation of endothelial cells but also directly repressed the abilities of HCC cells to migrate and invade extracellular matrix gel. Based on mouse models, we found that the induced expression of miR-195 dramatically reduced microvessel densities in xenograft tumors and repressed both intrahepatic and pulmonary metastasis. Subsequent investigations disclosed that miR-195 directly inhibited the expression of the proangiogenic factor vascular endothelial growth factor (VEGF) and the prometastatic factors VAV2 and CDC42. Knockdown of these target molecules of miR-195 phenocopied the effects of miR-195 restoration, whereas overexpression of these targets antagonized the function of miR-195. Furthermore, we revealed that miR-195 down-regulation resulted in enhanced VEGF levels in the tumor microenvironment, which subsequently activated VEGF receptor 2 signaling in endothelial cells and thereby promoted angiogenesis. Additionally, miR-195 down-regulation led to increases in VAV2 and CDC42 expression, which stimulated VAV2/Rac1/CDC42 signaling and lamellipodia formation and thereby facilitated the metastasis of HCC cells. Conclusion: miR-195 deregulation contributes to angiogenesis and metastasis in HCC. The restoration of miR-195 expression may be a promising strategy for HCC therapy. (HEPATOLOGY 2013;58:642-653) G lobally, hepatocellular carcinoma (HCC) is a common and highly lethal malignancy. Active angiogenesis and frequent metastasis are responsible for rapid recurrence and poor survival of HCC. Therefore, identifying molecules that can suppress angiogenesis and metastasis may provide novel targets for HCC therapies.MicroRNAs (miRNAs) constitute a class of endogenous small noncoding RNAs that suppress protein expression by base-pairing with the 3 0 -untranslated

Highly controlled Fe-catalyzed growth of monolayer hexagonal boron nitride (h-BN) films is demonstrated by the dissolution of nitrogen into the catalyst bulk via NH3 exposure prior to the actual growth step. This “pre-filling” of the catalyst bulk reservoir allows us to control and limit the uptake of B and N species during borazine exposure and thereby to control the incubation time and h-BN growth kinetics while also limiting the contribution of uncontrolled precipitation-driven h-BN growth during cooling. Using in situ X-ray diffraction and in situ X-ray photoelectron spectroscopy combined with systematic growth calibrations, we develop an understanding and framework for engineering the catalyst bulk reservoir to optimize the growth process, which is also relevant to other 2D materials and their heterostructures.

1 miR-122 is a highly abundant, hepatocyte-specific microRNA. The biomedical significance and regulatory mechanisms of miR-122 remain obscure. We explored the role of miR-122 in tumorigenesis in the context of gene regulatory network. The miR-122 promoter and its transactivator were identified by way of luciferase reporter system, electrophoretic mobility shift, and chromatin immunoprecipitation assays. The miR-122 regulatory circuitry and its implication in hepatocarcinogenesis were identified using livers of different development stages, human hepatocellular carcinoma (HCC) tissues and cell lines, and aflatoxin B 1 (AFB 1 )-transformed cells. We characterized the 25.3 to 24.8 kb region upstream of miR-122 precursor as miR-122 promoter. Further investigation revealed that deletion of predicted CCAAT/enhancer-binding protein alpha (C/EBPa) binding sites C/EBPa knockdown significantly reduced miR-122 promoter activity and endogenous miR-122 expression; and C/ EBPa directly interacted with the miR-122 promoter in vitro and in vivo. These data suggest that C/EBPa is a transactivator for miR-122 transcription. We further demonstrated that miR-122 suppressed insulin-like growth factor 1 receptor (IGF-1R) translation and sustained glycogen synthase kinase-3 beta (GSK-3b) activity. The activated GSK-3b not only repressed cell proliferation, but also activated C/EBPa, which maintained miR-122 levels and thereby enforced IGF-1R suppression. Interestingly, down-regulation of miR-122 and C/EBPa, and up-regulation of IGF-1R were frequently observed in HCC tissues, and decreased miR-122 levels were associated with worse survival of HCC patients. Moreover, AFB 1 exposure resulted in decreased activity in GSK-3b, C/EBPa, and miR-122 and increased levels of IGF-1R, whereas restoration of miR-122 suppressed the tumorigenicity of HCC and AFB 1 -transformed cells. Conclusion: We have identified a novel GSK-3b-C/EBPa-miR-122-IGF-1R regulatory circuitry whose dysfunction may contribute to the development of HCC. Our findings provide new insight into miR-122's function and the mechanisms of hepatocarcinogenesis. (HEPATOLOGY 2010;52:1702-1712

No abstract

BackgroundAbnormal activation of the NF-κB pathway is closely related to tumorigenesis and chemoresistance. Therefore, microRNAs that possess the NF-κB inhibitory activity may provide novel targets for anti-cancer therapy. miR-26 family members have been shown to be frequently downregulated in hepatocellular carcinoma (HCC) and correlated with the poor survival of HCC patients. To date, there is no report disclosing the regulatory role of miR-26 on the NF-κB pathway and its biological significance.MethodsThe effects of miR-26b on the NF-κB signaling pathway and the chemosensitivity of cancer cells were examined in two HCC cell lines, QGY-7703 and MHCC-97H, using both gain- and loss-of-function studies. The correlation between miR-26b level and apoptosis rate was further investigated in clinical HCC specimens.ResultsBoth TNFα and doxorubicin treatment activated the NF-κB signaling pathway in HCC cells. However, the restoration of miR-26b expression significantly inhibited the phosphorylation of IκBα and p65, blocked the nuclear translocation of NF-κB, reduced the NF-κB reporter activity, and consequently abrogated the expression of NF-κB target genes in TNFα or doxorubicin-treated HCC cells. Furthermore, the ectopic expression of miR-26b dramatically sensitized HCC cells to the doxorubicin-induced apoptosis, whereas the antagonism of miR-26b attenuated cell apoptosis. Consistently, the miR-26b level was positively correlated with the apoptosis rate in HCC tissues. Subsequent investigations revealed that miR-26b inhibited the expression of TAK1 and TAB3, two positive regulators of NF-κB pathway, by binding to their 3’-untranslated region. Moreover, knockdown of TAK1 or TAB3 phenocopied the effects of miR-26b overexpression.ConclusionsThese data suggest that miR-26b suppresses NF-κB signaling and thereby sensitized HCC cells to the doxorubicin-induced apoptosis by inhibiting the expression of TAK1 and TAB3. Our findings highlight miR-26b as a potent inhibitor of the NF-κB pathway and an attractive target for cancer treatment.

A novel imide‐functionalized arene, di(fluorothienyl)thienothiophene diimide (f‐FBTI2), featuring a fused backbone functionalized with electron‐withdrawing F atoms, is designed, and the synthetic challenges associated with highly electron‐deficient fluorinated imide are overcome. The incorporation of f‐FBTI2 into polymer affords a high‐performance n‐type semiconductor f‐FBTI2‐T, which shows a reduced bandgap and lower‐lying lowest unoccupied molecular orbital (LUMO) energy level than the polymer analog without F or with F‐functionalization on the donor moiety. These optoelectronic properties reflect the distinctive advantages of fluorination of electron‐deficient acceptors, yielding “stronger acceptors,” which are desirable for n‐type polymers. When used as a polymer acceptor in all‐polymer solar cells, an excellent power conversion efficiency of 8.1% is achieved without any solvent additive or thermal treatment, which is the highest value reported for all‐polymer solar cells except well‐studied naphthalene diimide and perylene diimide‐based n‐type polymers. In addition, the solar cells show an energy loss of 0.53 eV, the smallest value reported to date for all‐polymer solar cells with efficiency > 8%. These results demonstrate that fluorination of imide‐functionalized arenes offers an effective approach for developing new electron‐deficient building blocks with improved optoelectronic properties, and the emergence of f‐FBTI2 will change the scenario in terms of developing n‐type polymers for high‐performance all‐polymer solar cells.

Iridium and ruthenium and their oxides/hydroxides are the best candidates for the oxygen evolution reaction under harsh acidic conditions owing to the low overpotentials observed for Ru- and Ir-based anodes and the high corrosion resistance of Ir-oxides. Herein, by means of cutting edge operando surface and bulk sensitive X-ray spectroscopy techniques, specifically designed electrode nanofabrication and ab initio DFT calculations, we were able to reveal the electronic structure of the active IrO x centers (i.e., oxidation state) during electrocatalytic oxidation of water in the surface and bulk of high-performance Ir-based catalysts. We found the oxygen evolution reaction is controlled by the formation of empty Ir 5d states in the surface ascribed to the formation of formally Ir V species leading to the appearance of electron-deficient oxygen species bound to single iridium atoms (μ 1 -O and μ 1 -OH) that are responsible for water activation and oxidation. Oxygen bound to three iridium centers (μ 3 -O) remains the dominant species in the bulk but do not participate directly in the electrocatalytic reaction, suggesting bulk oxidation is limited. In addition a high coverage of a μ 1 -OO (peroxo) species during the OER is excluded. Moreover, we provide the first photoelectron spectroscopic evidence in bulk electrolyte that the higher surface-to-bulk ratio in thinner electrodes enhances the material usage involving the precipitation of a significant part of the electrode surface and near-surface active species.