BackgroundOur previous study identified AKT1, AKT2 and AKT3 as unfavorable prognostic factors for patients with hepatocellular carcinoma (HCC). However, limited data are available on their exact mechanisms in HCC. Since microRNAs (miRNAs) are implicated in various human cancers including HCC, we aimed to screen miRNAs targeting AKTs and investigate their underlying mechanisms in HCC by integrating bioinformatics prediction, network analysis, functional assay and clinical validation.MethodsFive online programs of miRNA target prediction and RNAhybrid which calculate the minimum free energy (MFE) of the duplex miRNA:mRNA were used to screen optimized miRNA-AKT interactions. Then, miRNA-regulated protein interaction network was constructed and 5 topological features (‘Degree’, ‘Node-betweenness’, ‘Edge-betweenness’, ‘Closeness’ and ‘Modularity’) were analyzed to link candidate miRNA-AKT interactions to oncogenesis and cancer hallmarks. Further systematic experiments were performed to validate the prediction results.ResultsSix optimized miRNA-AKT interactions (miR-149-AKT1, miR-302d-AKT1, miR-184-AKT2, miR-708-AKT2, miR-122-AKT3 and miR-124-AKT3) were obtained by combining the miRNA target prediction and MFE calculation. Then, 103 validated targets for the 6 candidate miRNAs were collected from miRTarBase. According to the enrichment analysis on GO items and KEGG pathways, these validated targets were significantly enriched in many known oncogenic pathways for HCC. In addition, miRNA-regulated protein interaction network were divided into 5 functional modules. Importantly, AKT1 and its interaction with mTOR respectively had the highest node-betweenness and edge-betweenness, implying their bottleneck roles in the network. Further experiments confirmed that miRNA-149 directly targeted AKT1 in HCC by a miRNA luciferase reporter approach. Then, re-expression of miR-149 significantly inhibited HCC cell proliferation and tumorigenicity by regulating AKT1/mTOR pathway. Notably, miR-149 down-regulation in clinical HCC tissues was correlated with tumor aggressiveness and poor prognosis of patients.ConclusionThis comprehensive analysis identified a list of miRNAs targeting AKTs and revealed their critical roles in HCC malignant progression. Especially, miR-149 may function as a tumor suppressive miRNA and play an important role in inhibiting the HCC tumorigenesis by modulating the AKT/mTOR pathway. Our clinical evidence also highlight the prognostic potential of miR-149 in HCC. The newly identified miR-149/AKT/mTOR axis might be a promising therapeutic target in the prevention and treatment of HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-253) contains supplementary material, which is available to authorized users.

Induced pluripotent stem cell (iPSC) provides a promising seeding cell for regenerative medicine. However, iPSC has the potential to form teratomas after transplantation. Therefore, it is necessary to evaluate the tumorigenic risks of iPSC and all its differentiated derivates prior to use in a clinical setting. Here, murine iPSCs were transduced with dual reporter gene consisting of monomeric red fluorescent protein (mRFP) and firefly luciferase (Fluc). Undifferentiated iPSCs, iPSC derivates from induced differentiation (iPSC-derivates), iPSC-derivated cardiomyocyte (iPSC-CMs) were subcutaneously injected into the back of nude mice. Non-invasive bioluminescence imaging (BLI) was longitudinally performed at day 1, 7, 14 and 28 after transplantation to track the survival and proliferation of transplanted cells. At day 28, mice were killed and grafts were explanted to detect teratoma formation. The results demonstrated that transplanted iPSCs, iPSC-derivates and iPSC-CMs survived in receipts. Both iPSCs and iPSC-derivates proliferated dramatically after transplantation, while only slight increase in BLI signals was observed in iPSC-CM transplanted mice. At day 28, teratomas were detected in both iPSCs and iPSC-derivates transplanted mice, but not in iPSC-CM transplanted ones. In vitro study showed the long-term existence of pluripotent cells during iPSC differentiation. Furthermore, when these cells were passaged in feeder layers as undifferentiated iPSCs, they would recover iPSC-like colonies, indicating the cause for differentiated iPSC's tumourigenicity. Our study indicates that exclusion of tumorigenic cells by screening in addition to lineage-specific differentiation is necessary prior to therapeutic use of iPSCs.

Pyroptosis is a type of proinflammatory programmed cell death mediated by caspase 1 activity and occurs in several types of eukaryotic tumor cells, including gliomas. MicroRNAs (miRNAs), small endogenous noncoding RNAs, have been demonstrated to be advantageous in glioma therapy. However, the question of whether miRNAs regulate pyroptosis in glioma remains unknown. The current study found that caspase 1 expression was substantially increased in both glioma tissues and glioma cell lines, U87 and T98G, while miR-214 expression was significantly downregulated. Luciferase reporter assay recognized caspase 1 as a target gene of miR-214. These findings demonstrate that miR-214 could inhibit cell proliferation and migration through the regulation of pyroptosis intermediated by caspase 1 in glioma U87 and T98G cells and may suggest a novel therapeutic for the intervention of glioma.

Background. Aquaporin (AQP) 3 and AQP 5 are involved in tumorigenesis and tumor progression of several tumor types. Aim. To investigate expression patterns and clinical significance of AQP3 and AQP5 in hepatocellular carcinoma (HCC). Methods. Immunohistochemistry was performed to detect the expression of AQP3 and AQP5 in HCC tissues. Results. Immunohistochemistry analysis showed the increased expression of AQP3 and AQP5 protein levels in HCC tissues compared with their adjacent nonneoplastic tissues (both P < 0.001). In addition, combined AQP3 and AQP5 protein expression was significantly associated with serum AFP (P = 0.008), tumor stage (P = 0.006), and tumor grade (P = 0.006). Moreover, HCC patients highly expressing both AQP3 and AQP5 proteins had worse 5-year disease-free survival and 5-year overall survival (P = 0.002 and 0.005, resp.). Furthermore, the Cox proportional hazards model showed that combined AQP3 and AQP5 protein expression was an independent poor prognostic factor for both 5-year disease-free survival (P = 0.009) and 5-year overall survival (P = 0.01) in HCC. Conclusion. Our data suggest for the first time that the aberrant expression of AQP3 and AQP5 proteins may be strongly related to tumor progression and prognosis in patients with HCC. The overexpression of AQP3 in combination with upregulation of AQP5 may be an unfavorable prognostic factor for HCC.

Considerable luminescence dissymmetry factor (g lum) is vital for application implementation of circularly polarized luminescence (CPL) materials. Moreover, a dual CPL switch has promising prospects in high-security encryption and sensor devices. Herein, we designed and synthesized an emissive chiral nematic liquid crystal (N*-LC) by doping a luminescent chiral additive (NO2-CS-C6-Chol) into a nematic liquid crystal (5CB). The helical assembly structure produced by inducing the formation of N*-LC endows the prepared emissive N*-LC with a larger g lum value. With the increase of the doping concentration from 1 to 10 wt %, the helical pitch (P) of N*-LC gradually decreases from 25.48 to 3.92 μm. The corresponding g lum value increases first, reaches the maximum value (−0.38) at 6 wt %, and then decreases slightly. Further, the prepared emissive N*-LC doped with 6 wt % NO2-CS-C6-Chol is injected into an indium-tin oxide (ITO)-coated LC cell, to which a direct current (DC) electric field is applied. The g lum value can be repeatedly shuttled between the “on” and “off” state by adjusting the applied voltage. Meanwhile, owing to the inherent thermal dependence of the liquid crystal phase structure, the g lum value can also be switched between the on and off state by regulating the temperature. Therefore, an electrically controlled and thermocontrolled dual CPL switching device is successfully constructed.

Several complex molecular events are involved in tumorigenesis of hepatocellular carcinoma (HCC). The interactions of these molecules may constitute the HCC imbalanced network. Gansui Banxia Tang (GSBXT), as a classic Chinese herbal formula, is a popular complementary and alternative medicine modality for treating HCC. In order to investigate the therapeutic effects and the pharmacological mechanisms of GSBXT on reversing HCC imbalanced network, we in the current study developed a comprehensive systems approach of integrating disease-specific and drug-specific networks, and successfully revealed the relationships of the ingredients in GSBXT with their putative targets, and with HCC significant molecules and HCC related pathway systems for the first time. Meanwhile, further experimental validation also demonstrated the preventive effects of GSBXT on tumor growth in mice and its regulatory effects on potential targets.

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Realizing anion−π interaction induced self-assembly with charge-neutral π receptors as building components is extremely challenging. We designed and synthesized a series of bisoxacalix[2]arene[2]triazines 7−11 in which two macrocyclic motifs are linked in diverse branching angle and rigidity. Crystal structures showed the use of rigid linkers is able to control the orientation of the two macrocyclic cavities. The interplay between the two cavities was revealed by binding studies of 8−11 with chloride in solution. Whereas 180°-and 120°branched hosts 8 and 9 possess dual complexation ability, 60°-branched and flexibly linked hosts 10 and 11 only form 1:1 complex with chloride. Association and self-assembly of these bismacrocyclic building units with dianionic naphthalene-1,5-disulfonate were systematically investigated. The formation of oligomeric self-assemblies and large aggregates in solution was suggested by 1 H NMR titrations, concentration-and temperature-variable 1 H NMR, diffusion-ordered spectroscopy (DOSY), ESI-MS, and dynamic light scattering (DLS). The anion−π induced long-distance self-assembly with coherent particle formation was revealed by SEM, TEM, cryo-TEM, and AFM techniques. The systematic studies allowed us to draw the conclusion that the dianion served to bridge the initial host aggregates through anion−π interactions and was responsible for the coherent particle formation. The cavity orientation of the bismacrocycle components was found to have a significant influence on the coherent particle morphology.