Hepatocellular carcinoma (HCC) has become a leading cause of cancer-related death, making the elucidation of its underlying mechanisms an urgent priority. Inflammation is an adaptive response to ...infection and tissue injury under strict regulations. When the host regulatory machine runs out of control, nonresolving inflammation occurs. Nonresolving inflammation is a recognized hallmark of cancer that substantially contributes to the development and progression of HCC. The HCC-associated inflammation can be initiated and propagated by extrinsic pathways through activation of pattern-recognition receptors (PRRs) by pathogen-associated molecule patterns (PAMPs) derived from gut microflora or damage-associated molecule patterns (DAMPs) released from dying liver cells. The inflammation can also be orchestrated by the tumor itself through secreting factors that recruit inflammatory cells to the tumor favoring the buildup of a microenvironment. Accumulating datas from human and mouse models showed that inflammation promotes HCC development by promoting proliferative and survival signaling, inducing angiogenesis, evading immune surveillance, supporting cancer stem cells, activating invasion and metastasis as well as inducing genomic instability. Targeting inflammation may represent a promising avenue for the HCC treatment. Some inhibitors targeting inflammatory pathways have been developed and under different stages of clinical trials, and one (sorafenib) have been approved by FDA. However, as most of the data were obtained from animal models, and there is a big difference between human HCC and mouse HCC models, it is challenging on successful translation from bench to bedside.
Background/Aims: Programmed death ligand1(PD-L1) plays a role in the development and progression of non-small cell lung cancer (NSCLC). This study aimed to identify miRNA(s) that are responsible for ...regulation of expression of PD-L1 in NSCLC, and to investigate the role of PD-L1 in regulation of the cell cycle in NSCLC. Methods: We predicted the target miRNA of PD-L1, which was miR-140, using the online tools TargetScan and miBase. In NSCLC cells obtained from clinical specimens, in addition to A549 and NCI-H1650 cell cultures, western blots were used to detect the level of expression of proteins, while real-time PCR was used to determine the level of expression of PD-L1, miR-140, cyclin E, and β-actin. Transfection with miR-140 mimics, miR-140 inhibitors, and PD-L1 siRNA were conducted using commercial kits. To determine whether miR-140 directly binds PD-L1, a luciferase reporter gene with wild type or mutated PD-L1 was used. Cell viability was measured with the MTT assay, and PI staining was used for cell cycle analysis. Results: We found low expression of miR-140 and high expression of PD-L1 and cyclin E in NSCLC cells. Over-expression of miR-140 suppressed the expression of PD-L1 by directly binding its 3’ UTR, and was also associated with decreased expression of cyclin E and inhibition of cellular proliferation in A549 and NCI-H1650 cells. Inhibition of PD-L1, in the absence of manipulations to miR-140, also decreased the expression of cyclin E. Conclusion: We conclude that miR-140 directly suppresses PD-L1 and inhibits the miR-140/PD-L1/cyclin E pathway in NSCLC.
Increasing evidence suggests that the presence of endotoxemia is of substantial clinical relevance to patients with cirrhosis, but it is unclear whether and how gut‐derived LPS amplifies the ...tumorigenic response of the liver. We found that the circulating levels of LPS were elevated in animal models of carcinogen‐induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor Toll‐like receptor 4 (TLR4) in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen‐induced toxicity via blocking NF‐κB activation and sensitizing the liver to reactive oxygen species (ROS)‐induced toxicity, but lessens inflammation‐mediated compensatory proliferation. Reconstitution of TLR4‐expressing myeloid cells in TLR4‐deficient mice restored diethylnitrosamine (DEN)‐induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. Meanwhile, deletion of gut‐derived endotoxin suppressed DEN‐induced cytokine production and compensatory proliferation, whereas in vivo LPS pre‐challenge promotes hepatocyte proliferation. Conclusion: Our data indicate that sustained LPS accumulation represents a pathological mediator of inflammation‐associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in patients with cirrhosis who are at risk of developing HCC. (Hepatology 2010.)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Hepatitis B virus X (HBx) protein is implicated in hepatitis B virus (HBV)‐associated liver carcinogenesis. However, it remains unclear whether HBx‐expressing hepatic progenitor cells (HPCs) are ...attributed to liver tumor formation. In this study, by using HBx transgenic mice and a 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC)‐induced liver injury model, the relationship between HBx expression and tumorigenicity of HPCs was analyzed. Compared with control mice, an elevated number of EpCAM+ cells with characteristics of HPCs was observed in HBx mice after 1 month and 4 months of DDC diet feeding. All HBx transgenic mice developed liver tumors characterized by histological features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma after 7 months of DDC feeding. Notably, EpCAM+ HPCs isolated from premalignant HBx mice exposed to a DDC diet for 4 months formed subcutaneous mixed‐lineage tumors (four out of six) in nonobese diabetic/severe‐combined immunodeficient (NOD/SCID) mice, and none of the cells from wildtype (WT) induced tumor, indicating that HBx may induce malignant transformation of HPCs that contributes to tumorigenesis. We also found higher titers of circulating interleukin (IL)‐6, activities of IL‐6/STAT3, and Wnt/β‐catenin signaling pathways in HBx transgenic mice, suggesting HBx may induce intrinsic changes in HPCs by way of the above signaling that enables HPCs with tumorigenicity potential. Finally, clinical evidence showed that high HBx expression in human HBV‐related HCC was statistically associated with expansion of EpCAM+ or OV6+ tumor cells and aggressive clinicopathologic features. Conclusion: HBx induces intrinsic cellular transformation promoting the expansion and tumorigenicity of HPCs in DDC‐treated mice, which may be a possible origin for liver cancer induced by chronic hepatitis infection. (HEPATOLOGY 2012)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background & Aims Due to its anatomic connection, the liver is constantly exposed to gut-derived bacterial products or metabolites. Disruption of gut homeostasis is associated with many human ...diseases. The aim of this study was to determine the role of gut homeostasis in initiation and progression of hepatocellular carcinoma (HCC). Methods Disruption of intestinal homeostasis by penicillin or dextran sulfate sodium (DSS) and its restoration by probiotics were applied in a diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. Results Patients with liver cirrhosis and HCC had significantly increased serum endotoxin levels. Chronic DEN treatment of rats was associated with an imbalance of subpopulations of the gut microflora including a significant suppression of Lactobacillus species, Bifidobacterium species and Enterococcus species as well as intestinal inflammation. Induction of enteric dysbacteriosis or intestinal inflammation by penicillin or DSS, respectively, significantly promoted tumor formation. Administration of probiotics dramatically mitigated enteric dysbacteriosis, ameliorated intestinal inflammation, and most importantly, decreased liver tumor growth and multiplicity. Interestingly, probiotics not only inhibited the translocation of endotoxin, which bears pathogen-associated molecular patterns (PAMPs) but also the activation of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1). As a result, the production of pro- and anti-inflammatory cytokines was skewed in favor of a reduced tumorigenic inflammation in the liver. Conclusions The data highlights the importance of gut homeostasis in the pathogenesis of HCC. Modulation of the gut microbiota by probiotics may represent a new avenue for therapeutic intervention to treat or prevent HCC development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Alloying Pt with earth-abundant metal (e.g. Cu, Ni and Co) can largely improve catalytic activity of Pt-based alloyed nanocrystals by down-shifting the Pt d-band center and modulating the final size, ...morphology and structure. Herein, Cu-rich rhombic dodecahedral PtCu nanoframes (NFs) were obtained via a one-pot solvothermal route with l-proline and cetyltrimethylammonium chloride (CTAC) as co-structure-directing and stabilizing agents, along with OAm as the reductant. The as-prepared Pt24Cu76 NFs were identified as bifunctional catalysts for oxygen reduction reaction (ORR) and hydrogen evolution reaction (HER) in alkaline electrolyte. Specifically, the catalyst showed excellent catalytic activity and durability for ORR with positive half-wave potential at 0.95 V, outperforming that of commercial Pt/C (20 wt%, 0.88 V). Besides, it exhibited dramatically enhanced HER activity with the more positive potential at 10 mA cm−2 and smaller Tafel slope (−18 mV, 52 mV dec−1) relative to those of Pt/C (−63 mV, 69 mV dec−1). All the results demonstrate the practical applications of robust PtCu electrocatalysts in energy conversion and storage.
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•Rhombic dodecahedral Pt26Cu74 NFs were prepared by a facile solvothermal method.•The nanoframes with highly open structures promoted the electron transfer kinetics and mass transport.•l-proline and CTAC worked as the co-structure directors.•The Pt26Cu74 NFs were highly active and stable for ORR and HER in alkaline electrolyte.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Nitrogen- and transition metal-dual doped carbon materials with low cost and high catalytic performances are considered as one of promising alternatives for noble metal catalysts in ...acceleration of oxygen reduction reaction (ORR). In this work, three-dimensional (3D) self-supporting superstructures of iron carbide (Fe3C) nanoclusters entrapped in manganese (Mn)- and nitrogen (N)-dual doped carbon nanosheets covered with double-sided nanoneedles carbon arrays (Fe3C/Mn,N-NCAs) are simply synthesized by a coordination pyrolysis method, in which dicyandiamide mainly behaves as nitrogen source and 1-(2-pyridylazo)-2-naphthol (PAN) as carbon source. Integration of the unique 3D self-supporting superstructures and synergistic effects of the multi-compositions, the as-obtained catalyst displays appealing ORR performance such as the much positive onset potential (Eonset = 0.98 V vs. RHE) and half-wave potential (E1/2 = 0.88 V vs. RHE), as well as a just 10 mV negative shift in E1/2 after 2000 cycles, surpassing commercial Pt/C. This work provides some valuable perspectives for preparation of high-efficiency and low-cost non-noble metal ORR electrocatalysts in energy transformation and storage correlated systems.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this letter, planar type self-powered short-wavelength infrared narrowband Si photodetector was realized based on a simple Schottky structure by increasing surface states and enlarging the ...distance between Schottky electrode and light irradiation region. With the assistance of pyramid microstructure, the distance needed for sub-100 nm narrowband detection effectively decreased from 1000 μ m to 200 μ m, which is vital to improving device sensitivity and reducing device size. The obtained photodetector exhibited a response peak at 1119 nm with full-width at half-maximum of 97 nm. At zero bias, a peak detectivity up to 2.25 × 10 11 Jones, linear dynamic range of 91 dB and fast response speed (Rise time of 88 μ s and fall time of 118 μ s) were achieved. The higher wavelength selectivity and sensitivity than its counterpart with flat surface should be ascribed to the large number of surface state and pronounced light confinement effect of pyramid microstructure. This work opens up a new avenue for achieving planar-type narrowband photodetector that can provide better integration capabilities for on-chip applications than vertical devices.
Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis
. Here we interrogated ...functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts
, during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual functions of HSCs in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSCs, protected against hepatocyte death and HCC development. By contrast, type I collagen, enriched in activated myofibroblastic HSCs, promoted proliferation and tumour development through increased stiffness and TAZ activation in pretumoural hepatocytes and through activation of discoidin domain receptor 1 in established tumours. An increased HSC imbalance between cytokine-producing HSCs and myofibroblastic HSCs during liver disease progression was associated with increased HCC risk in patients. In summary, the dynamic shift in HSC subpopulations and their mediators during chronic liver disease is associated with a switch from HCC protection to HCC promotion.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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