A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice.

Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1ß-C/EBPß-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1-486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1-486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1-486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer's disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.

Sustainable and feasible reagent-free electro-Fenton via sequential dual-cathode electrocatalysis.

Electro-Fenton processes aim at producing oxidizing radicals with fewer added chemicals and residues but are still unable to completely eliminate both. This study demonstrates that a reagent-free electro-Fenton process that runs solely on oxygen and electricity can be achieved by sequential dual-cathode electrocatalysis. H2O2 is produced on an electrodeposited PEDOT on carbon cloth (PEDOT/CC) cathode and subsequently converted to hydroxyl radicals on a stainless-steel-mesh cathode. The dual-cathode system demonstrates efficient decolorization and total organic carbon (TOC) removal toward organic dyes at optimized cathodic potentials of -0.9 V for PEDOT/CC and -0.8 V for the stainless-steel mesh. The sequential dual-cathode process also displays high reusability, no iron leaching, high removal efficiency using air instead of oxygen, and low installation and operation costs. This work demonstrates a preeminent and commercially viable example of pollution control rendered by the "catalysis instead of chemical reagent" philosophy of green chemistry.

Direction-Finding Study of a 1.7 mm Diameter Towed Hydrophone Array Based on UWFBG.

This paper investigates a 1.7 mm diameter ultra-weak fiber Bragg grating (UWFBG) hydrophone towed array cable for acoustic direction finding. The mechanism of the underwater acoustic waves received by this integrated-coating sensitizing optical cable is deduced, and it is shown that the amplitude of its response varies with the direction of the sound wave. An anechoic pool experiment is carried out to test the performance of such a hydrophone array. The test array is a selection of six sensing fibers, each of which is coiled into 9 cm diameter fiber ring suspended in the water to receive acoustic signals. An average sensitivity of -141.2 dB re rad/µPa at frequencies from 2.5 kHz to 6.3 kHz was achieved, validating the detection of the azimuth of underwater acoustic waves. The ultra-thin towing cable system, with free structure, high sensitivity, and underwater target-detection capability has demonstrated great potential for future unmanned underwater vehicle (UUV) applications.

Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy.

BACKGROUND & AIMS: The tumour microenvironment (TME) is a crucial mediator of cancer progression and therapeutic outcome. The TME subtype correlates with patient response to immunotherapy in multiple cancers. Most previous studies have focused on the role of different cellular components in the TME associated with immunotherapy efficacy. However, the specific structure of the TME and its role in immunotherapy efficacy remain largely unknown. METHODS: We combined spatial transcriptomics with single-cell RNA-sequencing and multiplexed immunofluorescence to identify the specific spatial structures in the TME that determine the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC) receiving anti-PD-1 treatment. RESULTS: We identified a tumour immune barrier (TIB) structure, a spatial niche composed of SPP1+ macrophages and cancer-associated fibroblasts (CAFs) located near the tumour boundary, which is associated with the efficacy of immune checkpoint blockade. Furthermore, we dissected ligand‒receptor networks among malignant cells, SPP1+ macrophages, and CAFs; that is, the hypoxic microenvironment promotes SPP1 expression, and SPP1+ macrophages interact with CAFs to stimulate extracellular matrix remodelling and promote TIB structure formation, thereby limiting immune infiltration in the tumour core. Preclinically, the blockade of SPP1 or macrophage-specific deletion of Spp1 in mice led to enhanced efficacy of anti-PD-1 treatment in mouse liver cancer, accompanied by reduced CAF infiltration and increased cytotoxic T-cell infiltration. CONCLUSIONS: We identified that the TIB structure formed by the interaction of SPP1+ macrophages and CAFs is related to immunotherapy efficacy. Therefore, disruption of the TIB structure by blocking SPP1 may be considered a relevant therapeutic approach to enhance the therapeutic effect of immune checkpoint blockade in HCC. IMPACT AND IMPLICATIONS: Only a limited number of patients with hepatocellular carcinoma (HCC) benefit from tumour immunotherapy, which significantly hinders its application. Herein, we used multiomics to identify the spatial structure of the tumour immune barrier (TIB), which is formed by the interaction of SPP1+ macrophages and cancer-associated fibroblasts in the HCC microenvironment. This structure constrains immunotherapy efficacy by limiting immune cell infiltration into malignant regions. Preclinically, we revealed that blocking SPP1 or macrophage-specific deletion of Spp1 in mice could destroy the TIB structure and sensitize HCC cells to immunotherapy. These results provide the first key steps towards finding more effective therapies for HCC and have implications for physicians, scientists, and drug developers in the field of HCC.

Glycoconjugate journal special issue on: the glycobiology of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that affects over 10 million aging people worldwide. This condition is characterized by the degeneration of dopaminergic neurons in the pars compacta region of the substantia nigra (SNpc) and by aggregation of proteins, commonly α-synuclein (SNCA). The formation of Lewy bodies that encapsulate aggregated proteins in lipid vesicles is a hallmark of PD. Glycosylation of proteins and neuroinflammation are involved in the pathogenesis. SNCA has many posttranslational modifications and interacts with components of membranes that affect aggregation. The large membrane lipid dolichol accumulates in the brain upon age and has a significant effect on membrane structure. The replacement of dopamine and dopaminergic neurons are at the forefront of therapeutic development. This review examines the role of membrane lipids, glycolipids, glycoproteins and dopamine in the aggregation of SNCA and development of PD. We discuss the SNCA-dopamine-neuromelanin-dolichol axis and the role of membranes in neuronal stem cells that could be a regenerative therapy for PD patients.

Clinical characteristics and management of 1572 patients with pyogenic liver abscess: A 12-year retrospective study.

BACKGROUND & AIMS: Pyogenic liver abscesses (PLA) are space-occupying lesions in the liver that produce high morbidity and mortality. The clinical characteristics and prognosis of abscesses is different depending on the bacterial culture results and require different strategies for management. The aim of this study was to investigate the clinical characteristics and prognostic factors of patients with PLA. METHODS: Clinical features, laboratory tests and etiology of PLA between 2006 to 2011 and 2012 to 2017 in a single hospital were retrospectively reviewed. The incidence and mortality of PLA caused by Escherichia coli and Klebsiella pneumoniae were compared and the risk factors for multiple organ dysfunction (MODS) and endophthalmitis were evaluated. RESULTS: Among the 1,572 PLA patients, the proportion with PLA increased from 333 (21.2%) in 2006-2011 to 1,239 (78.8%) in 2012-2017 without any investigation and treatment procedure differences. K pneumoniae was the main isolate in analysed pus cultures (85.6%). The mortality rate of patients with K pneumoniae infection was lower in the latter period (6.7% vs 0.7%, P = .035). Multivariate analyses revealed that age, fever, MODS and length of hospital stay were factors affecting poor prognosis (death + unhealed/uncured) in PLA patients after treatment and that cardiovascular disease, pleural effusion and pulmonary infection were risk factors for MODS, while diabetes mellitus was the only risk factor for endophthalmitis. Most patients (95.5%) with PLA recovered after abscess drainage/puncture and antibiotic therapy. CONCLUSIONS: Pleural effusion, fever, MODS and length of hospital stays were factors useful in predicting PLA outcomes.

Measurement of the Combined Levels of Serum Uric Acid and Alanine Aminotransferase and the Risk of Metabolic Syndrome in a Population Aged 60 Years or More in Northeastern China.

BACKGROUND Serum uric acid (SUA) and alanine aminotransferase (ALT) levels are increased in patients with metabolic syndrome. This study aimed to investigate the association between the combined levels of SUA and ALT and the risk of metabolic syndrome in residents ≥60 years of age in Northeastern China. MATERIAL AND METHODS A population study included nine communities in Shenyang, Northeast China, and 3,998 participants (1,434 men and 2,564 women) who were ≥60 years old. SUA and ALT measurements (levels 1-3) and clinical parameters were recorded. Metabolic syndrome was diagnosed according to the criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). The association between the combined SUA and ALT levels and metabolic syndrome was determined by multivariate logistic regression analysis in tertiles that included Groups 1-9. RESULTS The prevalence of metabolic syndrome was 43.2% (men), and 61.9% (women), and the prevalence and odds ratio (OR) values increased with increasing SUA and ALT levels. The OR values of metabolic syndrome in the ALT Groups 2-3 were 1.329 (95% CI, 1.137-1.554) and 2.362 (95% CI, 2.006-2.781), and in the SUA Groups 2-3 the OR values were 1.718 (95% CI, 1.466-2.015) and 2.743 (95% CI, 2.310-3.256). The OR of the combined increase in SUA and ALT and metabolic syndrome in Groups 1-9 ranged from 1.494-5.889 (all, p<0.05). CONCLUSIONS Increased combined SUA and ALT was more significantly associated with metabolic syndrome than an increase in SUA or ALT alone.

Erratum: Measurement of the Combined Levels of Serum Uric Acid and Alanine Aminotransferase and the Risk of Metabolic Syndrome in a Population Aged 60 Years or More in Northeastern China.

The authors informed the journal that several errors occurred in their manuscript and request the following to be corrected:  1. The affiliation for Jiabei Wang should be corrected from Department of Geriatric, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, P.R. China to:  Department of Geriatric, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, P.R. China Department of Geriatric, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China 2. The affiliation for Difei Wang should be corrected from: Department of Geriatric, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, P.R. China to: Department of Geriatric, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China Reference: 1. Wang J, Wang Y, Chen F, Ma G, Wang D. Measurement of the Combined Levels of Serum Uric Acid and Alanine Aminotransferase and the Risk of Metabolic Syndrome in a Population Aged 60 Years or More in Northeastern China. Med Sci Monit, 2020; 26: e916459. doi: 10.12659/MSM.916459.

Long non-coding RNA NEAT1-modulated abnormal lipolysis via ATGL drives hepatocellular carcinoma proliferation.

BACKGROUND: Abnormal metabolism, including abnormal lipid metabolism, is a hallmark of cancer cells. Some studies have demonstrated that the lipogenic pathway might promote the development of hepatocellular carcinoma (HCC). However, the role of the lipolytic pathway in HCC has not been elucidated. METHODS: We compared levels of adipose triglyceride lipase (ATGL) in human HCC and healthy liver tissues by real time PCR, western blot and immunohistochemistry. We measured diacylglycerol(DAG) and free fatty acid (FFA) levels in HCC cells driven by the NEAT1-ATGL axis and in HCC tissues. We also assessed the effects of ATGL, DAG, FFA, and NEAT1 on HCC cells proliferation in vitro and in an orthotopic xenograft HCC mouse model. We also performed a luciferase reporter assay to investigate the interaction between NEAT1/ATGL and miR-124-3p. RESULTS: We found that the lipolytic enzyme, ATGL is highly expressed in human HCC tissues and predicts poor prognosis. We also found that high levels of DAG and FFA are present in HCC tissues. Furthermore, the lncRNA-NEAT1 was found to modulate ATGL expression and disrupt lipolysis in HCC cells via ATGL. Notably, ATGL and its products, DAG and FFA, were shown to be responsible for NEAT1-mediated HCC cell growth. NEAT1 regulated ATGL expression by binding miR-124-3p. Additionally, NEAT1 knockdown attenuated HCC cell growth through miR-124-3p/ATGL/DAG+FFA/PPARα signaling. CONCLUSION: Our results reveal that NEAT1-modulates abnormal lipolysis via ATGL to drive HCC proliferation.

Decreased Taurine and Creatine in the Thalamus May Relate to Behavioral Impairments in Ethanol-Fed Mice: A Pilot Study of Proton Magnetic Resonance Spectroscopy.

Minimal hepatic encephalopathy (MHE) is highly prevalent, observed in up to 80% of patients with liver dysfunction. Minimal hepatic encephalopathy is defined as hepatic encephalopathy with cognitive deficits and no grossly evident neurologic abnormalities. Clinical management may be delayed due to the lack of in vivo quantitative methods needed to reveal changes in brain neurobiochemical biomarkers. To gain insight into the development of alcoholic liver disease-induced neurological dysfunction (NDF), a mouse model of late-stage alcoholic liver fibrosis (LALF) was used to investigate changes in neurochemical levels in the thalamus and hippocampus that relate to behavioral changes. Proton magnetic resonance spectroscopy of the brain and behavioral testing were performed to determine neurochemical alterations and their relationships to behavioral changes in LALF. Glutamine levels were higher in both the thalamus and hippocampus of alcohol-treated mice than in controls. Thalamic levels of taurine and creatine were significantly diminished and strongly correlated with alcohol-induced behavioral changes. Chronic long-term alcohol consumption gives rise to advanced liver fibrosis, neurochemical changes in the nuclei, and behavioral changes which may be linked to NDF. Magnetic resonance spectroscopy represents a sensitive and noninvasive measurement of pathological alterations in the brain, which may provide insight into the pathogenesis underlying the development of MHE.

Evaluation of Intravenous Parecoxib Infusion Pump of Patient-Controlled Analgesia Compared to Fentanyl for Postoperative Pain Management in Laparoscopic Liver Resection.

BACKGROUND As laparoscopic liver resection is becoming a commonly used method for hepatic surgery, postoperative pain management is emerging as one of the trickiest problems after surgery. The ideal method of pain management is controversial and the optimal strategy for postoperative pain management after surgery remains unclear. The present study evaluated the postoperative analgesic efficacy of parecoxib and fentanyl, and the benefit of a new intravenous parecoxib infusion pump with patient-controlled analgesia after laparoscopic liver resection. MATERIAL AND METHODS This controlled, prospective, randomized, double-blind trial compared VAS scores among 3 groups of patients: a fentanyl group (FEN group) using a fentanyl citrate pump, an intravenous parecoxib group (IVPA group) receiving intravenous parecoxib, and a parecoxib pump group (PUPA group) receiving parecoxib sodium by analgesia pump. We enrolled 124 patients planned for laparoscopic liver resection. The primary outcome was VAS score at rest and with movement. Secondary outcomes were adverse effects (including nausea), sedation, pruritus, and quality of life. RESULTS For all time intervals, the VAS scores were significantly lower in the PUPA group. VAS scores at rest and with movement in the PUPA group were the lowest among the 3 groups, while the scores in the FEN group were the highest. More adverse effects were detected in the FEN group, and no significant differences in adverse effects were found between the intravenous group and the parecoxib pump group. CONCLUSIONS Use of the intravenous infusion parecoxib pump for patient-controlled analgesia provides superior analgesic efficacy and fewer adverse effects for patients after laparoscopic liver resection.

N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway.

Increasing evidence supports a role for N-myc downstream-regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)-181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the NDRG2/LIF/miR-181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2 and increased levels of miR-181c and LIF compared with nontumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance, and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR-181c, and the down-regulation of NDRG2 was attributed to miR-181c overexpression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down-regulation of NDRG2 and overexpression of miR-181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR-181c, and LIF expression is a strong predictor of prognosis in CCA patients. CONCLUSION: These results establish the counteraction between NDRG2 and LIF/miR-181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2-mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR-181c, and transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606-1622).

Chimeric antigen receptor-engineered T cells for liver cancers, progress and obstacles.

Chimeric antigen receptor-engineered T cells therapy has become the hottest topic of immunotherapy, as its great successes achieved in treating refractory hematological malignancies. These successes also paved the road to novel strategies of treating various solid tumors including liver cancer. Many specific proteins can be expressed aberrantly in liver cancers; therefore, a series of experimental and clinical researches exploring chimeric antigen receptor-engineered T cells and liver cancer are in progress, acquiring obvious antitumor effect and revealing its feasibility in treating liver cancer. However, lots of challenges and obstacles are emerging simultaneously, such as low infiltration, side effects, safety of chimeric antigen receptor-engineered T cells, and limited data of studies or clinical trials. Researchers have been working out many innovative ways to directly stroke these obstacles, theoretically or practically. This review focuses more on the progress and obstacles from chimeric antigen receptor-engineered T cells therapy to treat liver cancer, summarizing new breakthroughs in shooting those obstacles, meanwhile, hoping to provide enlightenment to this promising immunotherapeutic method.

HINT1 in Neuropsychiatric Diseases: A Potential Neuroplastic Mediator.

Although many studies have investigated the functions of histidine triad nucleotide-binding protein 1 (HINT1), its roles in neurobiological processes remain to be fully elucidated. As a member of the histidine triad (HIT) enzyme superfamily, HINT1 is distributed in almost every organ and has both enzymatic and nonenzymatic activity. Accumulating clinical and preclinical evidence suggests that HINT1 may play an important role as a neuroplastic mediator in neuropsychiatric diseases, such as schizophrenia, inherited peripheral neuropathies, mood disorders, and drug addiction. Though our knowledge of HINT1 is limited, it is believed that further research on the neuropathological functions of HINT1 would eventually benefit patients with neuropsychiatric and even psychosomatic diseases.

Emerging Roles of Histidine Triad Nucleotide Binding Protein 1 in Neuropsychiatric Diseases.

The histidine triad nucleotide binding protein1(HINT1),which belongs to the histidine triad(HIT) enzyme superfamily,exerts its enzymic activities as hydrolase or transferase. Its physiological functions are still unclear. HINT1 protein is expressed in various tissues and plays an important role in transcription and signal transduction. Earlier studies have identified HINT1 as a haplo-insufficient tumor suppressor. Other evidences indicate that HINT1 is involved in a wide variety of physiological processes,some of which are irrelevant with its basic enzymic activities. Investigations recently suggest that HINT1 is closely related to many peripheral and central nervous system diseases,and plays a vital role in some of neuropsychiatric diseases such as inherited peripheral neuropathies,schizophrenia,mood disorder,drug addiction,and Down's syndrome. In this review,the role of HINT1 in above-mentioned neuropsychiatric disorders was summarised,and the research findings of HINT1 in each of the above diseases were summarized and analyzed,in order to provide some guidance for further research on this protein.

Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signaling in human cholangiocarcinoma.

UNLABELLED: Although gankyrin is involved in the tumorigenicity and metastasis of some malignancies, the role of gankyrin in cholangiocarcinoma (CCA) is unclear. In this study we investigated the expression of gankyrin in human CCA tissues and cell lines. The effects of gankyrin on CCA tumor growth and metastasis were determined both in vivo and in vitro. The results showed that gankyrin was overexpressed in CCA tissues and cell lines. Gankyrin expression was associated with CCA histological differentiation, TNM stage, and metastasis. The multivariate Cox analysis revealed that gankyrin was an independent prognostic indicator for overall survival. Gankyrin overexpression promoted CCA cell proliferation, migration, and invasion, while gankyrin knockdown inhibited CCA tumor growth, metastasis, and induced Rb-dependent senescence and G1 phase cell cycle arrest. Gankyrin increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and promoted the nuclear translocation of p-STAT3. Suppression of STAT3 signaling by small interfering RNA (siRNA) or STAT3 inhibitor interfered with gankyrin-mediated carcinogenesis and metastasis, while interleukin (IL)-6, a known upstream activator of STAT3, could restore the proliferation and migration of gankyrin-silenced CCA cells. The IL-6 level was decreased by gankyrin knockdown, while increased by gankyrin overexpression. Gankyrin regulated IL-6 expression by way of facilitating the phosphorylation of Rb; meanwhile, rIL-6 treatment increased the expression of gankyrin, suggesting that IL-6 was regulated by a positive feedback loop involving gankyrin in CCA. In the xenograft experiments, gankyrin overexpression accelerated tumor formation and increased tumor weight, whereas gankyrin knockdown showed the opposite effects. The in vivo spontaneous metastasis assay revealed that gankyrin promoted CCA metastasis through IL-6/STAT3 signaling pathway. CONCLUSION: Gankyrin is crucial for CCA carcinogenesis and metastasis by activating IL-6/STAT3 signaling pathway through down-regulating Rb protein.

Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis.

UNLABELLED: Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent extrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. However, the mechanisms that contribute to tumor metastasis remain unclear. Here we evaluate the effects of ATPase inhibitory factor 1 (IF1), an inhibitor of the mitochondrial H(+)-adenosine triphosphate (ATP) synthase, on HCC angiogenesis and metastasis. We found that increased expression of IF1 in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and metastasis, expressed high levels of IF1. Invasive tumors overexpressing IF1 were featured by active epithelial-mesenchymal transition (EMT) and increased angiogenesis, whereas silencing IF1 expression attenuated EMT and invasion of HCC cells. Mechanistically, IF1 promoted Snai1 and vascular endothelial growth factor (VEGF) expression by way of activating nuclear factor kappa B (NF-κB) signaling, which depended on the binding of tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) to NF-κB-inducing kinase (NIK) and the disruption of NIK association with the TRAF2-cIAP2 complex. Suppression of the NF-κB pathway interfered with IF1-mediated EMT and invasion. Chromatin immunoprecipitation assay showed that NF-κB can bind to the Snai1 promoter and trigger its transcription. IF1 was directly transcribed by NF-κB, thus forming a positive feedback signaling loop. There was a significant correlation between IF1 expression and pp65 levels in a cohort of HCC biopsies, and the combination of these two parameters was a more powerful predictor of poor prognosis. CONCLUSION: IF1 promotes HCC angiogenesis and metastasis by up-regulation of Snai1 and VEGF transcription, thereby providing new insight into HCC progression and IF1 function. (Hepatology 2014;60:1659-1673).

Chronic restraint stress attenuates p53 function and promotes tumorigenesis.

Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause this remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well-established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in p53(+/-) mice. The tumor suppressor protein p53 plays a central role in tumor prevention. Loss or attenuation of p53 function contriubutes greatly to tumorigenesis. We found that chronic restraint decreases the levels and function of p53 in mice, and furthermore, promotes the growth of human xenograft tumors in a largely p53-dependent manner. Our results show that glucocorticoids elevated during chronic restraint mediate the effect of chronic restraint on p53 through the induction of serum- and glucocorticoid-induced protein kinase (SGK1), which in turn increases MDM2 activity and decreases p53 function. Taken together, this study demonstrates that chronic stress promotes tumorigenesis in mice, and the attenuation of p53 function is an important part of the underlying mechanism, which can be mediated by glucocortcoids elevated during chronic restraint.

PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis.

BACKGROUND: Mounting epidemiological evidence supports a role for phosphatase and tensin homologue (PTEN)-T cell leukaemia 1 (Tcl1) signalling deregulation in hepatocarcinogenesis. OBJECTIVE: To determine the molecular and biochemical mechanisms by which the PTEN/Tcl1 axis regulates the pentose phosphate pathway (PPP) in hepatocellular carcinoma (HCC). METHODS: We compared levels of PTEN and glucose-6-phosphate dehydrogenase (G6PD) mRNA in human HCC and healthy liver tissue. We measured PPP flux, glucose consumption, lactate production, nicotinamide adenine dinucleotide phosphate (NADPH) levels and lipid accumulation. We investigated the PTEN/Tcl1 axis using molecular biology, biochemistry and mass spectrometry analysis. We assessed proliferation, apoptosis and senescence in cultured cells, and tumour formation in mice. RESULTS: We showed that PTEN inhibited the PPP pathway in human liver tumours. Through the PPP, PTEN suppressed glucose consumption and biosynthesis. Mechanistically, the PTEN protein bound to G6PD, the first and rate-limiting enzyme of the PPP and prevented the formation of the active G6PD dimer. Tcl1, a coactivator for Akt, reversed the effects of PTEN on biosynthesis. Tcl1 promoted G6PD activity and also increased G6PD pre-mRNA splicing and protein expression in a heterogeneous nuclear ribonucleoprotein (hnRNPK)-dependent manner. PTEN also formed a complex with hnRNPK, which inhibited G6PD pre-mRNA splicing. Moreover, PTEN inactivated Tcl1 via glycogen synthase kinase-3ß (GSK3ß)-mediated phosphorylation. Importantly, Tcl1 knockdown enhanced the sensitivity of HCC to sorafenib, whereas G6PD knockdown inhibited hepatocarcinogenesis. CONCLUSIONS: These results establish the counteraction between PTEN and Tcl1 as a key mechanism that regulates the PPP and suggest that targeting the PTEN/Tcl1/hnRNPK/G6PD axis could open up possibilities for therapeutic intervention and improve the prognosis of patients with HCC.

Nutlin-3 overcomes arsenic trioxide resistance and tumor metastasis mediated by mutant p53 in Hepatocellular Carcinoma.

BACKGROUND: Arsenic trioxide has been demonstrated as an effective anti-cancer drug against leukemia and solid tumors both in vitro and in vivo. However, recent phase II trials demonstrated that single agent arsenic trioxide was poorly effective against hepatocellular carcinoma (HCC), which might be due to drug resistance. METHODS: Mutation detection of p53 gene in arsenic trioxide resistant HCC cell lines was performed. The therapeutic effects of arsenic trioxide and Nutlin-3 on HCC were evaluated both in vitro and in vivo. A series of experiments including MTT, apoptosis assays, co-Immunoprecipitation, siRNA transfection, lentiviral infection, cell migration, invasion, and epithelial-mesenchy-mal transition (EMT) assays were performed to investigate the underlying mechanisms. RESULTS: The acquisition of p53 mutation contributed to arsenic trioxide resistance and enhanced metastatic potential of HCC cells. Mutant p53 (Mutp53) silence could re-sensitize HCC resistant cells to arsenic trioxide and inhibit the metastatic activities, while mutp53 overexpression showed the opposite effects. Neither arsenic trioxide nor Nutlin-3 could exhibit obvious effects against arsenic trioxide resistant HCC cells, while combination of them showed significant effects. Nutlin-3 can not only increase the intracellular arsenicals through inhibition of p-gp but also promote the p73 activation and mutp53 degradation mediated by arsenic trioxide. In vivo experiments indicated that Nutlin-3 can potentiate the antitumor activities of arsenic trioxide in an orthotopic hepatic tumor model and inhibit the metastasis to lung. CONCLUSIONS: Acquisitions of p53 mutations contributed to the resistance of HCC to arsenic trioxide. Nutlin-3 could overcome arsenic trioxide resistance and inhibit tumor metastasis through p73 activation and promoting mutant p53 degradation mediated by arsenic trioxide.