Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma.

BACKGROUND AND AIMS: Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy. APPROACH AND RESULTS: We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies. CONCLUSIONS: We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.

Adsorption Isotherm and Mechanism of Ca2+ Binding to Polyelectrolyte.

Polyelectrolytes, such as poly(acrylic acid) (PAA), can effectively mitigate CaCO3 scale formation. Despite their success as antiscalants, the underlying mechanism of binding of Ca2+ to polyelectrolyte chains remains unresolved. Through all-atom molecular dynamics simulations, we constructed an adsorption isotherm of Ca2+ binding to sodium polyacrylate (NaPAA) and investigated the associated binding mechanism. We find that the number of calcium ions adsorbed [Ca2+]ads to the polymer saturates at moderately high concentrations of free calcium ions [Ca2+]aq in the solution. This saturation value is intricately connected with the binding modes accessible to Ca2+ ions when they bind to the polyelectrolyte chain. We identify two dominant binding modes: the first involves binding to at most two carboxylate oxygens on a polyacrylate chain, and the second, termed the high binding mode, involves binding to four or more carboxylate oxygens. As the concentration of free calcium ions [Ca2+]aq increases from low to moderate levels, the polyelectrolyte chain undergoes a conformational transition from an extended coil to a hairpin-like structure, enhancing the accessibility to the high binding mode. At moderate concentrations of [Ca2+]aq, the high binding mode accounts for at least one-third of all binding events. The chain's conformational change and its consequent access to the high binding mode are found to increase the overall Ca2+ ion binding capacity of the polyelectrolyte chain.

Impact of Degree of Ethoxylation on Sodium Lauryl Ether Sulfate Surfactant Adsorption onto Silicone-in-Water Emulsion Droplets.

Silicone-in-water emulsions have found widespread use as lubricants, water repellants, softeners, binders, antiblocking agents, antislip agents, and defoamers across a diverse range of markets including textiles, coatings, pharmaceuticals, and home and personal care. Stable incorporation of silicone emulsions into formulated products for these applications can be a challenge. This study seeks to enable formulation by investigating the impact of the degree of ethoxylation of sodium lauryl ether sulfate (SLES) surfactants on their ability to displace surfactant stabilizer at the silicone-water interfaces of polydimethylsiloxane (PDMS)-in-water emulsion droplets. Building this understanding will greatly enable the manufacture of home and personal care products prepared by introducing silicone emulsions into SLES-rich formulations. Nuclear magnetic resonance (NMR) measurements reveal that SLES can displace the triethanolamine dodecylbenzenesulfonate stabilizer at the droplet surfaces. Both capillary electrophoresis (CE) measurements and molecular dynamics simulations of the interfacial tension (IFT) between silicone and water measurements suggest that SLES mixtures with a higher average degree of ethoxylation are more surface active at the silicone─water interface. The molecular dynamics simulations predict a systematic decrease in PDMS-water IFT with increase in degree of ethoxylation (simulations predict a decrease of 1.3 mN/m per mole of ethylene oxide). Optical microscopy reveals that the presence of SLES at the droplet surfaces promotes the formation of loose flocs of droplets that break up upon dilution. Overall, these fundamental insights will aid in formulating silicone emulsions into products to achieve optimal performance.

Modeling the competition between phase separation and polymerization under explicit polydispersity.

The dynamics of phase separation for polymer blends is important in determining the final morphology and properties of polymer materials; in practical applications, this phase separation can be controlled by coupling to polymerization reaction kinetics via a process called 'polymerization-induced phase separation'. We develop a phase-field model for a polymer melt blend using a polymerizing Cahn-Hilliard (pCH) formalism to understand the fundamental processes underlying phase separation behavior of a mixture of two species independently undergoing linear step-growth polymerization. In our method, we explicitly model polydispersity in these systems to consider different molecular-weight components that will diffuse at different rates. We first show that this pCH model predicts results consistent with the Carothers predictions for step-growth polymerization kinetics, the Flory-Huggins theory of polymer mixing, and the classical predictions of spinodal decomposition in symmetric polymer blends. The model is then used to characterize (i) the competition between phase separation dynamics and polymerization kinetics, and (ii) the effect of unequal reaction rates between species. For large incompatibility between the species (i.e. high χ), our pCH model demonstrates that the strength for phase separation directly corresponds to the kinetics of phase separation. We find that increasing the reaction rate k̃, first induces faster phase separation but this trend reverses as we further increase k̃ due to the competition between molecular diffusion and polymerization. In this case, phase separation is delayed for faster polymerization rates due to the rapid accumulation of slow-moving, high molecular weight components.

Kidney-type glutaminase is a biomarker for the diagnosis and prognosis of hepatocellular carcinoma: a prospective study.

PURPOSE: The pathological diagnosis and prognosis prediction of hepatocellular carcinoma (HCC) is challenging due to the lack of specific biomarkers. This study aimed to validate the diagnostic and prognostic efficiency of Kidney-type glutaminase (GLS1) for HCC in prospective cohorts with a large sample size. METHODS: A total of 1140 HCC patients were enrolled in our prospective clinical trials. Control cases included 114 nontumour tissues. The registered clinical trial (ChiCTR-DDT-14,005,102, chictr.org.cn) was referred to for the exact protocol. GLS1 immunohistochemistry was performed on the whole tumour section. The diagnostic and prognostic performances of GLS1 was evaluated by the receiver operating characteristic curve and Cox regression model. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, Youden index, and area under the curve of GLS1 for the diagnosis of HCC were 0.746, 0.842, 0.979, 0.249, 0.588, and 0.814, respectively, which could be increased to 0.846, 0.886, 0.987,0.366, 0.732, and 0.921 when combined with glypican 3 (GPC3) and alpha-fetoprotein (AFP), indicating better diagnostic performance. Further, we developed a nomogram with GPC3 and GLS1 for identifying HCC which showed good discrimination and calibration. GLS1 expression was also related with age, T stage, TNM stage, Edmondson-Steiner grade, microvascular invasion, Ki67, VEGFR2, GPC3, and AFP expression in HCC. GLS1 expression was negatively correlated with disease-free survival (P < 0.001) probability of patients with HCC. CONCLUSIONS: It was validated that GLS1 was a sensitive and specific biomarker for pathological diagnosis of HCC and had prognostic value, thus having practical value for clinical application.

PLAGL2-EGFR-HIF-1/2α Signaling Loop Promotes HCC Progression and Erlotinib Insensitivity.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, hence a major public health threat. Pleomorphic adenoma gene like-2 (PLAGL2) has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood. APPROACH AND RESULTS: In this study, we demonstrated that PLAGL2 was up-regulated in HCC compared with that of adjacent nontumorous tissues and also correlated with overall survival times. We further showed that PLAGL2 promoted HCC cell proliferation, migration, and invasion both in vitro and in vivo. PLAGL2 expression was positively correlated with epidermal growth factor receptor (EGFR) expression. Mechanistically, this study demonstrated that PLAGL2 functions as a transcriptional regulator of EGFR and promotes HCC cell proliferation, migration, and invasion through the EGFR-AKT pathway. Moreover, hypoxia was found to significantly induce high expression of PLAGL2, which promoted hypoxia inducible factor 1/2 alpha subunit (HIF1/2A) expression through EGFR. Therefore, this study demonstrated that a PLAGL2-EGFR-HIF1/2A signaling loop promotes HCC progression. More importantly, PLAGL2 expression reduced hepatoma cells' response to the anti-EGFR drug erlotinib. PLAGL2 knockdown enhanced the response to erlotinib. CONCLUSIONS: This study reveals the pivotal role of PLAGL2 in HCC cell proliferation, metastasis, and erlotinib insensitivity. This suggests that PLAGL2 can be a potential therapeutic target of HCC.

Loss of Xanthine Oxidoreductase Potentiates Propagation of Hepatocellular Carcinoma Stem Cells.

BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) exist in the tumor environment and are critically involved in the initiation and progression of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of self-renewal and maintenance of liver CSCs remain poorly understood. APPROACH AND RESULTS: We identified that xanthine oxidoreductase (XOR), which was expressed at low levels in human HCC samples and liver CSCs, restrained HCC formation and chemoresistance by attenuating liver CSC propagation. Mechanistically, XOR physically interacts with ubiquitin-specific peptidase 15 (USP15), thereby promoting deubiquitination of Kelch-like ECH associated protein 1 (KEAP1) to stabilize its expression, which leads to degradation of Nrf2 (nuclear factor erythroid 2-related factor 2) through ubiquitination and subsequently reactive oxygen species accumulation in liver CSCs. Finally, our data reveal that XOR promotes USP15-mediated Nrf2-KEAP1 signaling to block liver CSCs and tumor propagation. CONCLUSION: We identified that XOR may represent a potential therapeutic target for clinical intervention in HCC driven by liver CSCs.

Effect of Surfactant Concentration and Hydrophobicity on the Ordering of Water at a Silica Surface.

The performance of nonionic surfactants is mediated by the interfacial interactions at the solid-liquid interface. Here we applied sum frequency generation (SFG) vibrational spectroscopy to probe the molecular structure of the silica-nonionic surfactant solution interface in situ, supplemented by quartz crystal microbalance with dissipation monitoring (QCM-D) and molecular dynamics (MD) simulations. The combined studies elucidated the effects of nonionic surfactant solution concentration, surfactant composition, and rinsing on the silica-surfactant solution interfacial structure. The nonionic surfactants studied include ethylene-oxide (EO) and butylene oxide (BO) components with different ratios. It was found that the CH groups of the surfactants at the silica-surfactant solution interfaces are disordered, but the interfacial water molecules are ordered, generating strong SFG OH signals. Solutions with higher concentrations of surfactant lead to a slightly higher amount of adsorbed surfactant at the silica interface, resulting in more water molecules being ordered at the interface, or a higher ordering of water molecules at the interface, or both. MD simulation results indicated that the nonionic surface molecules preferentially adsorb onto silanol sites on silica. A surfactant with a higher EO/BO ratio leads to more water molecules being ordered and a higher degree of ordering of water molecules at the silica-surfactant solution interface, exhibiting stronger SFG OH signal, although less material is adsorbed according to the QCM-D data. A thin layer of surfactants remained on the silica surface after multiple water rinses. To the best of our knowledge, this is the first time the combined approaches of SFG, QCM-D and MD simulation techniques have been applied to study nonionic surfactants at the silica-solution interface, which enhances our understanding on the interfacial interactions between nonionic surfactants, water and silica. The knowledge obtained from this study can be helpful to design the optimal surfactant concentration and composition for future applications.

Dorsal approach with Glissonian approach for laparoscopic right anatomic liver resections.

BACKGROUND: Laparoscopic anatomic hepatectomy (LAH) has gradually become a routine surgical procedure. However, how to expose the whole hepatic vein and avoid the hepatic vein laceration is still a challenge because of the caudate lobe, particularly in right hepatectomy. We adopted a dorsal approach combined with Glissionian appraoch to perform laparoscopic right anatomic hepatectomy (LRAH). METHODS: Twenty patients who underwent LRAH from January 2017 to November 2018 were retrospectively analysed. Of these patients, seven patients underwent laparoscopic right hemihepatectomy (LRH group), seven patients who underwent laparoscopic right posterior hepatectomy (LRPH group), and six patients who underwent laparoscopic hepatectomy for segment 7 (LS7 group). The paracaval portion of caudate lobe could be transected firstly through dorsal approach and the corresponding major hepatic vein could be exposed from its root to the peripheral branches safely. Due to exposure along the major hepatic vein trunk, the remaining liver parenchyma could be quickly transected from dorsal to cranial side. RESULTS: The mean age of the patients was 53.8 years and the male: female ratio was 8:12. The median operation time was 306.0 ± 58.2 min and the mean estimated volume of blood loss was 412.5 ± 255.4 mL. The mean duration of postoperative hospital stay was 10.2 days. The mean Pringle maneuver time was 64.8 ± 27.7 min. Five patients received transfusion of 2-4 U of red blood cells. Two patients suffered from transient hepatic dysfunction and one suffered from pleural effusion. None of the patients underwent conversion to an open procedure. The operative duration, volume of the blood loss, Pringle maneuver time, and postoperative hospital stay duration did not differ significantly among the LRH, LRPH, and LS7 groups (P > 0.05). CONCLUSIONS: Dorsal approach combined with Glissonian approach for right lobe is feasible and effective in laparoscopic right anatomic liver resections.

Laparoscopic hepatectomy is superior to open procedures for hepatic hemangioma.

BACKGROUND: Laparoscopic hepatectomy (LH) has become increasingly popular for liver neoplasms, but its safety and effectiveness remain controversial. Hepatic hemangiomas are the most common benign liver neoplasm; the main approaches to hepatic hemangiomas include open hepatectomy (OH) and LH. In this study, we compared early outcomes between patients undergoing OH and those with LH. METHODS: Patients underwent OH or LH in our hospital for hepatic hemangiomas between December 2013 and December 2017 were enrolled. All patients underwent comprehensive preoperative evaluations. The clinicopathological index and risk factors of hemangioma resection were assessed. RESULTS: In total, 41 patients underwent OH while 53 underwent LH. There was no significant difference in any preoperative clinical variables, including liver function, prothrombin time, or platelet count. Hepatic portal occlusion time and operative time were 39.74 vs. 38.35 minutes (P = 0.717) and 197.20 vs. 203.68 minutes (P = 0.652) in the OH and LH groups, respectively. No mortality nor significant perioperative complications were observed between the two groups. In LH group, two cases were converted to OH, one for an oversized tumor and the other for hemorrhage. Compared with OH patients, those with LH had less blood loss (361.69 vs. 437.81 mL, P = 0.024), shorter postoperative hospital stay (7.98 vs. 11.07 days, P = 0.001), and lower postoperative C-reactive protein (43.63 vs. 58.21 mg/L, P = 0.026). CONCLUSIONS: LH is superior to OH in terms of postoperative recovery and blood loss for selected patients with hepatic hemangioma.

Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma.

BACKGROUND: Oncolytic viro-immunotherapy holds promise for cancer treatment. While immune activation can be robustly triggered by oncolytic viruses, negative feedback is often upregulated in the tumour microenvironment (TME). Lactate accumulation, signal transducer and activator of transcription 3 (STAT3) activation, indoleamine 2,3-dioxygenase 1 (IDO1) expression, and myeloid-derived suppressor cell (MDSC) infiltration coordinate to shape the immunosuppressive TME. METHODS: Representative hepatocellular carcinoma (HCC) cell lines and HCC-bearing mice were treated with oncolytic Newcastle disease virus (NDV), alone or in combination with dichloroacetate (DCA, a pyruvate dehydrogenase kinase (PDK) inhibitor). RESULTS: We found that infection with oncolytic NDV led to significant induction of the aforementioned suppressive factors. Interestingly, DCA significantly reduced lactate release, STAT3 activation, IDO1 upregulation, and MDSC infiltration in NDV-treated HCC. Consequently, DCA significantly enhanced the antitumour immune responses, leading to improved antitumour efficacy and prolonged survival in mouse models of ascitic and subcutaneous HCC. Furthermore, DCA increased NDV replication in a PDK-1-dependent manner in HCC. CONCLUSIONS: Targeting aerobic glycolysis by DCA improves NDV-mediated viro-immunotherapy in HCC by mitigating immune negative feedback and promoting viral replication. These findings provide a rationale for targeting reprogrammed metabolism together with oncolytic virus-mediated viro-immunotherapy for HCC treatment.

APOBEC3B interaction with PRC2 modulates microenvironment to promote HCC progression.

OBJECTIVE: APOBEC3B (A3B), a cytidine deaminase acting as a contributor to the APOBEC mutation pattern in many kinds of tumours, is upregulated in patients with hepatocellular carcinoma (HCC). However, APOBEC mutation patterns are absent in HCC. The mechanism of how A3B affects HCC progression remains elusive. DESIGN: A3B -promoter luciferase reporter and other techniques were applied to elucidate mechanisms of A3B upregulation in HCC. A3B overexpression and knockdown cell models, immunocompetent and immune-deficient mouse HCC model were conducted to investigate the influence of A3B on HCC progression. RNA-seq, flow cytometry and other techniques were conducted to analyse how A3B modulated the cytokine to enhance the recruitment of myeloid--derived suppressor cells (MDSCs) and tumour--associated macrophages (TAMs). RESULTS: A3B upregulation through non-classical nuclear factor-κB (NF-κB)signalling promotes HCC growth in immunocompetent mice, associated with an increase of MDSCs, TAMs and programmed cell death1 (PD1) exprssed CD8+ T cells. A CCR2 antagonist suppressed TAMs and MDSCs infiltration and delayed tumour growth in A3B and A3BE68Q/E255Q- expressing mouse tumours. Mechanistically, A3B upregulation in HCC depresses global H3K27me3 abundance via interaction with polycomb repressor complex 2 (PRC2) and reduces an occupancy of H3K27me3 on promoters of the chemokine CCL2 to recruit massive TAMs and MDSCs. CONCLUSION: Our observations uncover a deaminase-independent role of the A3B in modulating the HCC microenvironment and demonstrate a proof for the concept of targeting A3B in HCC immunotherapy.

Laennec's approach for laparoscopic anatomic hepatectomy based on Laennec's capsule.

BACKGROUND: Although isolating Glissonean pedicles and hepatic veins are critical procedures during anatomical hepatectomy, there is no standardized approach. We propose the novel Laennec's approach for laparoscopic anatomic hepatectomy (LAH) based on Laennec's capsule, which serves as the anatomic landmark for LAH. The aim of this study was to elucidate that the natural gap between Laennec's capsule and the adjacent tissues contributes to standardization of the surgical technique for LAH. METHODS: Eighty-four cases were enrolled in this observable clinical trial. They underwent LAH for liver diseases. Laennec's approach was proposed for LAH based on Laennec's capsule. The liver tissues close to Glissonean pedicle, hepatic veins, naked area, and inferior vena cava were collected for hematoxylin and eosin, resorcinol-fuchsin staining, and immunohistochemistry. RESULTS: The staining revealed capsule packaging of the whole liver independent of the adjacent tissues and intrahepatic vessels. A natural gap was found between Laennec's capsule and the adjacent tissues at different sites. Laennec's capsule served as the landmark for isolating Glissonean pedicle and hepatic veins, mobilizing the liver, and performing Hanging maneuver. Eighty-four cases underwent LAH for liver diseases using this strategy. The operation time was 277.23 min. The mean of hospital days was 9.8. CONCLUSIONS: Laennec's approach based on Laennec's capsule contributes to standardization of the surgical technique for LAH, and brings innovations that facilitates safe and effective liver resection under laparoscopy.

Geranylgeranyl diphosphate synthase (GGPPS) regulates non-alcoholic fatty liver disease (NAFLD)-fibrosis progression by determining hepatic glucose/fatty acid preference under high-fat diet conditions.

Patients with obesity have a high prevalence of non-alcoholic fatty liver disease (NAFLD) and, in parallel, increased susceptibility to fibrosis/cirrhosis/hepatocellular carcinoma (HCC). Herein, we report that a high-fat diet (HFD) can augment glycolysis and then accelerate NAFLD-fibrosis progression by downregulating the expression of geranylgeranyl diphosphate synthase (GGPPS), which is a critical enzyme in the mevalonate pathway. Long-term HFD overloading decreases GGPPS expression in mice, which shifts the fuel preference from fatty acids towards glucose. Liver-specific Ggpps deficiency drives the Warburg effect by impairing mitochondrial function, and then induces hepatic inflammation, thus exacerbating fibrosis. Ggpps deficiency also enhances the hyperfarnesylation of liver kinase B1, and promotes metabolic reprogramming by regulating 5'-AMP-activated protein kinase activity. Clinical data further imply that GGPPS expression can predict the stage of NAFLD and recurrence of NAFLD-associated HCC. We conclude that the level of GGPPS is a susceptibility factor for NAFLD-fibrosis progression, and requires more stringent surveillance to ensure early prediction and precision of treatment of NAFLD-related HCC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Glissonian approach combined with major hepatic vein first for laparoscopic anatomic hepatectomy.

BACKGROUND: Laparoscopic anatomic hepatectomy remains challenging because of the complex interior structures of the liver. Our novel strategy includes the Glissonian approach and the major hepatic vein first, which serves to define the external and internal landmarks for laparoscopic anatomic hepatectomy. METHODS: Eleven cases underwent laparoscopic anatomic hepatectomy, including three right hepatectomies, three left hepatectomies, three right posterior hepatectomies, and two mesohepatectomies. The Glissonian approach was used to transect the hepatic pedicles as external demarcation. The major hepatic vein near the hepatic portal was exposed and served as the internal landmark for parenchymal transection. The liver parenchyma below and above the major hepatic vein was transected along the major hepatic vein. Fifty-nine subjects were used to compare the distance between the major hepatic vein and secondary Glisson pedicles among different liver diseases. RESULTS: The average operative time was 327 min with an estimated blood loss of 554.55 mL. Only two patients received three units of packed red blood cells. The others recovered normally and were discharged on postoperative day 7. The distance between right posterior Glissonian pedicle and right hepatic vein was shorter in the patients with cirrhosis than that without cirrhosis, and this distance was even shorter in patients with hepatocellular carcinoma. CONCLUSION: The Glissonian approach with the major hepatic vein first is easy and feasible for laparoscopic anatomic hepatectomy, especially in patients with hepatocellular carcinoma and cirrhosis.

PP2Acα positively regulates the termination of liver regeneration in mice through the AKT/GSK3ß/Cyclin D1 pathway.

BACKGROUND & AIMS: Liver injury triggers a highly organized and ordered liver regeneration (LR) process. Once regeneration is complete, a stop signal ensures that the regenerated liver is an appropriate functional size. The inhibitors and stop signals that regulate LR are unknown, and only limited information is available about these mechanisms. METHODS: A 70% partial hepatectomy (PH) was performed in hepatocyte-specific PP2Acα-deleted (PP2Acα(-/-)) and control (PP2Acα(+/+)) mice. LR was estimated by liver weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were analyzed. RESULTS: We found that the catalytic subunit of PP2A was markedly upregulated during the late stage of LR. PP2Acα(-/-) mice showed prolonged LR termination, an increased liver size compared to the original mass and lower levels of serum ALT and AST compared with control mice. In these mice, cyclin D1 protein levels, but not mRNA levels, were increased. Mechanistically, AKT activated by the loss of PP2Acα inhibited glycogen synthase kinase 3ß (GSK3ß) activity, which led to the accumulation of cyclin D1 protein and accelerated hepatocyte proliferation at the termination stage. Treatment with the PI3K inhibitor wortmannin at the termination stage was sufficient to inhibit cyclin D1 accumulation and hepatocyte proliferation. CONCLUSIONS: PP2Acα plays an essential role in the proper termination of LR via the AKT/GSK3ß/Cyclin D1 pathway. Our findings enrich the understanding of the molecular mechanism that controls the termination of LR and provides a potential therapeutic target for treating liver injury.

GGPPS1 predicts the biological character of hepatocellular carcinoma in patients with cirrhosis.

BACKGROUND: Hepatocellular carcinoma (HCC) has been associated with diabetes and obesity, but a possible connection with the metabolic syndrome (MetS) and its potential interaction with hepatitis and cirrhosis are open to discussion. Our previous investigations have shown that GGPPS1 plays a critical role during hyperinsulinism. In this report, the expression and distribution of GGPPS1 in liver cancer, and its clinical significance were investigated. METHODS: 70 patients with hepatocellular carcinoma (HCC) were included in this study. Three different types of tissues from each HCC patient were assembled immediately after surgical resection: tumor-free tissue >5 cm far from tumor edge (TF), adjacent nonmalignant tissue within 2 cm (AT), and tissue from the tumor (TT). Normal liver tissues from 10 liver transplant donors served as healthy control (HC) while 10 patients with liver cirrhosis as cirrhosis control (CC). The expression and distribution of GGPPS1 were detected by immunohistochemistry, western blots, or real-time PCR. The relationship between the expression of GGPPS1 and clinic pathologic index were analyzed. RESULTS: We found that GGPPS1 was intensified mainly in the cytoplasm of liver tumor cells. Both the expression of GGPPS1 mRNA and protein were upregulated in TT comparing to AT or TF. Meanwhile, HCC patients with cirrhosis had relative higher expression of GGPPS1. In addition, many pathologic characters show close correlation with GGPPS1, such as tumor stage, vessel invasion, and early recurrence. CONCLUSION: GGPPS1 may play a critical role during the development of HCC from cirrhosis and is of clinical significance for predicting biological character of HCC.