[Retracted] Interaction of S100A1 with LATS1 promotes cell growth through regulation of the Hippo pathway in hepatocellular carcinoma.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the western blotting data shown in Figs. 2B and 3E were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to International Journal of Oncology, or were under consideration for publication at around the same time. In view of the fact that certain of these data had already apparently been published previously, the Editor of International Journal of Oncology has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 53: 592­602, 2018; DOI: 10.3892/ijo.2018.4431].

[Retracted] Downregulation of ROS­FIG inhibits cell proliferation, colony­formation, cell cycle progression, migration and invasion, while inducing apoptosis in intrahepatic cholangiocarcinoma cells.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the western blotting data shown in Fig. 9 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to International Journal of Molecular Medicine, or were under consideration for publication at around the same time. In view of the fact that certain of these data had already apparently been published previously, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 34: 661­668, 2014; 10.3892/ijmm.2014.1823].

Activation of cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis.

Inflammation plays an essential role in the development liver fibrosis.The Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a central cytoplasmic DNA sensor which can recognize cytoplasmic DNA, known to trigger stimulator of interferon genes (STING) and downstream proinflammatory factors. Here, we investigated the role of cGAS-STING signaling pathway in the pathogenesis of liver fibrosis.Differentially expressed genes (DEGs) in human liver tissue were identified using RNA-Seq analysis. As models of liver fibrosis, chronic Carbon tetrachloride (CCl4) exposure were applied in cGAS-knockout mice. LX-2 cells were co-cultured with human liver sinusoidal endothelial cells (LSECs) to explore the underlying mechanisms of hepatic sinusoidal microthrombosis in an inflammatory microenvironment. The endoscopic ultrasound-guided portal vein pressure gradient (EUS-PPG) method was used to analyze the associations between hepatic sinusoidal microthrombosis and PPG in patients with liver fibrosis and portal hypertension (PTH). The RNA-seq analysis results showed that DEGs were enriched in inflammation and endothelial cell activation. The upregulation of the cGAS-STING signaling exacerbated liver fibrosis and intrahepatic inflammation. It also exacerbated LSECs impairment and increased the contribution of hepatic sinusoidal microthrombosis to liver fibrosis in vivo and in vitro. Prothrombotic mediators and proinflammatory factors were associated with PPG in patients with liver fibrosis and portal hypertension. Therefore, activating cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis, which may lead to increased portal vein pressure.

Feasibility and Safety of ERCP in the Treatment of Biliary Strictures after Liver Transplantation: With a Report of 37 Cases.

Background: Liver transplantation (LT) is an effective treatment option for patients with end-stage liver disease; biliary complications are important cause of death in posttransplant patients. Endoscopic retrograde cholangiopancreatography (ERCP) has an irreplaceable role in the diagnosis and treatment of patients with biliary tract disease. Methods: The clinical data of patients with biliary strictures (BS) after LT treated with ERCP admitted to the Third Xiangya Hospital of Central South University from September 2016 to October 2021 were reviewed; the changes in temperature, bilirubin, and albumin before and after treatment and postoperative complications were analyzed. Results: A total of 41 patients were included in the study, and biliary stents were successfully placed in 37 cases (90.2%), while 4 cases (9.8%) were unsuccessful due to complete BS. Patients with ERCP guided biliary stenting had a significant improvement in bilirubin index compared to the preoperative period (P < 0.05). 27 patients (73.0%) had complete relief of symptoms after 1 ERCP-guided treatment, and 10 patients (27.0%) developed BS again at different times after the first ERCP treatment, among which 8 patients developed BS again within 1 year after the first treatment and 2 patients developed BS again after 1 year after the first treatment. The incidence of endoscopy-related adverse events was 35.14%, with no serious adverse events. Conclusion: ERCP-guided biliary stenting was an effective and safety treatment for BS after LT.

NEDD4 Induces K48-Linked Degradative Ubiquitination of Hepatitis B Virus X Protein and Inhibits HBV-Associated HCC Progression.

Neural precursor cell expressed developmentally downregulated gene 4 (NEDD4) plays two opposite roles in carcinogenesis. It has been reported that NEDD4 inhibits hepatocellular carcinoma (HCC) progression; however, little is known about its potential function and molecular mechanism in HCC in the context of hepatitis B virus (HBV) infection. In this study, we analyzed NEDD4 expression in 199 HCC specimens with or without HBV infection and observed that NEDD4 expression was unrelated to HBV exposure in HCC tumor tissue but that high NEDD4 expression conferred better overall survival (OS) and progression-free survival (PFS) than low NEDD4 expression in patients with HBV-associated HCC. Upregulation of NEDD4 inhibited proliferation, migration and invasion in HBV-related HCC cell lines. We demonstrated that NEDD4 interacts with HBV X protein (HBx) and that HBx upregulation could reverse the suppression of proliferation and mobility induced by NEDD4 overexpression. Furthermore, we confirmed that NEDD4 induced the degradation of HBx in a ubiquitin/proteasome-dependent manner via K48-linked ubiquitination. Our findings suggest that NEDD4 exerts a tumor-suppressive effect in HBV-associated HCC by acting as an E3 ubiquitin ligase for HBx degradation and provide new insights into the function of NEDD4.

Elevation of plasma tRNA fragments as a promising biomarker for liver fibrosis in nonalcoholic fatty liver disease.

Fibrotic tissue remodelling in nonalcoholic fatty liver disease (NAFLD) will probably emerge as the leading cause of end-stage liver disease in the coming decades, but the ability to diagnose liver fibrosis in NAFLD patients noninvasively is limited. The abnormal expression of tRNA-derived small RNA (tsRNA) in plasma provides a novel idea for noninvasive diagnosis of various diseases, however, the relationship between tsRNAs and NAFLD is still unknown. Here, we took advantage of small RNA-Seq technology to profile tsRNAs in NAFLD patients and found the ubiquitous presence of hepatic tsRNAs secreted into circulating blood. Verification in a cohort of 114 patients with NAFLD and 42 patients without NAFLD revealed that three tsRNAs (tRF-Val-CAC-005, tiRNA-His-GTG-001, and tRF-Ala-CGC-006) were significantly elevated in the plasma of NAFLD patients, and the expression level are associated with NAFLD activity score (calculated from 0 to 8) and fibrosis stage (scored from 0 to 4). In mouse models, we further found that increased plasma levels of these three tsRNAs were positively correlated with the degree of liver fibrosis. Our study potentially identifies a new class of NAFLD biomarkers and reveal the possible existence of tsRNAs in the blood that can be used to predict fibrogenesis risk in patients diagnosed with NAFLD.

LncRNA Neat1 expedites the progression of liver fibrosis in mice through targeting miR-148a-3p and miR-22-3p to upregulate Cyth3.

Liver fibrosis is a common response to chronic liver injury, ultimately leading to cirrhosis. The activation of hepatic stellate cells (HSCs) plays a dominant role in liver fibrosis. The regulatory roles of long noncoding RNAs (lncRNAs) in multiple human diseases have been observed. This study was dedicated to investigating the regulatory effects of the lncRNA nuclear paraspeckle assembly transcript 1 (Neat1) on liver fibrosis and HSC activation. Upregulation of Neat1 and cytohesin 3 (Cyth3) and downregulation of miR-148a-3p and miR-22-3p were observed in mouse fibrotic liver tissues. Knockdown of Neat1 or Cyth3 attenuated liver fibrosis and collagen deposition in vivo and the activation of HSCs in vitro. An miR-148a-3p and miR-22-3p inhibitor facilitated HSC activation and collagen fiber expression. Neat1 directly targeted miR-148a-3p and miR-22-3p to modulate Cyth3 expression. Knockdown of Neat1 inhibited Cyth3 expression via the competing endogenous RNA (ceRNA) mechanism of sponging miR-148a-3p and miR-22-3p to regulate liver fibrosis and HSC activation. The ceRNA regulatory network may promote a better understanding of liver fibrogenesis, contribute to an original agreement of liver fibrosis etiopathogenesis and provide insights into the development of a novel domain of lncRNA-directed therapy against liver fibrosis.

TIGIT/PVR and LncRNA ANRIL dual-targetable PAMAM polymeric nanoparticles efficiently inhibited the hepatoma carcinoma by combination of immunotherapy and gene therapy.

Herein, a novel polymeric nanoparticle was designed to inhibit hepatoma carcinoma by simultaneously targeting the T cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor (PVR) and long noncoding RNAs antisense noncoding RNA in the INK4 locus (LncRNA ANRIL). Firstly, the siANRIL-loaded nanoparticles (NP-siANRIL) was developed by methoxy-poly (ethylene glycol)-polyamidoamine (mPEG-PAMAM) and polyamidoamine-poly (ethylene glycol)-disulphide bond-carboxyl (PAMAM-PEG-S2-COOH) using the self-assembly method. Then the DTBP-3 peptide, a newly developed identified peptide which could occupy the binding interface and effectively block the interaction of TIGIT with its ligand PVR, was further conjugated on the surface of NP-siANRIL via the glutathione (GSH)-sensitive disulphide linkage. In this way, the binding ability of DTBP-3 to TIGIT was remained once they were entrapped into the tumour tissues which were abundant of GSH. The present study demonstrated that DTBP-3NP-siANRIL exhibited an excellent anti-tumour effect on hepatoma carcinoma in vivo by simultaneously inhibited the expression of miR-203a and its downstream genes and increased the percentages of NK cells and T cells. In a word, the present study has presented a novel strategy for treatment of hepatoma carcinoma by simultaneously targeting of TIGIT/PVR and LncRNA ANRIL.

CircFoxo3 Promotes Adriamycin Resistance Through Regulation of miR-199a-5p/ATP Binding Cassette Subfamily C Member 1 Axis in Hepatocellular Carcinoma.

INTRODUCTION: Chemotherapy resistance is the main cause of poor prognosis in patients with hepatocellular carcinoma (HCC). Therefore, it is important to understand the molecular mechanism of adriamycin (ADM) resistance in HCC. Increasing evidence indicates that circular RNAs (circRNAs) play a crucial regulatory role in different pathological processes. In the current study, we aimed to investigate the roles and the underlying molecular mechanism of circFoxo3 in ADM-resistant HCC. MATERIALS AND METHODS: Twenty-five pairs of clinical tumors samples and matched normal tissues were collected from patients with HCC. Gain- and loss-function experiments were performed to investigate the role of circFoxo3 in ADM-resistant cells. RESULTS: CircFoxo3 expression was increased in ADM-resistant HCC tissues and HCC cell lines and in metastatic tissues compared with non-metastatic tissues. CircFoxo3 knockdown reduces and circFoxo3 overexpression enhances HCC cell invasion and tumor growth. In addition, circFoxo3 interacted with miR-199a-5p and regulated miR-199a-5p expression. Furthermore, ATP Binding Cassette Subfamily C Member 1 (ABCC1) was identified as a new target of miR-199a-5p. CircFoxo3 interacted with miR-199a-5p to positively regulate ABCC1 expression, contributing to epithelial-mesenchymal transition progression. CONCLUSION: CircFoxo3 knockdown reduces and circFoxo3 overexpression enhances HCC cell invasion and tumor growth through regulation of miR-199a-5p/ABCC1 axis. Our findings reveal that circFoxo3 may be novel biomarkers and therapeutic target for HCC treatment.

Long noncoding RNA CCAT1 inhibits miR-613 to promote nonalcoholic fatty liver disease via increasing LXRα transcription.

Nonalcoholic fatty liver disease (NAFLD) is regarded as a threat to public health; however, the pathologic mechanism of NAFLD is not fully understood. We attempted to identify abnormally expressed long noncoding RNA (lncRNAs) and messenger RNA that may affect the occurrence and development of NAFLD in this study. The expression of differentially expressed lncRNAs in NAFLD was determined in oleic acid (OA)-treated L02 cells, and the functions of CCAT1 in lipid droplet formation were evaluated in vitro. Differentially expressed genes (DEGs) were analyzed by microarray analysis, and DEGs related to CCTA1 were selected and verified by weighted correlation network analysis. The dynamic effects of LXRα and CCTA1 on lipid droplet formation and predicted binding was examined. The binding between miR-631 and CCAT1 and LXRα was verified. The dynamic effects of miR-613 inhibition and CCTA1 silencing on lipid droplet formation were examined. The expression and correlations of miR-631, CCAT1, and LXRα were determined in tissue samples. As the results show, CCAT1 was induced by OA and upregulated in NAFLD clinical samples. CCAT1 silencing significantly suppressed lipid droplet accumulation in vitro. LXRα was positively correlated with CCAT1. By inhibiting miR-613, CCAT1 increased the transcription of LXRα and promoted LXRα expression. The expression of LXRα was significantly increased in NAFLD tissues and was positively correlated with CCAT1. In conclusion, CCAT1 increases LXRα transcription by serving as a competing endogenous RNA for miR-613 in an LXRE-dependent manner, thereby promoting lipid droplet formation and NAFLD. CCAT1 and LXRα might be potent targets for NAFLD treatment.

Evaluation of Single-Cell Cytokine Secretion and Cell-Cell Interactions with a Hierarchical Loading Microwell Chip.

Comprehensive evaluation of single T cell functions such as cytokine secretion and cytolysis of target cells is greatly needed in adoptive cell therapy (ACT) but has never been fully fulfilled by current approaches. Herein, we develop a hierarchical loading microwell chip (HL-Chip) that aligns multiple cells and functionalized beads in a high-throughput microwell array with single-cell/bead precision based on size differences. We demonstrate the potential of the HL-Chip in evaluating single T cell functions by three applications: high-throughput longitudinal secretory profiling of single T cells, large-scale evaluation of cytolytic activity of single T cells, and integrated T cell-tumor cell interactions. The HL-Chip is a simple and robust technology that constructs arrays of defined cell/object combinations for multiple measurements and material retrieval.

LncRNA SNHG11 Promotes Proliferation, Migration, Apoptosis, and Autophagy by Regulating hsa-miR-184/AGO2 in HCC.

BACKGROUND: The most common malignant tumor of the digestive system is HCC. However, the mechanism and pathogenesis of HCC occurrence and progress are still unknown. LncRNA is closely related to the occurrence and progress of HCC. It is important to investigate the effect and role of lncRNA in HCC. MATERIALS AND METHODS: LncRNA microarray assay was used to screen the differential expression profile of lncRNA. SNHG11, miR-184 and GO2 expression was analyzed by RT-PCR. The ability of SNHG11 to serve as a sponge for miRNA and the fact that miR-184 directly targets mRNA were revealed by dual luciferase assay and RIP. Apoptosis and autophagy related proteins were detected by Western blot. Cell proliferation, invasion, migration, and apoptosis were detected by CCK-8 assay, wound healing assay, transwell assay, and flow cytometry. RESULTS: LncRNA microarray assay and RT-PCR results revealed that the expression of SNHG11 was increased in HCC tumor tissues and also upregulated in HCC cells. SNHG11 had a connection with poor survival rate in HCC. In addition, dual luciferase assay and RIP results revealed that SNHG11 serves as a sponge for miR-184 and miR-184 directly targets AGO2. Pearson correlation analysis showed that SNHG11 with miR-184 and miR-184 with AGO2 were negative correlations, and SNHG11 with AGO2 was a positive correlation. Cell function assay and Western blot showed SNHG4/miR-184/AGO2 regulatory loop was critical for HCC cell proliferation, migration, apoptosis, and autophagy. CONCLUSION: Our study demonstrated that the expression of SNHG11 is higher in HCC; moreover, SNHG11 promotes proliferation, migration, apoptosis, and autophagy by regulating AGO2 via miR-184 in HCC. Our verification of the role of SNHG11 may provide a novel biomarker for the diagnosis, therapy, and prognosis of HCC.

Immune-Responsive Gene 1/Itaconate Activates Nuclear Factor Erythroid 2-Related Factor 2 in Hepatocytes to Protect Against Liver Ischemia-Reperfusion Injury.

BACKGROUND AND AIMS: Itaconate, a metabolite of the tricarboxylic acid cycle, plays anti-inflammatory roles in macrophages during endotoxemia. The mechanisms underlying its anti-inflammatory roles have been shown to be mediated by the modulation of oxidative stress, an important mechanism of hepatic ischemia-reperfusion (I/R) injury. However, the role of itaconate in liver I/R injury is unknown. APPROACH AND RESULTS: We found that deletion of immune-responsive gene 1 (IRG1), encoding for the enzyme producing itaconate, exacerbated liver injury and systemic inflammation. Furthermore, bone marrow adoptive transfer experiments indicated that deletion of IRG1 in both hematopoietic and nonhematopoietic compartments contributes to the protection mediated by IRG1 after I/R. Interestingly, the expression of IRG1 was up-regulated in hepatocytes after I/R and hypoxia/reoxygenation-induced oxidative stress. Modulation of the IRG1 expression levels in hepatocytes regulated hepatocyte cell death. Importantly, addition of 4-octyl itaconate significantly improved liver injury and hepatocyte cell death after I/R. Furthermore, our data indicated that nuclear factor erythroid 2-related factor 2 (Nrf2) is required for the protective effect of IRG1 on mouse and human hepatocytes against oxidative stress-induced injury. Our studies document the important role of IRG1 in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that the IRG1/itaconate pathway activates Nrf2-mediated antioxidative response in hepatocytes to protect liver from I/R injury. CONCLUSIONS: Our data expand on the importance of IRG1/itaconate in nonimmune cells and identify itaconate as a potential therapeutic strategy for this unfavorable postsurgical complication.

MicroRNA-137 inhibits autophagy and chemosensitizes pancreatic cancer cells by targeting ATG5.

PURPOSE: Autophagy play an important role in tumor chemotherapy resistance. It has been reported that miR-137 expression was reducedand involved in the regulation of sensitivity of PC cells to chemotherapy. However, little is known about the underlying molecular mechanisms. In this study, we hypothesized that miR-137 might sensitize PC cells to chemotherapy thought regulating cell autophagy. METHODS: Cell survival was determined with MTT assay. Apoptotic cells were assessed with flow cytometric analysis. Fluorescence intensity of GFP-LC3 and RFP-GFP-LC3 were examined with immunofluorescence analysis to determine the autophagy and autophagic flux level. Western blotting assay was used to determine protein expression levels of LC3II/LC3I, P62, FUNDC1 and ATG5. mRNA expression level of miR-137 was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Dual-luciferase reporter assay was used to evaluate the directly binding of miR-137 with its targets. Xenograft model was setup to evaluate tumor growth. RESULTS: The results showed that doxorubicin (Dox) induced autophagy but downregulated the expression level of miR-137 in pancreatic cancer (PC) cells. In turn, overexpression of miR-137 enhanced the effect of Dox on decreasing cell survival, inducing cell apoptosis and inhibiting autophagy rather than influencing autophagic flux in PC cells. Further mechanistic study identified that ATG5 was a direct target of miR-137. Moreover, overexpression of ATG5 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by higher expression level of miR-137. We also demonstrated that miR-137 sensitized PANC-1 cells to Dox through inhibiting ATG5 and autophagy in vivo. CONCLUSIONS: Our findings demonstrated for the first time that miR-137 was able to promote sensitivity of PC cells to chemotherapy via inhibition of autophagy mediated by ATG5. Therefore, miR-137 may act as a potential therapeutic target for pancreatic cancer.

LncRNA MEG3 functions as a ceRNA in regulating hepatic lipogenesis by competitively binding to miR-21 with LRP6.

BACKGROUND: Hepatic lipogenesis dysregulation is essential for the development of non-alcoholic fatty liver disease (NAFLD). Emerging evidence indicates the importance of the involvement of long non-coding RNAs (LncRNAs) in lipogenesis. However, the specific mechanism underlying this process is not clear. OBJECTIVE: This study aimed to investigate the functional implication of LncRNA MEG3 (MEG3) in fatty degeneration of hepatocytes and in the pathogenesis of NAFLD. METHODS: The expression of MEG3 was analysed in in vitro and in vivo models of NAFLD, which were established by free fatty acid (FFA)-challenged HepG2 cells and high-fat diet-fed mice, respectively. Endogenous MEG3 was over-expressed by a specific pcDNA3.1-MEG3 to evaluate the regulatory function of MEG3 on triglyceride (TG)- and lipogenesis-related genes. Bioinformatic analysis was used to predict the target genes and binding sites, and the targeted regulatory relationship was verified with a dual luciferase assay. Finally, the possible pathway that regulates MEG3 was also evaluated. RESULTS: We found that the downregulation of MEG3 in vitro and in vivo models of NAFLD was negatively correlated with lipogenesis-related genes and that overexpression of MEG3 reversed FFA-induced lipid accumulation in HepG2 cells. miR-21 was upregulated in the FFA-challenged HepG2 cells and was physically associated with MEG3 in the process of lipogenesis. Our mechanistic studies demonstrated that MEG3 competitively binds to miR-21 with LRP6, followed by the inhibition of the mTOR pathway, which induces intracellular lipid accumulation. CONCLUSION: Our data are the first to document the working model of MEG3 functions as a potential hepatocyte lipid degeneration suppressor. MEG3 helps to alleviate lipid over-deposition, probably by binding to miR-21 to regulate the expression of LRP6. Our results suggest the potency of MEG3 as a biomarker for NAFLD and as a therapeutic target for treatment.

RELA/NEAT1/miR-302a-3p/RELA feedback loop modulates pancreatic ductal adenocarcinoma cell proliferation and migration.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy due to distant metastasis. RELA, a major component of the NF-κB pathway, could serve as an oncogene through activating proliferation or migration-related gene expression, including NEAT1, a well-known oncogenic long noncoding RNA. In the current study, the expression and function of RELA and NEAT1 in PDAC were examined. The potential upstream regulatory microRNAs of RELA were screened and verified for their correlation with RELA and NEAT1. The expression and function of the selected miR-302a-3p were evaluated. RELA and NEAT1 expression were upregulated in PDAC tissues, particularly in PDAC tissues with lymph node metastasis, and their expression correlated with clinical parameters. RELA overexpression promoted PDAC cell proliferation and migration, which could be partially attenuated by the NEAT1 knockdown. By binding to RELA, miR-302a-3p inhibited RELA expression, as well as PDAC cell proliferation and migration. RELA downstream NEAT1 expression was negatively regulated by miR-302a-3p; the suppressive effect of NEAT1 knockdown on PDAC cell proliferation and migration was partially attenuated by miR-302a-3p inhibition. Moreover, through direct binding, the expression of miR-302a-3p was also negatively regulated by NEAT1. The expression of miR-302a-3p was downregulated and negatively correlated with RELA or NEAT1 in tissue samples, indicating that rescuing miR-302a-3p expression may inhibit PDAC cell proliferation and migration through RELA/NEAT1. In summary, RELA, NEAT1, and miR-302a-3p form a feedback loop in PDAC to modulate PDAC cell proliferation and migration.

Overexpression of long noncoding RNA LINC00882 is associated with poor prognosis in hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the third major cause of malignant tumor-related death worldwide because it is initially diagnosed in the advanced stage and its therapeutic outcomes are usually poor. Based on this, it is urgent to identify effective early diagnosis biomarkers and new therapeutic targets to promote HCC treatment. Long noncoding RNAs (lncRNAs) have been reported as promising biomarkers for tumor diagnosis and treatment. MATERIALS AND METHODS: In this study, we profiled expression patterns and dysregulation of lncRNAs in HCC tissues by analyzing two datasets GSE55191 and GSE64631 from Gene Expression Omnibus database firstly, each of which contains expression profiles of 3 primary HCC tissues and 3 normal liver tissues, respectively. RESULTS: LncRNA 882 (LINC00882) is one of the lncRNAs that was significantly upregulated in HCC tissues compared with normal liver tissues. We verified the upregulation of LINC00882 in HCC by using two separate cohorts that contained 85 HCC tissues and paired adjacent noncancerous tissues and 86 HCC tissues and 89 independent noncancerous liver tissues, respectively. DISCUSSION: We found that upregulation of LINC00882 is correlated with poorer prognosis of HCC patients. In vitro cell experiments demonstrated that knockdown of LINC00882 inhibits proliferation, migration and invasion of HCC cell lines. CONCLUSION: These results indicated that LINC00882 promotes HCC progression and could be a potential prognostic biomarker and therapeutic target for HCC.

Novel and Recurring Disease-Causing NF1 Variants in Two Chinese Families with Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder primarily characterized by multiple café-au-lait macules, peripheral neurofibromas, skinfold freckling, and Lisch nodules. The causative genetic factor is the neurofibromin 1 gene (NF1), which encodes a Ras GTPase-activating protein called neurofibromin. NF1 variants may lead to loss of neurofibromin function and activation of downstream cell growth. This study aims to discover the disease-causing variants responsible for NF1 in two Han Chinese families by using exome sequencing combined with Sanger sequencing. A recurrent missense variant c.269T>C (p.Leu90Pro) and a novel nonsense variant c.2993dupA (p.Tyr998*) in the NF1 gene were identified. These variants co-segregated with the disorder in the pedigrees and were absent in the normal controls. The results broaden the NF1 mutation spectrum responsible for NF1. This may be helpful in genetic counseling, clinical management, and gene-targeted therapies for NF1.

Interaction of S100A1 with LATS1 promotes cell growth through regulation of the Hippo pathway in hepatocellular carcinoma.

Despite advances in surgery and chemotherapy, the prognosis of patients with hepatocellular carcinoma (HCC) remains poor. In the present study, the role of S100A1 in the progression of HCC was investigated. Immunohistochemical staining was used to measure the expression of S100A1 in HCC tissues. S100A1 was knocked down by siRNA. A battery of experiments was used to evaluate the biology functions of S100A1. It was found that S100A1 was upregulated in HCC tissues, and its upregulation was associated with a large tumor size, low differentiation and shorter survival time. The biological experiments demonstrated that S100A1 functions as an oncogene in HCC. It was also found that S100A1 knockdown enhanced the inhibitory effects of cisplatin on HCC cells. The results showed that the downregulation of S100A1 induced the phosphorylation of yes­associated protein (YAP), and treatment with CHX demonstrated that the downregulation of S100A1 accelerated YAP protein degradation. The downregulation of S100A1 did not alter the expression of mammalian sterile 20­like kinase (MST)1/2 or phosphorylated MST1/2, but upregulated the phosphorylation of large tumor suppressor kinase 1 (LATS1). It was further confirmed that S100A1 interacted with LATS1. LATS1 depletion significantly reduced the effects of S100A1 on cell growth rate and apoptosis, and there was a positive correlation between phosphorylated LATS1 and S100A1 in clinical samples, indicating that LATS1 was responsible for the S100A1-induced changes in cancer cell growth and Hippo signaling. In conclusion, the results of the present study indicated that S100A1 functions as an oncogene and may be a biomarker for the prognosis of patients with HCC. S100A1 exerted its oncogenic function by interacting with LATS1 and activating YAP. S100A1 may serve as a target for novel therapies in HCC.

Liver X Receptor Inverse Agonist SR9243 Suppresses Nonalcoholic Steatohepatitis Intrahepatic Inflammation and Fibrosis.

Abnormal metabolism of cholesterol may be a contributing factor in nonalcoholic steatohepatitis (NASH) pathogenesis. Accumulating evidence has shown that liver X receptor (LXR) is closely related to intrahepatic inflammation and fibrosis. In this study, we evaluated the effects of a novel liver-specific LXR inverse agonist, SR9243, on antifibrosis in NASH mice. A high-cholesterol diet was employed to induce NASH in BALB/c mice by either carbon tetrachloride (CCL4) administration or bile-duct ligation (BDL). Once NASH was induced, mice were treated with SR9243 for one month by intraperitoneal (i.p.) injection. Liver tissues were collected to determine the degree of fibrosis and intrahepatic inflammation via pathological examination and QPCR; serum was collected to analyze the plasma lipid levels and liver function by clinical biochemistry. The mice developed hepatic steatosis, severe hepatic inflammation, and fibrosis by BDL or CCL4. Treatment with SR9243 significantly reduced the severity of hepatic inflammation and ameliorated hepatic fibrosis; simultaneously, body weight, serum glucose, and plasma lipid levels were controlled effectively. Our data demonstrate that SR9243 exerts an antifibrotic and anti-inflammatory effect in NASH mice; hence these findings highly suggest that LXR inverse agonist could be therapeutically important in NASH treatment.