Development Of Hepatocellular Cancer Research Articles

β-Catenin Activation in Hepatocellular Cancer: Implications in Biology and Therapy.

Simple SummaryLiver cancer is a dreadful tumor which has gradually increased in incidence all around the world. One major driver of liver cancer is the Wnt–β-catenin pathway which is active in a subset of these tumors. While this pathway is normally important in liver development, regeneration and homeostasis, it’s excessive activation due to mutations, is detrimental and leads to tumor cell growth, making it an important therapeutic target. There are also some unique characteristics of this pathway activation in liver cancer. It makes the tumor addicted to specific amino acids and in turn to mTOR signaling, which can be treated by certain existing therapies. In addition, activation of the Wnt–β-catenin in liver cancer appears to alter the immune cell landscape making it less likely to respond to the new immuno-oncology treatments. Thus, Wnt–β-catenin active tumors may need to be treated differently than non-Wnt–β-catenin active tumors.Hepatocellular cancer (HCC), the most common primary liver tumor, has been gradually growing in incidence globally. The whole-genome and whole-exome sequencing of HCC has led to an improved understanding of the molecular drivers of this tumor type. Activation of the Wnt signaling pathway, mostly due to stabilizing missense mutations in its downstream effector β-catenin (encoded by CTNNB1) or loss-of-function mutations in AXIN1 (the gene which encodes for Axin-1, an essential protein for β-catenin degradation), are seen in a major subset of HCC. Because of the important role of β-catenin in liver pathobiology, its role in HCC has been extensively investigated. In fact, CTNNB1 mutations have been shown to have a trunk role. β-Catenin has been shown to play an important role in regulating tumor cell proliferation and survival and in tumor angiogenesis, due to a host of target genes regulated by the β-catenin transactivation of its transcriptional factor TCF. Proof-of-concept preclinical studies have shown β-catenin to be a highly relevant therapeutic target in CTNNB1-mutated HCCs. More recently, studies have revealed a unique role of β-catenin activation in regulating both tumor metabolism as well as the tumor immune microenvironment. Both these roles have notable implications for the development of novel therapies for HCC. Thus, β-catenin has a pertinent role in driving HCC development and maintenance of this tumor-type, and could be a highly relevant therapeutic target in a subset of HCC cases.

Role of fibroblast growth factor signalling in hepatic fibrosis.

Fibrotic remodelling is a highly conserved protective response to tissue injury and it is essential for the maintenance of structural and functional tissue integrity. Also hepatic fibrosis can be considered as a wound-healing response to liver injury, reflecting a balance between liver repair and scar formation. In contrast, pathological fibrosis corresponds to impaired wound healing. Usually, the liver regenerates after acute injury. However, if the damaging mechanisms persist, the liver reacts with progressive and uncontrolled accumulation of extracellular matrix proteins. Eventually, excessive fibrosis can lead to cirrhosis and hepatic failure. Furthermore, cirrhosis is the major risk factor for the development of hepatocellular cancer (HCC). Therefore, hepatic fibrosis is the most critical pathological factor that determines the morbidity and mortality of patients with chronic liver disease. Still, no effective anti-fibrogenic therapies exist, despite the very high medical need. The regulation of fibroblast growth factor (FGF) signalling is a prerequisite for adequate wound healing, repair and homeostasis in various tissues and organs. The FGF family comprises 22 proteins that can be classified into paracrine, intracrine and endocrine factors. Most FGFs signal through transmembrane tyrosine kinase FGF receptors (FGFRs). Although FGFRs are promising targets for the treatment of HCC, the expression and function of FGFR-ligands in hepatic fibrosis is still poorly understood. This review summarizes the latest advances in our understanding of FGF signalling in hepatic fibrosis. Furthermore, the potential of FGFs as targets for the treatment of hepatic fibrosis and remaining challenges for the field are discussed.

Circulating Cell-Free DNA Combined to Magnetic Resonance Imaging for Early Detection of HCC in Patients with Liver Cirrhosis.

Simple SummaryLiver cirrhosis can develop into malignant disease over time. Frequent monitoring would be advisable to detect the earliest signs of HCC progress resulting in a possible earlier treatment of the patient. Our study showed that the combination of genetic analysis of DNA freely circulating in the blood of the cirrhotic patients with MRI can represent a powerful strategy to timely identify suspect lesions, which can then be followed up more closely and thus potentially be treated earlier. In this way, personalized medicine can be applied to liver diseases such as cirrhosis.Liquid biopsy based on circulating cell-free DNA (cfDNA) is a promising non-invasive tool for the prognosis of hepatocellular cancer (HCC). In this exploratory study we investigated whether cfDNA and gene variants associated with HCC may be found in patients with liver cirrhosis (LC) and thus identify those at an increased risk for HCC. A cohort of 40 LC patients with no suspect neoplastic lesions was included in this study. Next generation sequencing (NGS) of cfDNA isolated from plasma was performed on a panel of 597 selected genes. Images of the patients who underwent MRI with hepatospecific contrast media during the study period were retrospectively re-evaluated (imaging was not part of the prospective study). cfDNA was detected in the plasma of 36 patients with LC. NGS-based analyses identified 20 variants in different combinations. Re-evaluation of the MRI images that were available for a proportion of the patients (n = 27) confirmed the absence of lesions in 8 cases carrying cfDNA without variants. In 6 of 19 patients with identified variants and MRI images available, MRI revealed a precursor lesion compatible with HCC and new lesions were discovered at follow-up in two patients. These precursor lesions were amenable for curative treatments. Mutation analysis revealed selective HCC related gene mutations in a subset of patients with LC, raising the suspect that these patients were at an increased risk for HCC development. MRI findings confirmed suspect nodular lesions of early stage HCC not detected with current standard screening procedures, which were only seen in patients carrying cfDNA variants. This opens a perspective for an HCC screening strategy combining both liquid biopsy and MRI in patients with LC.

Comparison of mutational landscape of non-alcoholic fatty liver disease, viral hepatitis, and alcohol consumption related hepatocellular carcinoma.

e16614 Background: Hepatocellular cancer (HCC) is the seventh most common cancer and the fourth leading cause of cancer-related death worldwide. The most common risk factors of HCC have traditionally included hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol-related liver disease (ALD). Recently, Non-Alcoholic Fatty Liver Disease (NAFLD) has emerged as the fastest growing risk factor for the development of HCC. This study reports the mutation landscape of NAFLD-related hepatocellular carcinoma (HCC) versus other etiologies. Methods: Mutation data of 219 HCC samples were collected from TCGA database, including 13 NAFLD, 87 HBV, 37 HCV, and 82 ALD-related samples. We analyzed mutations for different type of HCC samples using GDC level 3 mutation data. Driver mutations were called by applying software MuSig2CV. Results: In 219 samples, a total of 32189 mutations were identified, including 3163 in NAFLD, 11430 in HBV, 6390 in HCV, and 11206 in ALD-related HCC samples. Driver genes shared by viral hepatitis and ALD-related samples were TP53 (32% for ALD, 33% for HBV, 42% for HCV) and CTNNB1(32 % for HCV, 26% for HBV,29% for ALD), while TP53 was not among the highest frequency of mutations in NAFLD-related samples. As lack of NAFLD-related HCC samples (n = 13), most frequently mutated genes in NAFLD-related HCC samples were computed instead of driver genes. Top 5 mutated genes in NAFLD-related HCC samples were TTN (36%), CACNA1B (27%), DSCAM (27%), GLI2 (27%), and BEB (27%). Conclusions: From our results, TP53 has a lower mutation frequency in NAFLD-related HCC samples than in other types of HCC. To further validate this finding, a larger size of NAFLD-related HCC samples is essential.

Structure of Patients with Hepatocellular Cancer (Data Analysis from Two Specialised Centres)

Aim. To identify trends in the structure of patients with liver diseases, in particular hepatocellular cancer (HCC), by analysing the experience of two specialised medical centres.Materials and methods. A retrospective analysis of the medical records of hepatological patients who sought medical treatment at to the V.Kh. Vasilenko Clinic of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology of the Sechenov University in 2013, 2014 and 2017 (total 2459 patients) was carried out. The number of patients with chronic viral hepatitis (CVH) was 651, with non-alcoholic fatty liver disease (NAFLD) — 590, with alcoholic liver disease (ALD) — 66, with autoimmune liver diseases — 416, with liver cirrhosis (LC) of any etiology 407, other liver diseases — 329. A retrospective analysis of the medical records of patients with HCC who were examined and treated at the N.V. Sklifosovsky Research Institute for Emergency Medicine in the period from 2008 to 2017 (n = 86) was carried out.Results. The ratio of patients with chronic hepatitis C and B in 2013–2017 significantly changed. An almost twofold decrease in the number of patients with chronic hepatitis C (210 patients in 2013 and 141 patients in 2017) and an increase in the number of patients with chronic hepatitis B (20 patients in 2013 and 45 patients in 2017) was observed. An almost twofold increase in the total number of NAFLD patients was detected (163 patients in 2013 and 276 patients in 2017). The number of ALD patients increased from 12 patients in 2013 to 31 patients in 2017. The proportion of patients with autoimmune liver diseases in the overall structure of patients who applied to the department was 20 % in 2013, 13.6 % in 2014 and 10.8 % in 2017. An almost twofold decrease in the number of patients with alcoholic LC and LC associated with HBV was observed (73 patients and 17 patients in 2013 and 38 patients and 6 patients in 2017, respectively) as well as a noticeable increase in the number of patients with alcoholic LC and LC associated with HCV (6 patients and 51 patients in 2013 and 26 patients and 75 patients in 2017, respectively). In the analysis of HCC patients, the ratio of men to women was 3:1 (64 men and 22 women), the median age was 54.5 years (IQR 48–59). The median time from the establishment of chronic liver disease to the detection of HCC was 7.5 years (IQR 3–14.5). In 86 % of cases, the HCC development was preceded by cirrhosis (Child-Pugh A: n = 24; Child-Pugh B: n = 30; Child-Pugh C: n = 20), in 14 % — by chronic hepatitis. Viral liver lesions were the leading cause of HCC in 79 % (n = 68), ALD in 4 % (n = 3), NAFLD in 1 % (n = 1), AIH in 1 % (n = 1). In 10 % (n = 9), a combined liver lesion was observed, in 5 % (n = 4), no previous liver disease was known. The highest five-year survival rate (100 %) was found in the group of patients who received antiviral therapy (AVT) before and after liver transplantation.Conclusions. NAFLD, ALD, and chronic hepatitis B patients began to seek medical help more frequently. An increase in the number of patients with autoimmune LC and LC associated with chronic hepatitis C virus (HCV) infection was observed. The conducted analysis of trends in the structure of HCC patients showed that chronic HCV and HBV infection is the main prerequisite for the development of cancer. Liver transplantation is the most effective treatment for HCC. AVT before and after liver transplantation allows a statistically significant increase in the five-year posttransplant survival of HCC patients with chronic hepatitis C to be achieved.

Concomitant NFE2L2 and CTNNB1 mutations in a subset of HCC patients: Synergy between Nrf2 and Wnt pathway in hepatocarcinogenesis

BackgroundHepatocellular cancer (HCC) remains a major clinical need with gradually increasing incidence and currently lacks precision therapy. Thus, there is a need to better characterize molecular drivers in HCC and generate relevant models to test biology and therapies. In the USA, CTNNB1 mutations occur in 26% of all HCCs, however they alone are insufficient to lead to tumors as shown by preclinical studies suggesting cooperation with other pathways.MethodsWe assessed TCGA and other publically available databases for aberrations that co‐occur with CTNNB1 in HCC cases. We used sleeping beauty transposon/transposase (SBT) to express such clinically relevant mutants in a subset of hepatocytes in vivo in mice using hydrodynamic tail vein injection (HTVI). Specifically, we co‐delivered T41A‐CTNNB1 and wild type (WT)‐NFE2L2, G31A‐NFE2L2 or T80K‐NFE2L2 into 6–8 weeks old FVB mice via SBT‐HTVI and assessed tumorigenesis over time. WGS was performed on mouse tumors to identify differentially expressed genes and pathways. Similarity between the mouse model and human HCC subset was addressed by overlap between the most significantly altered pathways.ResultsOf the 377 HCC patients in TCGA, 99 patients showed CTNNB1 mutations. Analysis for Nrf2 pathway showed 15 HCCs with NFE2L2 and 18 with KEAP1 mutations. 12 patients showed coexistence of CTNNB1 mutations with wither NFE2L2 (n=6) or KEAP1 (n=6). Co‐expression of T41A‐CTNNB1 with G31A‐NFE2L2 or T80K‐NFE2L2 but not WT‐NFE2L2 led to HCC by 13–14 weeks. H&E staining confirmed the presence of well‐differentiated HCC. Immunostaining and WB showed HCCs to be strongly positive for b‐catenin targets (GS and pmTOR) and also for Nrf2 targets including NAD(P)H dehydrogenase [quinone] 1 and peroxiredoxin‐1. Next RNA‐Seq analysis on tumor‐bearing livers in mice using FDR=0.1 as cutoff showed many significantly altered pathways. Analysis of Nrf2‐CTNNB1 mutant HCC in TCGA also identified 64 pathways that were significantly altered using the FDR=0.1 as cutoff. 21 common and significant pathways were identified between our mouse model and patients, which have well known correlation with HCC development.ConclusionsThus, Nrf2 and Wnt pathway cooperate in HCC pathogenesis in a subset of patients. Co‐expression of mutant NFE2L2 and mutant CTNNB1 leads to HCC in mice with notable similarity in pathway alterations to the human HCC subset. This will be a valuable model to study biology and treatment for this subset of HCC cases.Support or Funding InformationThis work was supported by NIH grants R01CA204586 to S.P.M

Clariant and Anhui Guozhen and Chemtex announce licence agreement on Sunliquid cellulosic ethanol technology in China

Both non-alcoholic steatohepatitis (NASH) and alcoholic hepatitis (AH) can lead to cirrhosis and hepatocellular carcinoma. However, the rate of progression to cirrhosis and tumorigenesis in AH is greater than that in NASH. We asked whether there are differences between the two conditions in the expression levels of proteins involved in the pathogenesis of hepatocellular carcinoma. The proteins tested were presented at the 2017 American Association for the Study of Liver Diseases (AASLD) Liver Meeting as overexpressed in hepatocellular carcinoma: KLF4, SCL19A1, FANCG, HRH-1, DNMT1, DNMT3B, TNFR2, DUSP4, EGFR, Integrin α6, HDACII, PDE3A, BCL-XL, and MTCO2. The expression of these proteins was measured in liver biopsy sections from NASH and AH patients using immunohistochemical staining with fluorescent antibodies and then quantifying the fluorescence intensity morphometrically. In AH patients, levels of all tested proteins except HRH-1 were elevated compared to normal patients. In NASH patients, KLF4, SCL19A1, FANCG, HDACII, BCL-XL levels were increased compared to normal controls while HRH-1, DNMT1 and PDE3A levels were decreased. The relative expression of all proteins studied except BCL-XL was significantly higher in AH compared to NASH. In conclusion, proteins involved in hepatocellular cancer development are more highly expressed in AH compared to NASH and normal liver, which corresponds with the higher rate of tumorigenesis in AH patients compared to NASH patients.

Beta-catenin mutations in hepatocellular cancer, tumor cell metabolism, and the response of these tumors to mTOR inhibition.

583 Background: Hepatocellular cancer (HCC) continues to grow in incidence despite approval of many new therapies including immune checkpoint inhibitors (ICIs) and TKIs. Genomic landscape of HCC is becoming increasing apparent through WGS and WES. One major driver of HCC is the Wnt/b-catenin pathway. Mutations in CTNNB1, which encodes for b-catenin, are evident in 26-37% of all human HCCs. However, expression of mutant-b-catenin in liver in mice is insufficient for HCC development. Indeed, analysis of HCC cases has revealed CTNNB1 mutations to significantly co-exist with other aberrations including activation/overexpression of Met and Myc and mutations in TERT promoter or mutations in NFE2L2/KEAP1, APOB and ARID2. Methods: Using sleeping beauty transposon/transposase and hydrodynamic tail vein injection, we co-expressed mutant-CTNNB1 (S45Y, S33Y or T41A) and one other clinically relevant co-occurrence to study significance and biology of HCC. Any novel findings in the preclinical model were validated in HCC patient cohorts. Results: Co-expression of mutant-CTNNB1 and one relevant co-occurrence led to development of HCC in mice in 6-10 weeks. All HCC in these models showed a dramatic increase in glutamine synthetase (GS), encoded by Glul, a known target of the Wnt/b-catenin signaling pathway in the liver. This led to an increase in glutamine levels in the tumor-bearing livers. Increased glutamine in the tumors in turn led to increased levels of phospho-mTOR-S2448, a marker of mTORC1 activation. In fact, examination of ~400 patient HCCs showed a significant correlation between positive GS and p-mTOR-S2448 staining. Treatment of Met-b-catenin model with Rapamycin led to notable and significant decrease in HCC burden. Conclusions: Our studydemonstrates b-catenin-mutated HCC to be positive for both GS and in turn mTORC1 active. This provides a novel opportunity for personalized medicine in HCC and CTNNB1-mutated HCCs may be vulnerable to therapeutic targeting by mTOR and more specially, mTORC1 inhibitors.

Assessment of external risk factors of hepatocellular cancer development and markers of genetic predisposition to its development in the ethnic group of yakut - men

To establish the main external and genetically determined risk factors for the development of hepatocellular cancer in the ethnic group of male Yakuts living in the Republic of Sakha (Yakutia) [RS (Y)] in the epidemiologically unfavorable conditions of the incidence of viral hepatitis. A total of 97 male Yakuts were examined, including 44 people diagnosed with hepatocellular cancer and 53 people diagnosed with chronic viral hepatitis. HCC risk factors were identified by analyzing medical records and questioning patients. In the experimental and control groups, genetic studies of single nucleotide polymorphisms of genes mapped on the X-chromosome and involved in the activation of antiviral immunity along the TLR7 signaling pathway were performed. In 100% of patients with hepatocellular cancer, infection with hepatitis B, C, D viruses or co - infection with these agents was detected. Every fourth patient with HCC in the RS (Y) was infected with hepatitis D. The course of hepatocellular cancer associated with HDV was characterized by rapid progression of liver cirrhosis, development of portal hypertension, bleeding from varicose veins of the stomach and esophagus (36.4%) and edematous ascitic syndrome (63.6%). In addition to viral agents, additional risk factors for liver cancer were identified, such as alcohol abuse, overweight, diabetes mellitus, and smoking. Among the studied variation sites of genes localized on the X-chromosome and encoding the reaction of innate antiviral immunity, no genetic marker was found with a sufficient degree of confidence determining the likelihood of hepatocellular cancer developing. The high incidence of hepatocellular carcinoma of the male population in the RS (Y) is due to the widespread prevalence of parenteral viral hepatitis, especially viral hepatitis D. Due to the introduction of mass vaccination of the population against hepatitis B in the Russian Federation in the foreseeable future in the RS (Y) we should see a decrease in the proportion of hepatocellular cancer associated with hepatitis B and D viruses, and therefore the focus should be on the treatment and prevention of hepatitis C virus and non - infectious risk factors.

Alcoholic-related liver disease: pathogenesis, management and future therapeutic developments.

Alcohol-related liver disease (ALD) is the most frequent cause of advanced chronic liver disease worldwide. Excessive and prolonged alcohol use leads to ALD, which ranges from early forms such as alcoholic fatty liver (AFL) and alcoholic steatohepatitis (ASH), through progressive fibrosis to cirrhosis and the development of hepatocellular cancer (HCC). In addition, patients with underlying ALD and continuous alcohol use can develop alcoholic hepatitis (AH), which presents a rapid progression of liver failure and has a high short-term mortality. Genetic, environmental and epigenetic factors influence the progression of ALD to more severe forms. The pathogenesis of ALD is complex and involves multiple pathways. Recent translational studies have demonstrated a key role of the gut-liver axis and innate immunity in hepatocellular damage and fibrosis. In severe forms, hepatocellular de-differentiation and systemic inflammation contribute to liver failure and multiorgan failure. Alcohol abstinence is the cornerstone of therapy for ALD and the prevention of its complications, but the efficacy and accessibility of psycho-familial-social interventions is still poor and effective public health policies to limit problematic alcohol use need to be implemented. Prednisolone is the only current option for AH, with a transient beneficial effect over placebo. For patients with decompensated ALD-cirrhosis and/or development of HCC, liver transplantation (LT) may be required. In recent years, early LT is being increasingly offered to carefully selected AH patients, with excellent long-term survival. New trials of AH treatments are currently ongoing, and translational studies in human samples are paving the way to new promising targeted therapies.

Liver regeneration: solved and problem issues

It is known that liver is able to restore own dimensions and functional properties in response to various injuries. Despite extensive injuries, liver can preserve functional activity. Analysis of liver regeneration mechanisms allowed us to obtain significant results in the treatment of hepatitis, cirrhosis and liver failure. Liver regeneration processes substantiate the development of hepatocellular cancer following cirrhosis. Modern experimental and clinical data on liver regeneration, as well as current methods of stimulating this process are summarized in the manuscript. Despite significant advances in this issue, there are still many questions in scientific understanding of liver regeneration.

Hepatocellular carcinoma in alcoholic and non-alcoholic fatty liver disease-one of a kind or two different enemies?

Hepatocellular cancer (HCC) is a cancer with an overall poor prognosis and an alarming globally rising incidence. While viral etiology of chronic liver disease and HCC is down-trending, alcohol and excess calorie intake have emerged as major culprits. Alcohol related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) share similar pathogenetic mechanism of hepatic injury and in promoting development of HCC; yet some genetic and epigenetic features are distinct and may promise clinical utility. Population based intervention are urgently needed to reduce alcohol use and improve metabolic factors such as obesity and diabetes. The goal is to identify at-risk patients, to link these patients to care and to provide effective management of chronic liver disease and HCC. This review focuses on the epidemiology, pathophysiology including genetic and epigenetic altercation as well as clinical aspects of ALD and NAFLD associated HCC.

Survivin expression starts before hepatocellular cancer development in the liver of chronic hepatitis B patients: a pilot, cross-sectional study.

IntroductionSurvivin expression is well known feature of hepatocellular carcinoma (HCC); however, there is no information about survivin expression in chronic hepatitis B (CHB).AimInvestigating survivin expression in the liver of CHB patients.Material and methodsThis is a single-centre, cross-sectional study. Seventy-five CHB patients and eight control patients were enrolled into the study between 2008 and 2018. Immunohistochemical study was performed by using anti-survivin antibody to evaluate survivin immunoreactivity.ResultsSurvivin immunoreactivity was significantly higher in CHB patients compared to controls (p = 0.008). Also, the degree of survivin immunoreactivity was significantly higher in CHB patients (p = 0.027). Between the anti-survivin-positive and anti-survivin-negative groups, baseline laboratory parameters and initial pathology features were not significantly different.ConclusionsThis is the first study evaluating survivin expression in CHB patients. Understanding the possible relationship between survivin expression and HCC development in this population can promote new studies in terms of new therapies and treatment timing.

PERSPECTIVES OF INVESTIGATION OF ONCOLOGICAL ASPECTS OF INFECTION CAUSED WITH HEPATITIS C VIRUS

The paper is dedicated to several problems of study of infection caused with hepatitis C virus directly connected with modern theoretical and clinical oncology and professionally interesting from point of view of oncologists, hematologists and specialists in field of medical radiology. The author summarizes data which demonstrated the real existence of at the least main five oncological aspects of the infection. They present material reflected important significance some of these aspects for physician working in oncological units and researchers working in other fields of medicine. First oncological aspect of the infection is based on direct connection of these infection chronic forms with development of hepatocellular cancer of liver. It is interesting that hepatitis C virus today is not considered as a carcinogenic virus and its participation in hepatocarcinogenesis connected with some special mechanisms. Second oncological aspect of the infection is demonstrated with widely spreading this infection among oncological and especially among oncohematological patients staying in profile departments. Existence of this aspect has mainly epidemiologic significance and connected with prevention this infection in oncological units. Third oncological aspect of the infection is that spreading of HCV-infection at oncological patients has important clinical significance. This connected with ability of infection negatively influence to course and prognosis some type of cancer. Besides the infection can play a role of factor limiting possibilities of treatment of cancer patients. Fourth oncological aspect of this infection is that participation of this infection chronic form in some type of non-Hodgkin lymphomas development. Mechanisms of connection this infection with named lymphomas development is not identified. Finally, fifth oncological aspect of the infection consists the modern data demonstrated the statistic connection between the infection and in development of some widely spread non-hepatic malignant tumor. These data have important significance for modern oncology. The authors suggest that further systematic investigation of above mentioned aspects of above mentioned infection may positive influence to development of medical science in general.

Effect of diabetes mellitus on prognosis and development of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis

Aim: Hepatitis C virus (HCV) infection and diabetes mellitus (DM) negatively affect each other. HCV patients diagnosed with DM have more complications than patients with HCV infection alone. In this study, we aimed to investigate the effect of DM on complication rate, hepatocellular cancer (HCC) development and mortality in HCV RNA (+) cirrhosis patients. Material and Methods: Patients admitted with Hepatitis C-related cirrhosis and followed up for at Izmir Katip Celebi University Ataturk Training and Research Hospital Gastroenterology and Internal Medicine Clinic for at least six months between 2005and 2014 were retrospectively evaluated. Results: A total of 146 patients with HCV-related cirrhosis were included in the study. Of these patients, 53 (36.3%) had diagnosis of DM. In 108 patients who did not develop hepatocellular carcinoma (HCC), the mean CHILD score at final admission (p=0.024), difference between mean CHILD scores at final and initial admission (p=0.011), and annual rate of increase in CHILD score (p=0.047) was significantly higher in the DM group. There was no significant difference between the DM and non-DM groups according to both overall survival (p=0.115) and time of HCC development (p=0.567). Conclusion: While HCC development and overall survival were similar in both groups, in the subgroup of patients who did not develop HCC, the annual increase in CHILD score and final CHILD score were significantly higher in DM patients.

NASH and HCC Are Driven by Different Signaling Pathways with a Common Regulator

Oxidative stress is uniformly present in non-alcoholic steatohepatitis (NASH), but its role in the development of liver inflammation and hepatocellular cancer (HCC) and the relationship between these two pathologies arepoorly understood. In a recent issue of Cell, Grohmann etal. (2018) demonstrate a vital role of obesity-induced oxidative stress in deactivating the phosphatase TCPTP, resulting in activation of STAT-1 and STAT-3, which each independently drive the development of NASH and HCC, respectively.

LncRNA CRNDE promotes hepatocellular carcinoma cell proliferation, invasion, and migration through regulating miR-203/ BCAT1 axis.

To investigate the impact of long noncodingRNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) on hepatocellular cancer (HCC) cell propagation, invasion, and migration by mediating miR-203/ BCAT1 axis. Microarray analysis was based on 25 pairs of HCC cancerous tissues and adjacent tissues. The expression levels of CRNDE, miR-203, and BCAT1 in HCC tissues were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The liver cell line L-02 and HCC cell lines HepG2 and Huh-7 were utilized to assess the regulatory effects of CRNDE and miR-203 on HCC progression in vitro. Western blot was used to qualify BCAT1 protein expression level. Cell proliferation and apoptosis were evaluated using CCK-8 and flow cytometry analysis, whereas cell invasion and migration assay were performed by the Transwell assay. The relationship among CRNDE, miR-203, and BCAT1 was validated by dual luciferase assay. Tumor Xenograft study was established to verify the pathological effect of CRNDE on HCC development in vivo. The expression levels of the CRNDE and BCAT1 were upregulated in HCC tissues and cells, whereas miR-203 was downregulated in HCC. Knockdown of CRNDE or miR-203 overexpression would inhibit HCC cell propagation and metastasis, and induced cell apoptosis. Moreover, miR-203 was negatively correlated with CRNDE, the same as miR-203 with BCAT1. Dual luciferase assay showed that miR-203 was an inhibitory target of CRNDE, and BCAT1 was directly targeted by miR-203 as well. LncRNA CRNDE could enhance HCC tumorgenesis by sponging miR-203 and mediating BCAT1. LncRNA CRNDE might facilitate HCC cell propagation, invasiveness, and migration through regulating miR-203/ BCAT1 axis.

Expression of Miscellaneous Genes Upregulated in Hepatocellular Carcinoma in Patients with Alcoholic (ASH) and Non‐alcoholic Steatohepatitis (NASH)

Both non‐alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) can lead to cirrhosis and hepatocellular carcinoma. However, the rate of progression to cirrhosis and tumorigenesis in ASH is greater than that in NASH. We asked whether there are differences between the two conditions in the expression levels of proteins involved in the pathogenesis of hepatocellular carcinoma. The proteins tested were presented at the 2017 AASLD Liver Meeting as overexpressed in hepatocellular carcinoma: KLF4, SCL19A1, FANCG, HRH‐1, DNMT1, DNMT3B, TNFR2, DUSP4, EGFR, Integrin, HDACII, and PDE3A. The expression of these proteins was measured in liver biopsy sections from NASH, ASH and normal patients using immunohistochemical staining with fluorescent antibodies and then quantifying the fluorescence intensity morphometrically. In ASH patients, levels of all tested proteins except HRH‐1 were elevated compared to normal patients. In NASH patients, KLF4, SCL19A1, FANCG, DNMT1, DNMT3B, and HDACII levels were increased compared to normal controls while HRH‐1 and PDE3A levels were decreased. The relative expression of all proteins studied except DNMT‐1 was higher in ASH compared to NASH. In conclusion, proteins involved in hepatocellular cancer development are more highly expressed in ASH compared to NASH and normal liver, which corresponds with the higher rate of tumorigenesis in ASH patients compared to NASH patients.Support or Funding InformationThis study was funded by NIH/AAA grant # UO‐21898‐05This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Expression of proteins upregulated in hepatocellular carcinoma in patients with alcoholic hepatitis (AH) compared to non-alcoholic steatohepatitis (NASH): An immunohistochemical analysis of candidate proteins

Both non-alcoholic steatohepatitis (NASH) and alcoholic hepatitis (AH) can lead to cirrhosis and hepatocellular carcinoma. However, the rate of progression to cirrhosis and tumorigenesis in AH is greater than that in NASH. We asked whether there are differences between the two conditions in the expression levels of proteins involved in the pathogenesis of hepatocellular carcinoma. The proteins tested were presented at the 2017 American Association for the Study of Liver Diseases (AASLD) Liver Meeting as overexpressed in hepatocellular carcinoma: KLF4, SCL19A1, FANCG, HRH-1, DNMT1, DNMT3B, TNFR2, DUSP4, EGFR, Integrin α6, HDACII, PDE3A, BCL-XL, and MTCO2. The expression of these proteins was measured in liver biopsy sections from NASH and AH patients using immunohistochemical staining with fluorescent antibodies and then quantifying the fluorescence intensity morphometrically. In AH patients, levels of all tested proteins except HRH-1 were elevated compared to normal patients. In NASH patients, KLF4, SCL19A1, FANCG, HDACII, BCL-XL levels were increased compared to normal controls while HRH-1, DNMT1 and PDE3A levels were decreased. The relative expression of all proteins studied except BCL-XL was significantly higher in AH compared to NASH. In conclusion, proteins involved in hepatocellular cancer development are more highly expressed in AH compared to NASH and normal liver, which corresponds with the higher rate of tumorigenesis in AH patients compared to NASH patients.

Does TIPS reduce the risk for HCC development in liver cirrhosis patients?

Liver cirrhosis favors portal hypertension which causes complications like variceal bleeding, therapy-refractory ascites, and hepatorenal syndrome. Transjugular intrahepatic portosystemic shunt (TIPS) is used for the treatment of portal hypertension. However, parenchymal portal venous flow after TIPS insertion is reduced. TIPS therefore might induce ischemic liver injury which has been discussed to favor hepatocarcinogenesis resulting in the development of hepatocellular cancer (HCC).