LncRNA-ATB promotes autophagy by activating Yes-associated protein and inducing autophagy-related protein 5 expression in hepatocellular carcinoma

BACKGROUND Long non-coding RNAs (lncRNAs) play important roles in many diseases, including hepatocellular carcinoma (HCC). Autophagy is a metabolic pathway that facilitates cancer cell survival in response to stress. The relationship between autophagy and the lncRNA-activated by transforming growth factor beta (lncRNA-ATB) in HCC remains unknown. AIM To explore the influence of lncRNA-ATB in regulating autophagy in HCC cells and the underlying mechanism. METHODS In the present study, we evaluated lncRNA-ATB expression in tumor and adjacent non-tumor tissues from 72 HCC cases by real-time PCR. We evaluated the role of lncRNA-ATB in the proliferation and clonogenicity of HCC cells in vitro. The effect of lncRNA-ATB on autophagy was determined using a LC3-GFP reporter and transmission electron microscopy. Furthermore, the mechanism by which lncRNA-ATB regulates autophagy was explored by immunofluorescence staining, RNA immunoprecipitation (RIP), and Western blot. RESULTS The expression of lncRNA-ATB was higher in HCC tissues than in normal liver tissues, and lncRNA-ATB expression was positively correlated with tumor size, TNM stage, and poorer survival of patients with HCC. Moreover, ectopic overexpression of lncRNA-ATB promoted cell proliferation and clonogenicnity of HCC cells in vitro. LncRNA-ATB promoted autophagy by activating Yesassociated protein (YAP). Moreover, lncRNA-ATB interacted with autophagy-related protein 5 (ATG5) mRNA and increased ATG5 expression. CONCLUSION LncRNA-ATB regulates autophagy by activating YAP and increasing ATG5 expression. Our data demonstrate a novel function for lncRNA-ATB in autophagy and suggest that lncRNA-ATB plays an important role in HCC.

Significance of tumor-infiltrating immunocytes for predicting prognosis of hepatitis B virus-related hepatocellular carcinoma

BACKGROUND Hepatitis B virus (HBV) has been recognized as a leading cause of hepatocellular carcinoma (HCC). Numerous reports suggest that immune infiltration can predict the prognosis of HCC. Nonetheless, no creditable markers for prognosis of HBV-related HCC have been established by systematically assessing the immune-related markers based on tumor transcriptomes. AIM To establish an immune-related marker based on the cell compositions of immune infiltrate obtained based on tumor transcriptomes, so as to enhance the prediction accuracy of HBV-related HCC prognosis. METHODS RNA expression patterns as well as the relevant clinical data of HCC patients were obtained from The Cancer Genome Atlas. Twenty-two immunocyte fraction types were estimated by cell type identification by estimating relative subsets of RNA transcripts. Subsequently, the least absolute shrinkage and selection operator (LASSO) Cox regression model was employed to construct an immunoscore based on the immunocyte fraction types. Afterwards, the receiver operating characteristic (ROC) curve, Kaplan-Meier, and multivariate Cox analyses were performed. Additionally, a nomogram for prognosis that integrated the immunoscore as well as the clinical features was established. Meanwhile, the correlation of immunoscore with immune genes was also detected, and gene set enrichment analysis (GSEA) of the immunoscore was conducted. RESULTS A total of 22 immunocyte fraction types were predicted and compared among the tumor as well as non-tumor samples. An immunoscore was constructed through adopting the LASSO model, which contained eight immunocyte fraction types. Meanwhile, the areas under the ROC curves for the immunoscore biomarker prognostic model were 0.971, 0.912, and 0.975 for 1-, 3-, and 5-year overall survival (OS), respectively. Difference in OS between the high-immunoscore group and the low-immunoscore group was statistically significant [hazard ratio (HR)= 66.007, 95% confidence interval (CI): 8.361-521.105;P < 0.0001]. Moreover, multivariable analysis showed that the immunoscore was an independent factor for predicting the prognosis (HR = 2.997, 95%CI: 1.737-5.170). A nomogram was established, and the C-index was 0.757 (95%CI: 0.648-0.866). The immunoscore showed a significant negative correlation with the expression of PD-1 (P = 0.024), PD-L1 (P = 0.026), PD-L2 (P = 0.029), and CD27 (P = 0.033). Eight pathways were confirmed by GSEA. CONCLUSION The established immunoscore can potentially serve as a candidate marker to estimate the OS for HBV-related HCC cases.

Health-related quality of life evaluated by tumor node metastasis staging system in patients with hepatocellular carcinoma

AIM: To investigate and evaluate the change in healthrelated quality of life (HRQoL) by tumor node metastasis (TNM) staging system in patients with hepatocellular carcinoma (HCC). METHODS: A total of 140 patients diagnosed with HCC between June 2008 and April 2009 in our department were enrolled to this study. One hundred and thirty-five (96.5%) patients had liver cirrhosis secondary to hepatitis B virus (HBV) infection, 73 (54.07%) of them being HBV DNA positive; the other etiologies of liver cirrhosis were alcoholic liver disease (1.4%), hepatitis C (1.4%) or cryptogenic (0.7%). All subjects were fully aware of their diagnosis and provided informed consent. HRQoL was assessed before treatment using the functional assessment of cancer therapy-hepatobiliary (FACT-Hep) questionnaire. Descriptive statistics were used to evaluate demographics and disease-specific characteristics of the patients. One-way analysis of variance and independent samples t tests were used to compare the overall FACT-Hep scores and clinically distinct TNM stages. Scores for all FACT-Hep items were analyzed by frequency analyses. The mean scores obtained from the FACT-Hep in different Child-Pugh classes were also evaluated. RESULTS: The mean FACT-Hep scores were reduced significantly from TNM StageⅠto Stage Ⅱ, Stage ⅢA, Stage ⅢB group (687 ± 39.69 vs 547 ± 42.57 vs 387 ± 51.24 vs 177 ± 71.44, P = 0.001). Regarding the physical and emotional well-being subscales, scores decreased gradually from Stage Ⅰ to Stage ⅢB (P = 0.002 vs Stage Ⅰ; P = 0.032 vs Stage Ⅱ; P = 0.033 vs Stage ⅢA). Mean FACT-Hep scores varied by Child-Pugh class, especially in the subscales of physical well-being, functional well-being and the hepatobiliary cancer (P = 0.001 vs Stage I; P = 0.036 vs Stage Ⅱ; P = 0.032 vs Stage ⅢA). For the social and family well-being subscale, only Stage ⅢB scores were significantly lower as compared with Stage Ⅰ scores (P = 0.035). For the subscales of functional well-being and hepatobiliary cancer, there were significant differences for Stages ⅡΙ, ⅢA and ⅢB (P = 0.002vs StageⅠ). CONCLUSION: HRQoL of patients with HCC worsens gradually with progression of TNM stages. The most impaired subscales of HRQoL, as measured by FACT-Hep, were physical and emotional well-being.

Multistep hepatocarcinogenesis from a dysplastic nodule to well-differentiated hepatocellular carcinoma in a patient with alcohol-related liver cirrhosis

We describe a rare case of the transformation of a dysplastic nodule into well-differentiated hepato- cellular carcinoma (HCC) in a 56-year-old man with alcoholrelated liver cirrhosis. Ultrasound (US) disclosed a 10 mm hypoechoic nodule and contrast enhanced US revealed a hypovascular nodule, both in segment seven. US-guided biopsy revealed a high-grade dysplastic nodule characterized by enhanced cellularity with a high N/C ratio, increased cytoplasmic eosinophilia, and slight cell atypia. One year later, the US pattern of the nodule changed from hypoechoic to hyperechoic without any change in size or hypovascularity. US-guided biopsy revealed well-differentiated HCC of the same features as shown in the first biopsy, but with additional pseudoglandular formation and moderate cell atypia. Moreover, immunohistochemical staining of cyclase- associated protein 2, a new molecular marker of well- differentiated HCC, turned positive. This is the first case of multistep hepatocarcinogenesis from a dysplastic nodule to well-differentiated HCC within one year in alcohol-related liver cirrhosis.

Autophagy related protein 9A increase in hepatitis B virusassociated hepatocellular carcinoma and the role in apoptosis

The majority of hepatocellular carcinoma(HCC)cases are associated with the hepatitis B virus(HBV)infection.Autophagy related protein 9A(ATG9A)is a transmembrane protein required for autophagosome formation.In order to investigate the role of ATG9A in HBV-associated HCC,ATG9A protein expression was determined in tumor liver tissues and compared with adjacent nontumor tissues from HCC patients with or without HBV infection.In HBVassociated HCC tissues,ATG9A protein level was increased in tumor liver tissues,but not in cases of non-HBV HCC.Our findings suggested that ATG9A might be involved in HBV and cancer cell survival.Therefore,we aimed to analyze the function of ATG9A in HBV replication using RNA interference to evaluate the HBV DNA level using real-time PCR.In the present study,there were no significant differences between shATG9A-transfected HepG2.2.15 cells and the mock control.However,we found that silencing ATG9A affected apoptosis in HepG2.2.15 and HepG2 cell lines.Our results indicated that ATG9A might be partly involved in the survival of HCC.Thus,the inhibition of ATG9A together with other targets might be a potential drug target for HCC treatment.

Clinical significance of serum sB7-H3 and IL-1 in patients with hepatitis B related hepatocellular carcinoma

Objective: To explore the clinical significance of serum sB7-H3 and IL-1 in patients with hepatitis B associated hepatocellular carcinoma. Methods: 122 cases of patients with hepatitis B related liver diseases admitted to our hospital from January 2015 to June 2018 were selected, including 47 cases of patients with hepatitis B related hepatocellular carcinoma, 41 cases of patients with hepatitis B related cirrhosis and 34 cases of patients with hepatitis B virus, and 45 cases of healthy persons in the same period as normal control group. The serum sB7-H3, IL-1α, IL-1β levels were compared among the four groups. The relationship between serum sB7-H3, IL-1α, IL-1β and clinicopathological characteristics was analyzed, and the correlation of sB7-H3, IL-1α and IL-1β was analyzed by Pearson method. The efficacy of serum sB7-H3, IL-1α, IL-1β in early diagnosis and prognostic evaluation for hepatitis B associated hepatocellular carcinoma were analyzed by ROC and Logistic regression analysis. Results: The serum sB7-H3, IL-1α, IL-1β levels in the four groups were in order from high to low: hepatitis B related hepatocellular carcinoma>hepatitis B related cirrhosis>hepatitis B virus>normal control group, all above had statistical difference (P<0.05). The high levels of serum sB7-H3, IL-1α, IL-1β were significantly correlated with TNM stage, alpha fetoprotein level and lymph node metastasis (P<0.05). Spearman correlation analysis results showed that the serum level of sB7-H3 was positively correlated with IL-1α and IL-1β(r=0.837, 0.756;P<0.05), the serum level of IL-1α was positively correlated with IL-1β(r=0.734, P<0.05). The ROC curve and Logistic regression analysis showed that the AUC of sB7-H3, IL-1α, IL-1β and combined detection for the diagnosis of hepatitis B associated hepatocellular carcinoma was 0.893, 0.887, 0.881, 0.961 (P<0.05), respectively;the AUC of sB7-H3, IL-1α, IL-1β and combined detection for the prognostic evaluation for hepatitis B associated hepatocellular carcinoma was 0.843, 0.837, 0.834, 0.917, respectively. Conclusion:Serum sB7-H3, IL-1α, IL-1β levels could all be used for the early diagnosis and prognostic evaluation of hepatitis B associated hepatocellular carcinoma, and the combined detection is more effective, which has important clinical significance.

Promoter polymorphism of MRP1 associated with reduced survival in hepatocellular carcinoma

AIM:To investigate the effect of the G-1666A polymorphism in the multidrug resistance related protein-1 (MRP1) on outcome of hepatocellular carcinoma (HCC). METHODS:A cohort of 162 patients with surgically resected HCC who received no postsurgical treatment until relapse was studied. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. Electrophoretic mobility shift assay (EMSA) was used to evaluate the influence of the G-1666A polymorphism on the binding affinity of the MRP1 promoter with its putative transcription factors. RESULTS:Kaplan-Meier analysis showed that patients with GG homologues had a reduced 4-year disease-free survival compared with those carrying at least one A allele (P = 0.011). Multivariate Cox regression analysis indicated that the-1666GG genotype represented an independent predictor of poorer disease-free survival [hazard ratio (HR) = 3.067,95% confidence interval (CI):1.587-5.952,P = 0.001],and this trend became worse in men (HR = 3.154,95% CI:1.604-6.201,P = 0.001). A similar association was also observed between 4-year overall survival and the polymorphism in men (HR = 3.342,95% CI:1.474-7.576,P = 0.004). Moreover,EMSA suggested that the G allele had a stronger binding affinity to nuclear proteins. CONCLUSION:The MRP1-1666GG genotype predicted a worse outcome and was an independent predictor of poor survival in patients with HCC from Southeast China.

Construction of a risk score prognosis model based on hepatocellular carcinoma microenvironment

BACKGROUND Hepatocellular carcinoma(HCC)is a common cancer with a poor prognosis.Previous studies revealed that the tumor microenvironment(TME)plays an important role in HCC progression,recurrence,and metastasis,leading to poor prognosis.However,the effects of genes involved in TME on the prognosis of HCC patients remain unclear.Here,we investigated the HCC microenvironment to identify prognostic genes for HCC.AIM To identify a robust gene signature associated with the HCC microenvironment to improve prognosis prediction of HCC.METHODS We computed the immune/stromal scores of HCC patients obtained from The Cancer Genome Atlas based on the ESTIMATE algorithm.Additionally,a risk score model was established based on Differentially Expressed Genes(DEGs)between high and lowimmune/stromal score patients.RESULTS The risk score model consisting of eight genes was constructed and validated in the HCC patients.The patients were divided into high-or low-risk groups.The genes(Disabled homolog 2,Musculin,C-X-C motif chemokine ligand 8,Galectin 3,B-cell-activating transcription factor,Killer cell lectin like receptor B1,Endoglin and adenomatosis polyposis coli tumor suppressor)involved in our risk score model were considered to be potential immunotherapy targets,and they may provide better performance in combination.Functional enrichment analysis showed that the immune response and T cell receptor signaling pathway represented the major function and pathway,respectively,related to the immune-related genes in the DEGs between high-and low-risk groups.The receiver operating characteristic(ROC)curve analysis confirmed the good potency of the risk score prognostic model.Moreover,we validated the risk score model using the International Cancer Genome Consortium and the Gene Expression Omnibus database.A nomogram was established to predict the overall survival of HCC patients.CONCLUSION The risk score model and the nomogram will benefit HCC patients through personalized immunotherapy.

Overexpression of DNA methyltransferase 1 and its biological significance in primary hepatocellular carcinoma

AIM:To explore the relationship between DNA methyltransferase 1 (DNMT1) and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and its biological significance in primary HCC.METHODS: We carried out an immunohistochemical examination of DNMT1 in both HCC and paired non-neoplastic liver tissues from Chinese subjects. DNMT1 mRNA was further examined in HCC cell lines by real-time PCR. We inhibited DNMT1 using siRNA and detected the effect of depletion of DNMT1 on cell proliferation ability and cell apoptosis in the HCC cell line SMMC-7721.RESULTS: DNMT1 protein expression was increased in HCCs compared to histologically normal non-neoplastic liver tissues and the incidence of DNMT1 immunoreactivity in HCCs correlated signifi cantly with poor tumor differentiation (P=0.014). There were more cases with DNMT1 overexpression in HCC with HBV (42.85%) than in HCC without HBV (28.57%). However, no signif icant difference in DNMT1 expression was found in HBV-positive and HBV-negative cases in the Chinese HCC group. There was a trend that DNMT1 RNA expression increased more in HCC cell lines than in pericarcinoma cell lines and normal liver cell lines. In addition, we inhibited DNMT1 using siRNA in the SMMC-7721 HCC cell line and found depletion of DNMT1 suppressed cells growth independent of expression of proliferating cell nuclear antigen (PCNA), even in HCC cell lines where DNMT1 was stably decreased.CONCLUSION: The f indings implied that DNMT1 plays a key role in HBV-related hepatocellular tumorigenesis. Depletion of DNMT1 mediates growth suppression in SMMC-7721 cells.

Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)represents a global health problem.Infections with hepatitis B or C virus,non-alcoholic steatohepatitis disease,alcohol abuse,or dietary exposure to aflatoxin are the major risk factors to the development of this tumor.Regardless of the carcinogenic insult,HCC usually develops in a context of cirrhosis due to chronic inflammation and advanced fibrosis.Galectins are a family of evolutionarily-conserved proteins defined by at least one carbohydrate recognition domain with affinity forβ-galactosides and conserved sequence motifs.Here,we summarize the current literature implicating galectins in the pathogenesis of HCC.Expression of"proto-type"galectin-1,"chimera-type"galectin-3 and"tandem repeat-type"galectin-4 is up-regulated in HCC cells compared to their normal counterparts.On the other hand,the"tandemrepeat-type"lectins galectin-8 and galectin-9 are downregulated in tumor hepatocytes.The abnormal expression of these galectins correlates with tumor growth,HCC cell migration and invasion,tumor aggressiveness,metastasis,postoperative recurrence and poor prognosis.Moreover,these galectins have important roles in other pathological conditions of the liver,where chronic inflammation and/or fibrosis take place.Galectin-based therapies have been proposed to attenuate liver pathologies.Further functional studies are required to delineate the precise molecular mechanisms through which galectins contribute to HCC.

Liver expression of Nrf2-related genes in different liver diseases

BACKGROUND： The KEAP1-Nrf2 antioxidant signaling pathway is important in protecting liver from various insults. However,little is known about the expression of Nrf2-related genes in human liver in different diseases.METHODS： This study utilized normal donor liver tissues（n=35）, samples from patients with hepatocellular carcinoma（HCC, n=24）, HBV-related cirrhosis（n=27）, alcoholic cirrhosis（n=5） and end-stage liver disease（n=13）. All of the liver tissues were from the Oriental Liver Transplant Center, Beijing,China. The expressions of Nrf2 and Nrf2-related genes, including its negative regulator Kelch-like ECH-associated protein 1（KEAP1）, its targeted gene NAD（P）H-quinone oxidoreductase 1（NQO1）, glutamate-cysteine ligase catalytic subunit（GCLC） and modified subunit（GCLM）, heme oxygenase 1（HO-1） and peroxiredoxin-1（PRDX1） were evaluated. RESULTS： The expression of Nrf2 was decreased in HCC, increased in alcoholic cirrhosis and end-stage liver disease. The expression of KEAP1 was increased in all of the liver samples.The most notable finding was the increased expression of NQO1 in HCC（18-fold）, alcoholic cirrhosis（6-fold）, endstage liver disease（5-fold） and HBV-related cirrhosis（3-fold）.Peri-HCC also had 4-fold higher NQO1 m RNA as compared to the normal livers. GCLC m RNA levels were lower only in HCC, as compared to the normal livers and peri-HCC tissues.GCLM m RNA levels were higher in HBV-related cirrhosis and end-stage liver disease. HO-1 m RNA levels were increased in all liver tissues except for HCC. Peri-HCC had higher PRDX1 m RNA levels compared with HCC and normal livers.CONCLUSION： Nrf2 and Nrf2-related genes are aberrantly expressed in the liver in different diseases and the increase of NQO1 was the most notable finding, especially in HCC.

Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis

AIM To investigate gender-specific liver estrogen receptor(ER) expression in normal subjects and patients with hepatitis C virus(HCV)-related cirrhosis and hepatocellular carcinoma(HCC).METHODS Liver tissues from normal donors and patients diagnosed with HCV-related cirrhosis and HCV-related HCC were obtained from the NIH Liver Tissue and Cell Distribution System. The expression of ER subtypes, ERα and ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERα and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression ofinflammatory [activated NF-κB and IκB-kinase(IKK)] and oncogenic(cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERα and ERβ was correlated with the expression of activated NF-κB, activated IKK and cyclin D1 by Spearman's correlation. RESULTS Both ER subtypes were expressed in normal livers but male livers showed significantly higher expression of ERα than females(P < 0.05). We observed significantly higher m RNA expression of ERα in HCV-related HCC liver tissues as compared to normals(P < 0.05) and ERβ in livers of HCV-related cirrhosis and HCV-related HCC subjects(P < 0.05). At the protein level, there was a significantly higher expression of nuclear ERα in livers of HCV-related HCC patients and nuclear ERβ in HCV-related cirrhosis patients as compared to normals(P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF-κB and cyclin D1 in diseased livers(P < 0.05). There was a positive correlation between the expression of nuclear ER subtypes and nuclear cyclin D1 and a negative correlation between cytoplasmic ER subtypes and cytoplasmic phosphorylated IKK in HCV-related HCC livers. These findings suggest that dysregulated expression of ER subtypes following chronic HCVinfection may contribute to the progression of HCVrelated cirrhosis to HCV-related HCC.CONCLUSION Gender differences were observed in ERα expression in normal livers. Alterations in ER subtype expression observed in diseased livers may influence genderrelated disparity in HCV-related pathogenesis.

Metabonomic window into hepatitis B virus-related hepatic diseases

Metabonomics has recently been widely used todiscover the pathogenesis and find potential metabolic markers with high sensitivity and specificity. Furthermore, it develops new diagnosis and treatment methods, increases early phase diagnosis rates of certain diseases and provides a new basis for targeted therapy. This review mainly analyzes the research progress of the metabonomics of hepatitis B virus(HBV)-related hepatic diseases, hoping to discover some potential metabolic markers for identification of HBVrelated hepatic diseases from other etiologies and for HBV-related hepatitis, liver cirrhosis and hepatocellular carcinoma. This can contribute to early discovery, diagnosis and treatment, eventually increasing the survival rate of HBV-related hepatic diseases.

Comparison of Milan and UCSF criteria for liver transplantation to treat hepatocellular carcinoma

AIM:To assess the validity of the Milan and University of California San Francisco(UCSF) criteria and examine the long-term outcome of orthotopic liver transplantation(OLT) in patients with hepatocellular carcinoma(HCC) in a single-center study.METHODS:This study is a retrospective review of prospectively collected data.Between 1998 and 2009,56 of 356 OLTs were performed in patients with HCC.Based on pathological examination of liver explants,patients were retrospectively categorized into 3 groups:Milan +(n = 34),Milan-/UCSF +(n = 7) and UCSF-(n = 14).RESULTS:Median follow-up period was 39.5(1-124) mo.The 5-year overall survival rates in the Milan +,Milan-/UCSF + and UCSF-groups were 87.7%,53.6% and 33.3%,respectively(P < 0.000).Within these groups,tumor recurrence was determined in 5.8%,14.3% and 40% of patients,respectively(P < 0.011).Additionally,the presence of microvascular invasion within the explanted liver had a negative effect on the 5-year disease free survival(74.7% vs 46.7%,P < 0.044).CONCLUSION:The Milan criteria are reliable in the selection of suitable candidates for OLT for the treatment of HCC.For cases of OLT involving living donors,the UCSF criteria may be applied.

TRAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies

AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resistance in hepatocellular carcinoma(HCC)and to study the efficacy of agonistic TRAIL antibodies,as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis. METHODS:Surface expression of TRAIL receptors (TRAIL-R1-4)and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting,respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs.HCC cellswere treated with kinase inhibitors and chemotherapeutic drugs.Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS:TRAIL-R1 and-R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However,treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates.Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002[inhibition of phosphoinositol- 3-kinase(PI3K)],AG1478(epidermal growth factor receptor kinase),PD98059(MEK1),rapamycin(mam- malian target of rapamycin)and the multi-kinase inhibitor Sorafenib.Furthermore,the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance:knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells.Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION:Our data identify the blockage of survival kinases,combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC.

Rising costs and hospital admissions for hepatocellular carcinoma in Portugal(1993-2005)

AIM:To determine,for hepatocellular carcinoma(HCC),the patient demographic profile and costs of their admissions to the hospitals of the Portuguese National Health System from 1993 to 2005.METHODS:The National Registry(ICD-9CM,Inter-national Classification of Diseases,155.0)provided data from the 97 Hospitals in Portugal.RESULTS:We studied 7932 admissions that progres-sively rose from 292 in 1993 to 834 in 2005,having a male predominance of 78%(6130/7932).The global rate of hospital admissions for HCC rose from 3.1/105 in 1993 to 8.3/105 in 2005.The average length of stay decreased from 17.5 ± 17.9 d in 1993 to 9.3 ± 10.4 d in 2005,P < 0.001.The average hospital mortality for HCC remained high over these years,22.3% in 1993 and 26.7% in 2005.Nationally,hospital costs(in Euros-€)rose in all variables studied:overall costs from €533 000 in 1993,to €4 629 000 in 2005,cost per day of stay from €105 in 1993,to €597 in 2005,average cost of each admission from €1828 in 1993,to €5550 in 2005.In 2005,1.8%(15/834)of hospital admissions for HCC were related to liver transplant,and responsible for a cost of about €1.5 million,corresponding to one third of the overall costs for HCC admissions in that same year.CONCLUSION:From 1993 to 2005 hospital admissions in Portugal for HCC tripled.Overall costs for these admissions increased 9 times,with all variables related to cost analysis rising accordingly.Liver transplant,indicated in a small group of patients,showed a disproportionate increase in costs.

肝细胞癌预后相关的炎症反应关键基因的筛选及其预后价值

目的:筛选与肝细胞癌(hepatocellular carcinoma,HCC)预后密切相关的炎症反应关键基因,构建预后风险评分模型,并评估该模型在HCC中的预后价值。方法:从TCGA数据库获取HCC患者肝肿瘤组织及正常肝组织的mRNA表达数据作为训练集,从GEO数据库中获取HCC患者的mRNA表达数据作为验证集。筛选出与HCC预后相关的炎症反应相关基因,运用LASSO回归和随机生存森林(RSF)方法筛选与HCC预后相关的炎症反应关键基因。基于这些关键基因构建预后风险评分模型并验证,应用Cox比例风险回归评估该模型对患者预后的影响。构建列线图并进行一致性分析。结果:共筛选出15个与HCC预后相关的炎症反应基因,经LASSO回归和RSF分析,确定11个炎症反应关键基因,即IL18RAP、MEP1A、RIPK2、CYBB、SLC7A1、ADM、IL7R、P2RX4、ACVR2A、SERPINE1、SLC7A2。构建的预后风险评分模型在训练集和验证集上预测1、3、5年生存率,AUC值均超过0.60;Kaplan-Meier分析显示高风险组总生存期(OS)显著低于低风险组(P<0.01);PCA和t-SNE分析显示该模型能有效区分高、低风险患者。Cox回归分析提示预后风险评分是独立的预后因素,且与OS显著相关(P<0.01)。列线图模型C-index为0.672,具有较高的预测精度,1年和3年校准曲线与标准曲线吻合度好,5年吻合度稍弱。结论:本研究成功构建并验证了一个基于炎症反应相关基因的风险评分模型,筛选出的11个炎症反应关键基因(IL18RAP、MEP1A、RIPK2、CYBB、SLC7A1、ADM、IL7R、P2RX4、ACVR2A、SERPINE1、SLC7A2)与HCC进展密切相关,且在模型中显示出较强的预后预测能力。

计算机断层扫描引导下微波消融治疗乙型肝炎相关肝细胞癌肺寡转移瘤的临床应用

目的:评估前靶免治疗时代,乙肝相关肝癌合并肺转移瘤患者行微波消融治疗疗效、安全性和应用价值。方法:收集2010年11月至2014年12月在我院诊断为乙肝相关肝癌合并肺转移瘤行微波消融术患者30例,其中男24例,女6例;年龄35~74岁,经胸部CT发现肺部67个转移瘤,共消融67个病灶。肿瘤直径为0.5~4.1cm,平均直径为1.37cm。采用Kaplan-Meier法计算局部肿瘤控制率、中位生存期并观察并发症发生情况。结果:对67个肝癌肺转移瘤成功地进行了46次微波消融治疗。消融后1~3个月,肺部增强CT提示靶病灶区未见强化,肿瘤的完全消融率为100%,中位生存期为27.5个月,主要并发症包括局部疼痛(6例)、阵咳(13例)、少量咳血(3例),有10例患者发生少量气胸,未予特殊处理,有3例患者发生中等量至大量气胸,即刻行胸腔闭式引流。结论:CT引导下微波消融治疗乙肝相关肝癌肺转移瘤,安全有效,是晚期肝癌患者局部治疗的重要手段。

免疫检查点抑制剂对肝细胞癌患者甲状腺功能影响的研究进展

免疫检查点抑制剂(ICIs)给中晚期肝细胞癌(HCC)患者带来了生存希望,但通常伴随着免疫相关不良反应(irAEs)的发生。甲状腺功能障碍(TD)是最常见的ICIs内分泌相关不良反应,而HCC患者常合并有肝硬化等基础肝病,也可出现TD,二者可同时发生在同一患者中,互为促进,从而加重疾病进展。研究就ICIs对HCC患者甲状腺功能影响的研究进展进行综述,总结现有可能的发病机制、临床管理、预测生物标志物以及对HCC患者预后的影响。从而提高临床医师对甲状腺irAEs的认知,掌握发生甲状腺irAEs的HCC患者的治疗特点,早期监测、治疗后随访,减轻irAEs给癌症患者带来的影响。

免疫治疗相关性甲状腺功能异常与不可切除/晚期肝细胞癌患者预后改善相关

目的:探讨免疫治疗相关性甲状腺功能异常与不可切除/晚期肝细胞癌(HCC)患者预后改善的相关性。方法:回顾性分析45例接受免疫检查点抑制剂(ICIs)治疗的不可切除/晚期HCC患者。根据ICIs治疗过程中是否出现免疫相关性甲状腺功能异常分为甲状腺功能正常组(28例)和异常组(17例),比较2组患者的预后和免疫应答情况,主要终点指标为中位总生存期(OS)、无进展生存期(PFS),次要终点指标为疾病控制率(DCR)。结果:所有患者的中位OS、PFS分别为10.8个月(95%CI:3.0~18.6)和5.0个月(95%CI:3.0~12.2)。正常组中位OS为5.8个月(95%CI:3.7~7.9),异常组中位OS尚未达到(P=0.026)。异常组中位PFS长于正常组(8.2个月vs.3.1个月,P=0.011),DCR高于正常组(52.9%vs.21.5%,P=0.030)。多因素Cox回归分析显示,甲状腺功能异常是达到6个月OS(HR=0.213,95%CI:0.048~0.944,P=0.042)和PFS(HR=0.383,95%CI:0.151~0.967,P=0.042)的独立影响因素;甲状腺功能异常(HR=0.403,95%CI:0.185~0.877,P=0.022)、基线无大血管侵犯(MVI)(HR=2.848,95%CI:1.406~5.768,P=0.004)、Child-Pugh A级(HR=2.404,95%:1.099~5.255,P=0.028)与12个月PFS相关。结论:免疫治疗相关性甲状腺功能异常的不可切除/晚期HCC患者预期生存和免疫应答效果更佳。治疗期间出现甲状腺功能异常、基线无MVI、Child-Pugh A级与患者预后改善相关。