Related Hepatocellular Carcinoma Research Articles

Postoperative direct-acting antiviral treatment after liver resection in patients with hepatitis C virus-related hepatocellular carcinoma.

We investigated effects of direct-acting antiviral (DAA)-induced sustained virological response (SVR) after liver resection in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) for postoperative recurrence and survival. Surgical outcomes in 18 patients with postoperative DAA-induced SVR (HCC-DAA group) were compared with those in 23 patients with preoperative DAA-induced SVR (DAA-HCC group) and those in 10 patients who did not receive DAA therapy (control group). Patients who received DAA therapy >1year after surgery and those with recurrence <1year after surgery were excluded. Serum concentrations of aminotransferases improved 1year after surgery in both the HCC-DAA and DAA-HCC groups. The number of HCC-DAA patients with albumin-bilirubin (ALBI) grade 1 increased from 11 to 15. The disease-free survival rate did not differ between HCC-DAA group (3years, 60%) and the other two groups (DAA-HCC group, 92% and control group, 60%). The 3-year overall survival rates were better in the DAA-HCC group (84%) and HCC-DAA group (100%) than in the control group (46%; all ps<0.05 according to Holm's test). Multivariable analysis revealed that tumor stage was an independent risk factor for postoperative recurrence, and ALBI grade at 1year after surgery was predictive of postoperative survival, but DAA-induced SVR was neither. Although postoperative DAA-induced SVR itself may not suppress postoperative recurrence, improvement in liver function as a result of DAA administration after surgery may prolong postoperative survival.

Antiviral Therapy Improves Survival in Hepatocellular Carcinoma with Microvascular Invasion: A Propensity Score Analysis.

To investigate the effect of postoperative adjuvant antiviral therapy (AVT) on hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) with microvascular invasion (MVI) after R0 liver resection. A total of 1008 patients with HBV-related HCC with MVI were recruited, which comprises 378 non-AVT groups and 630 AVT groups. Propensity score matching (PSM) was developed to reduce any bias in patient selection. Independent risk factors were identified by Cox regression analysis. After PSM, the 1-, 3-, and 5-year overall survival rates in the AVT group and non-AVT group were 89.2%, 62.4%, 42.1%, and 73.3%, 46.3%, 22.1%, (p < 0.01), respectively. The 1-, 3-, and 5-year recurrence-free survival rates in the AVT group and non-AVT group were 52.5%, 30.4%, 22.1%, and 46.3%, 26.8%, 13.2% (p = 0.02), respectively. Multivariate Cox analysis revealed that postoperative adjuvant AVT was the independent protective factor associated with mortality (HR = 0.55, 95%CI = 0.46-0.67, p < 0.01) and tumor recurrence (HR = 0.81, 95%CI = 0.69-0.96, p = 0.01). Among patients who underwent curative hepatectomy for HBV-related HCC with MVI, postoperative adjuvant AVT was the independent protective factor associated with mortality and tumor recurrence. Given the high rate of postoperative recurrence and poor prognosis of HBV-related HCC with MVI, our findings may have useful clinical significance in the prevention of tumor recurrence in these patients.

Effectiveness of direct acting antiviral agents for hepatitis C virus related recurrent hepatocellular carcinoma patients who had multiple courses of recurrence.

Eradication of hepatitis C virus (HCV) using direct acting antiviral agents (DAAs) has been reported to alter liver function and reduce the recurrence rate after curative treatment in naïve hepatocellular carcinoma (HCC) patients. However, it is not well known whether administration of DAAs had favourable effect on HCC patients with multiple courses of recurrence. We retrospectively extracted 146 HCV-related HCC (C-HCC) patients who received curative treatment using radiofrequency ablation (RFA) followed by eradication treatment with DAA between 1 January 2015 and 31 December 2017. We also extracted 184 C-HCC patients who were curatively treated using RFA without HCV eradication treatment between 1 January 2009 and 31 July 2014 as controls. We used propensity score matching method and adjusted following factors between the 2 groups: age, sex, liver function, number of recurrence times, tumour diameter and tumour numbers. We finally enrolled 47 C-HCC patients with eradication of HCV, and 47 C-HCC patients without HCV eradication as controls. Primary end point was time to curative treatment failure. We defined time to curative treatment failure as the interval from curative treatment initiation to premature discontinuation of this type of therapy. Their clinical data, time to curative treatment failure and overall survival were compared. We also assessed the prognostic values of time to curative treatment failure and overall survival using multivariate Cox proportional hazard models. The median age was 74.8years, 60 patients (63.8%) were male, and 81 patients (86.2%) were Child-Pugh class A. The median tumour number was 1, tumour diameter was 20mm, and frequency of recurrence was 3 times. There were no significant differences about patients' backgrounds between the 2 groups. The cumulative time to curative treatment failure rates of patients who received DAA were 93.6% and 73.2% at 1 and 3years, respectively; those of controls were 72.5%, and 37.1% (p<.01). Multivariate analysis indicated that eradication with DAAs (HR 0.23, 95% CI; 0.12-0.43, p<.01) and DCP>50mAU/ml (HR 2.62, 95% CI; 1.45-4.74, p<.01) as independent factors contributed to time to curative treatment failure. The cumulative overall survival rates of patients who received DAAs were 93.6% and 72.6% at 1 and 3years, respectively; those of controls were 72.8% and 37.4% (p<.01). Multivariate analysis indicated that eradication with DAAs (HR 0.32, 95% CI; 0.17-0.60, p<.01) and frequency of recurrence times (HR 1.20 per 1 time, 95% CI; 1.01-1.42, p=.038) as independent factors related to overall survival. Eradication of HCV using DAAs prolonged not only time to curative treatment failure but also overall survival even in C-HCC patients with multiple courses of recurrence.

Involvement of TRPC7-AS1 Expression in Hepatitis B Virus-Related Hepatocellular Carcinoma.

Objective To investigate the expression of transient receptor potential (TRP) superfamily genes, especially TRPC7-AS1 in hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC). Methods Three cancer samples of HBV-related HCC at phase IV and matched paracancerous liver tissues were included in the study. Total RNA was extracted, and differential expression of RNA was screened by high-throughput transcriptome sequencing. The expression of TRPC7-AS1 was detected by quantitative real-time PCR. The N6-adenosyl methylation RNA in MHCC97H, HepG2, and HL-7702 was enriched by coimmunoprecipitation with m6A antibody, and the relative level of N6-adenosyl methylation RNA in TRPC7-AS1 was detected. Results The expression of TRP family genes in cancer tissues was higher than that in paracancerous liver tissues, including TRPC7-AS1, TRPC4AP, PKD1P6, and PKD1P1. Moreover, the expression level of TRPC7-AS1 in MHCC97H and HepG2 was also significantly higher than that in L02, a normal liver cell. The methylation level of N6-adenosine of TRPC7-AS1 was lower in HepG2 cells than that in L02 cells. Conclusion TRP superfamily genes, especially TRPC7-AS1, were highly expressed in HBV-related HCC. TRPC7-AS1 could be a potential therapeutic target or diagnostic marker for HCC.

Impact of Model for End-Stage Liver Disease allocation system on outcomes of deceased donor liver transplantation: A single-center experience.

Backgrounds/AimsFrom June of 2016, the Model for End-Stage Liver Disease (MELD)-based allocation system replaced the Child- Turcotte-Pugh (CTP) score-based system for organ allocation liver in Korea. The aim of this study was to analyze changes in outcomes and arising issues before and after the implementation of the MELD system.MethodsFrom June 2014 to June 2018, 129 patients were selected from recipients who underwent deceased donor liver transplantation (DDLT) in Seoul National University Hospital. Pediatric cases were excluded. According to the allocation system, patients were divided into two groups (52 in the MELD group and 77 in the CTP group).ResultsMELD scores of the two groups differed significantly (37.8 ± 2.0 in the MELD group vs. 31.0 ± 8.2 in the CTP group; p = 0.001). The etiology of patients was changed for liver transplantation. The proportion of alcoholic liver cirrhosis increased in the era of the MELD allocation system. However, proportions of hepatitis B related liver cirrhosis and hepatocellular carcinoma were decreased. Six-month mortality rate of the MELD group was 25.0%, which was higher than that (11.7%) of the CTP group (p = 0.022). The 90-day complication rate was significantly higher in the MELD group than in the CTP group (11.5% vs. 2.6%; p = 0.040).ConclusionsWhen the MELD allocation system was used to distribute livers to severely ill patients, it resulted in poorer outcomes after surgery and higher proportion of alcoholic cirrhosis. Thus, it is necessary to adjust the MELD allocation system so that outcomes after DDLT could be improved.

Serum MiRNA-23a as a Diagnostic and Prognostic Biomarker of Hepatitis C Related Hepatocellular Carcinoma

Background: Micro-ribonucleic acids (MiRNAs) are small, non-coding RNA molecules which regulate gene expression. Several miRNAs including miR-23a were found to be frequently deregulated in hepatocellular carcinoma (HCC). Objective: This study aimed to evaluate serum miR-23a as a biomarker of hepatitis C related HCC. Methods: This study was conducted on 60 hepatitis C virus (HCV) infected patients (group I: without cirrhosis, group II with cirrhosis and group III with HCV associated HCC) and a control group of 20 healthy volunteers. All patients were submitted to history taking, clinical examination in addition to categorization and staging of HCC patients. Following extraction of RNA from serum samples, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed. Calculation of serum miR-23a was done using the comparative cycle threshold (Ct) method (2–ΔΔCT). Results: Serum miR-23a levels (2-ΔΔCT) were significantly higher in cirrhotic and HCC patients compared to chronic hepatitis C patients (CHC). However, no significant difference was noted between cirrhotic and HCC patients. The sensitivity and specificity of miR-23a levels for discriminating HCC patients from cirrhotic patients were 55% and 65%, respectively. MiR-23a levels had sensitivity of 90% and specificity of 70% for discriminating metastatic from non-metastatic HCC patients. Conclusion: Higher miR-23a levels were detected among metastatic HCC patients than among those without metastasis. The sensitivity and specificity of miR-23a levels for discriminating HCC patients from cirrhotic patients were lower than those of alpha fetoprotein (AFP).

Role of circulating microRNA-21 and microRNA-215 in the diagnosis of hepatitis C related hepatocellular carcinoma.

Several micro ribonucleic acids (miRNAs) are deregulated in hepatocellular carcinoma (HCC). Others are linked to clinical pathological features of HCC. The goal of this study was to investigate whether miRNA-21 and miRNA-215 gene expression could be used as a non-invasive diagnostic tool to diagnose HCC. The gene expression of mature miRNA -21 and miRNA -215 in serum was analysed retrospectively using singleplex TaqMan two-step stem-loop quantitative real-time reverse-transcription PCR in 40 patients with HCC, 40 with chronic hepatitis C virus (HCV) with cirrhosis and 40 apparently healthy controls. Expression of miRNA -21 was significantly more down regulated in patients with HCC than in those with non-cirrhotic HCV (P = 0.007; odds ratio = 5; 95% confidence interval 1.6-15.4). The receiver operating curve analysis of the ability of miRNA-21 expression to discriminate between HCC and non-cirrhotic HCV revealed an area under the curve of 0.712 with 70% sensitivity and 68% specificity at a cut-off of ≤ 1.4468. Thus, the expression level of miRNA -21 could discriminate HCC from non-cirrhotic HCV. Significant positive correlation was observed between expression levels of microRNA-21 and miRNA -215 (r = 0.783, p < 0.001), but no association was observed between expression level of miR-215 and HCC or chronic HCV (p = 0.474). MiRNA-21 may be a useful, non-invasive tool for diagnosing HCC. Non-cirrhotic HCV patients have five times the risk of developing HCC when the miRNA -21 level ≤ 1.4468.

Application of human liver organoids as a patient-derived primary model for HBV infection and related hepatocellular carcinoma.

The molecular events that drive hepatitis B virus (HBV)-mediated transformation and tumorigenesis have remained largely unclear, due to the absence of a relevant primary model system. Here we propose the use of human liver organoids as a platform for modeling HBV infection and related tumorigenesis. We first describe a primary ex vivo HBV-infection model derived from healthy donor liver organoids after challenge with recombinant virus or HBV-infected patient serum. HBV-infected organoids produced covalently closed circular DNA (cccDNA) and HBV early antigen (HBeAg), expressed intracellular HBV RNA and proteins, and produced infectious HBV. This ex vivo HBV-infected primary differentiated hepatocyte organoid platform was amenable to drug screening for both anti-HBV activity and drug-induced toxicity. We also studied HBV replication in transgenically modified organoids; liver organoids exogenously overexpressing the HBV receptor sodium taurocholate co-transporting polypeptide (NTCP) after lentiviral transduction were not more susceptible to HBV, suggesting the necessity for additional host factors for efficient infection. We also generated transgenic organoids harboring integrated HBV, representing a long-term culture system also suitable for viral production and the study of HBV transcription. Finally, we generated HBV-infected patient-derived liver organoids from non-tumor cirrhotic tissue of explants from liver transplant patients. Interestingly, transcriptomic analysis of patient-derived liver organoids indicated the presence of an aberrant early cancer gene signature, which clustered with the hepatocellular carcinoma (HCC) cohort on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset and away from healthy liver tissue, and may provide invaluable novel biomarkers for the development of HCC and surveillance in HBV-infected patients.

Identifying key genes and screening therapeutic agents associated with diabetes mellitus and HCV-related hepatocellular carcinoma by bioinformatics analysis

Incidence of both Type 2 diabetes mellitus (T2DM) and hepatocellular carcinoma (HCC) are rapidly increasing worldwide. One of the leading causes of HCC is hepatitis C virus (HCV), which is a resource of blood-borne viral infection. HCV increases the risk for HCC probably by promoting fibrosis and cirrhosis. Association among T2DM and HCV related HCC remains significant, indicating that such association is clinically reliable and robust. Lawson was the first who uncovered HCC in person suffered from T2DM. Until now, genetic association between HCV related HCC and T2DM is poorly known. Current work was designed to figure out the molecular mechanisms of both diseases by identifying the hub genes and therapeutic drugs using integrated bioinformatics analysis. Four microarray datasets were downloaded from GEO database and analyzed using R in order to obtain different expressed genes (DEGs). Protein-protein interaction (PPI) networks was constructed using STRING tool and visualized by Cytoscape. Moreover, hub genes were identified on the basis of their degree of connectivity. Finally, Networkanalyst and DGIdb were used for the identification of transcription factors (TFs) and selection of candidate drugs, respectively. A total of 53 DEGs were identified, of which 41 were upregulated genes and 12 were downregulated genes. PPI network obtained from STRING were subjected to Cytoscape plugin cytoHubba, and top 10 genes (AURKA, JUN, AR, MELK, NCOA2, CENPF, NCAPG, PCK1, RAD51AP1, and GTSE1) were chosen as the target hub genes based on the highest degree of connectivity. Furthermore, 47 drugs of AURKA, JUN, AR, MELK, and NCOA2 were found having therapeutic potential to treat HCV-HCC in patients with T2DM. This study updates the information and yield a new perspective in context of understanding the pathogenesis and development of HCV related HCC in affected persons with T2DM. In vivoandin vitroinvestigation of hub genes and pathway interaction is essential to delineate the specific roles of the novel hub genes, which may help to reveal the genetic association between HCV-HCC and T2DM. In future, hub genes along with their candidate drugs might be capable of improving the personalized detection and therapies for both diseases.

Impact of successful HCV treatment using direct acting antivirals on recurrence of well ablated hepatocellular carcinoma

ABSTRACT Background There are many contradictory studies that dealt with hepatocellular carcinoma (HCC) recurrence rate of well ablated hepatitis C virus (HCV) related HCC. We aim to assess the recurrence rate of previously ablated HCC in patients who received direct acting antiviral (DAA) for their HCV. Research design and methods This is a retrospective data analysis of 523 HCV patients who have a history of successfully ablated HCC and eligible for HCV treatment. Retrieval was done to demographic/clinical data, HCV pretreatment investigations, HCV treatment outcome. Follow up for survival and HCC recurrence was done every 3 months using abdominal ultrasound and alfa-fetoprotein. Results Mean age was 53.83 years. Sofosbuvir/daclatasvir/ribavirin was the most used regimen (35.4%) with 438 patients (83.7%) achieved sustained virologic response (SVR). The median duration for surveillance was 159 weeks. Hundred and five patients developed recurrent HCC, with a crude recurrence rate of 20.1%. There was no difference between HCV responders and non-responders in crude recurrence rate (p = 0.94) but HCC developed earlier in non-responders (p = <0.01). Conclusion Recurrence of HCC remains a threat in HCV patients even after achieving an SVR. Implementation of long-term surveillance programs is highly recommended.

Evaluation of toll-like receptor 4 polymorphism in patients with hepatitis c virus-induced hepatocellular carcinoma

Background: Liver related pathologies including Hepatocellular Carcinoma (HCC) is a universal problem. Innate immunity receptors were accused in the etiopathogenesis of HCC with many conflicts. TLR4 is one of pathogen recognition receptors involved in the pathogenesis of many diseases and malignancies. TLR4 receptor polymorphisms were investigated in HCV related morbidities along with inconclusive results Objectives: to study the role of TLR4 rs 2149356 and rs 1927914 genotypes polymorphisms in HCV related HCC development. Methodology: 200 Chronically infected HCV patients were enrolled in this study. they were divided according to lab and clinical data into 100 CHC group and 100 HCC patients who were compared to health individual. The blood samples obtained were further proceed to full lab and TLR4 genotyping by RFLP-PCR technique Results: GT genotype and T allele of TLR4 rs 2149356 at 95% CI of 0.38 (0.21-0.70) was significantly increased in control group than in HCC and CHC groups. At 0.32(0.17-0.63) TLR4 rs 1927914 C allele and CT genotype was significantly increased in Controls than diseased groups while T allele is significantly increased in HCC than control group. Conclusions: TLR4 genotypes may play a protective role against HCC development among chronic HCV patients.

State of the art vaccination strategies as primary prevention to reduce incidence of gastrointestinal cancers.

Immunizations have influenced the epidemiology of numerous gastrointestinal cancers. Human papillomavirus (HPV) is a common sexually transmitted infection (STI). Although most infections are transient and asymptomatic, persistent infections with oncogenic strains of HPV can progress to cervical, anal, penile, vaginal, vulvar, and oropharyngeal cancers. The introduction of HPV vaccinations has drastically reduced incidences of HPV-vaccine related infections and HPV related cervical cancers. The vaccine has proven to be safe and effective however, HPV vaccination rates have yet to reach target goals in the U.S. and many countries worldwide have not incorporated the vaccine into national immunization programs. The first successful nationwide vaccination program was employed against hepatitis B virus (HBV) in Taiwan in 1984 and demonstrated a statistically significant decrease in the incidence of hepatocellular carcinoma (HCC) in the 6 to 10 years after implementation of universal HBV vaccinations in infants. Twenty-year follow-up studies have continued to demonstrate statistically significant decreased rates of HBV related HCC among vaccinated populations. Despite the successful decrease in incidence of HBV-related HCC, efforts to create an effective prophylactic vaccination against hepatitis C virus (HCV) to prevent chronic HCV infection and its associated morbidity, including HCV-related HCC, have to date been unsuccessful.

Prognostic value of preoperative protein induced vitamin K absence or antagonist II after hepatectomy for hepatitis B related hepatocellular carcinoma: Nationwide multicenter study

The prognostic value of PIVKA-II has been insufficiently elucidated. This study is aimed to determine the prognostic value of preoperative serum PIVKA-II after hepatectomy for hepatitis B related HCC. The nationwide multicenter database of the Korean Liver Cancer Association was reviewed. Patients with hepatitis B related HCC who underwent liver resection as a first treatment after initial diagnosis between 2008 and 2014 were selected. Comparative analysis between low versus high PIVKA-II was performed. Survival outcomes of propensity score-matched groups were compared. Kaplan-Meier and multivariable analyses were performed to identify risk factors for disease-specific survival. Univariable and multivariable Cox proportional hazards regression were used. Among 6,770 randomly selected patients with hepatitis B related HCC, 987 patients were included. The disease-specific 5-year survival rate was 84.6% in patients with PIVKA-II of 106.5 mAU/mL or less compared with 76.3% for those with a level exceeding 106.5 mAU/mL (p = 0.041). After propensity score matching, the two groups were well balanced (n = 263, each). In univariable analysis, high PIVKA-II (> 106.5 mAU/mL) was a significant predictor for worse survival (hazard ratio [HR], 1.527; p = 0.047). In multivariable analysis, lymph node positivity (HR, 6.123; p = 0.023), hyponatremia (< 135 mEq/L) (HR, 4.187; p = 0.002), tumor size ≥ 5.0 cm (HR, 3.399; p < 0.001), preoperative ascites (HR, 3.874; p = 0.001), microvascular invasion (HR, 2.639; p = 0.001), thrombocytopenia (< 100 × 103/µL) (HR, 2.620; p = 0.001), and multiple HCC (HR, 2.068; p = 0.007) were independent predictors for worse disease-specific survival, but not preoperative high PIVKA-II. Preoperative high PIVKA-II is significantly associated with worse disease-specific survival after hepatectomy for hepatitis B related HCC, nonetheless, not a strong prognostic factor.

SMAC-Survivin apoptotic “switch” is regulated through the PI3K-Src-p at the α1-Na/K-ATPase in NASH related hepatocellular carcinoma: Studies in-vitro/vivo and in humans

Hepatocellular carcinoma (HCC) is the second and fastest-growing cause of cancer related mortality worldwide. Our group has described the signaling properties of the α1-Na/K-ATPase providing a pathway for organogenesis during cell development. We hypothesized that during hepatocarcinogenesis, regulation of Src-phosphorylation at the α1-subunit of the NKA causes an imbalance of the Smac/DIABLO-Survivin apoptotic signaling process, favoring cell division and tumorigenesis. Expression of Cav-1/Smac/Survivin proteins was performed on immuno-stained HCC cell lines (Hep3 & SNU475), and livers from a NASH-HCC rodent model, and humans. Furthermore, signaling pathway studies were explored in-vitro guided by RNA sequencing. Selective blockage of Src-phosphorylation at its kinase domain was performed by administration of a synthetic peptide (33aa = pNaKtide, developed from N domain of Na/K-ATPase). Significant differences among groups were accepted at p < 0.05 using ANOVA/t-test. α1-NKA/Src-p inhibition promoted apoptosis of cell lines, and receptor' IC50 drove concomitantly both, Survivin's downregulation and SMAC's upregulation expressions (dose-related, p < 0.01). In-vivo, liver tumor burden was significantly lower in animals treated with pNaKtide (p < 0.01), and the expressions of Cav-1/Survivin were significantly higher in liver tumor tissue from non-treated when compared to treated animals (p < 0.01). A similar pattern of Cav-1 and survivin expressions was noted in tumors from patients with NASH ± HCC when compared to liver tissue from healthy subjects or subjects with liver metastases (p < 0.05). In-vitro, Src-p at the α1-NKA activates PI3K/Akt dependent and independent to EGFr/Grb2 pathways. α1-NKA/Src-p in Caveola regulates Survivin/SMAC expressions which in turn modulate a cellular "switch" from apoptosis to cell division involving two signaling pathways.

Determining the Traditional Chinese Medicine (TCM) Syndrome with the Best Prognosis of HBV-Related HCC and Exploring the Related Mechanism Using Network Pharmacology.

Background In traditional Chinese medicine (TCM), TCM syndrome is a key guideline, and Chinese materia medicas are widely used to treat hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC) according to different TCM syndromes. However, the prognostic value of TCM syndromes in HBV-related HCC patients has never been studied. Methods A retrospective cohort of HBV-related HCC patients at Shenzhen Traditional Chinese Medicine Hospital from December 2005 to October 2017 was analyzed. The prognostic value of TCM syndromes in HBV-related HCC patients was assessed by Kaplan–Meier survival curves and Cox analysis, and the TCM syndrome with the best prognosis of HBV-related HCC patients was determined. To further study the relevant mechanisms, key Chinese materia medicas (KCMMs) for the TCM syndrome with the best prognosis were summarized, and network pharmacology was also performed. Results A total of 207 HBV-related HCC patients were included in this research, and we found that HBV-related HCC patients with TCM excess syndrome had better OS. Then, a total of eight KCMMs for TCM excess syndrome were identified, whose crucial ingredients included quercetin, beta-sitosterol, kaempferol, luteolin, and XH-14, and KCMMs could play a therapeutic role through MAPK, JAK-STAT, Wnt, Hippo, and other pathways. Moreover, TP53, SRC, STAT3, MAPK3, PIK3R1, HRAS, VEGFA, HSP90AA1, EGFR, and JAK2 were determined as the key targets. Conclusion We propose a new research method of “prognosis of TCM syndromes-KCMMs-network pharmacology” to reveal the prognostic value of TCM syndromes and the potential mechanism by which TCM syndromes affect prognosis.

Liver Field during Immunotherapy of Hepatocellular Carcinoma: Some Like It Hot

Liver Field during Immunotherapy of Hepatocellular Carcinoma: Some Like It Hot

High HBV Load Weakens Predictive Effect of Serum miR-122 on Response to Sorafenib in Hepatocellular Carcinoma Patients.

Background MiR-122 is a liver-specific microRNA. The aim of the study was to explore the association of serum miR-122 with response to sorafenib in hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC) patients and to further reveal the effect of the virus load on such potential relationship. Methods A total of 588 patients with HCC were retrospectively included. All of them were diagnosed with HBV-related locally advanced HCC and were treated with sorafenib. Therapeutic and prognostic information and other information were collected from medical records. Stored blood specimens that were obtained before sorafenib treatment were adopted to detect miR-122. Results The patients were divided into high-level group and low-level group according to the median of serum miR-122 level, and each group contained 294 patients. During the first 24 weeks after sorafenib treatment, the patients in the high-level group had more opportunities to experience progression-free survival (PFS) and overall survival (OS) than those in the low-level group (HR: 2.47, 95%CI: 1.24∼4.88; HR: 1.20, 95%CI: 1.09∼1.32). In the subgroup analysis, the relationship between serum miR-122 level and overall survival still existed in the patients with relatively lower HBV load (HR: 1.22, 95%CI: 1.09∼1.36), but not in the patients with higher HBV load (HR: 1.12, 95%CI: 0.93∼1.35). Conclusion Higher serum level of miR-122 at baseline was associated with a better response to sorafenib in HBV-related locally advanced HCC patients, and relatively high HBV load weakened such predictive effect mentioned above.

A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

BackgroundHepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people.MethodsThe expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells.ResultALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells’ growth and migration in vitro and in vivo.ConclusionsHBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.

Adjuvant therapy using ex vivo-expanded allogenic natural killer cells in hepatectomy patients with hepatitis B virus related solitary hepatocellular carcinoma: MG4101 study.

Backgrounds/AimsFewer reports have been published regarding hepatectomy patients with solitary hepatocellular carcinoma (HCC) who received immunotherapeutic agents as adjuvant therapy. We evaluated the safety and efficacy of ex vivo-expanded allogenic natural killer (NK) cells in those patients with modified International Union Against Cancer (UICC) stage T3.MethodsFrom August 2014 to October 2015, five patients who underwent hepatic resection received ex vivo-expanded allogenic NK cells. Patients received five rounds of NK cells (2-3×107 cells/kg) at postoperative 4, 6, 8, 12, and 16 weeks. This study is registered with ClinicalTrials.gov, number NCT02008929.ResultsThe median age of the five patients (three men and two women) was 44.8 years (range, 36-54 years). All had hepatitis B virus-related HCC, and the median tumor size was 2.2 cm (range, 2.1-8.2 cm). None of the patients had any adverse events. HCC recurrence developed in two patients at one year after hepatic resection, but four patients were alive at 3 years. The two recurrence-free patients showed a higher ratio of CD8+ T lymphocyte populations before and after administration of ex vivo-expanded allogenic NK cells compared with the three patients who experienced recurrence.ConclusionsImmunotherapy using ex vivo-expanded allogenic NK cells in hepatectomy patients can be used safely. Further studies should be investigated for efficacy.

Prognostic value of IL-26 level in hepatocellular carcinoma tissue in postoperative patients with hepatitis B related hepatocellular carcinoma

Prognostic value of IL-26 level in hepatocellular carcinoma tissue in postoperative patients with hepatitis B related hepatocellular carcinoma