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Preoperative α-fetoprotein (AFP) level levels may help select patients with hepatocellular carcinoma (HCC) for surgery. The objective of the current study was to assess an AFP model to predict tumor recurrence and patient survival after curative resection for HCC. Patients undergoing curative-intent resection for HCC between 2000 and 2017 were identified from a multi-institutional database. AFP score was calculated based on the last evaluation before surgery. Probabilities of tumor recurrence and overall survival (OS) were compared according to an AFP model. A total of 825 patients were included. An optimal cut-off AFP score of 2 was identified with an AFP score ≥3 versus ≤2 independently predicting tumor recurrence and OS. Net reclassification improvements indicated the AFP model was superior to the Barcelona Clinic Liver Cancer (BCLC) system to predict recurrence (p < 0.001). Among patients with BCLC B–C, AFP score ≤2 identified a subgroup of patients with AFP levels of ≤100 ng/mL with a low 5-year recurrence risk (≤2 45.2% vs. ≥3 61.8%, p = 0.046) and favorable 5-year OS (≤2 54.5% vs. ≥3 39.4%, p = 0.035). In contrast, among patients within BCLC 0-A, AFP score ≥3 identified a subgroup of patients with AFP values > 1000 ng/mL with a high 5-year recurrence (≥3 47.9% vs. ≤2% 38.4%, p = 0.046) and worse 5-year OS (≥3 47.8% vs. ≤2 65.9%, p < 0.001). In addition, the AFP score independently correlated with vascular invasion, tumor differentiation and capsule invasion. The AFP model was more accurate than the BCLC system to identify which HCC patients may benefit the most from surgical resection. • The AFP score ≥3 versus ≤2 independently predicted tumor recurrence and overall survival (OS). • A high AFP model score ≥3 was strongly correlated with adverse tumor features and behavior, and, in turn, was able to discriminated patients with low versus high risk of recurrence and death. • The AFP model performed better than the BCLC staging as use of the model was able to differentiate patients with BCLC stage 0-A who did poorly after surgery, as well as identify a subgroup of patients with BCLC B–C who actually fared well after resection. [ABSTRACT FROM AUTHOR]

Biomarkers for early diagnosis of hepatocellular carcinoma (HCC) are needed in chronic hepatitis B virus (HBV) infection, a leading cause of HCC. We evaluated whether measurement of serum pentraxin 3 (PTX3) could improve diagnosis of HCC in chronic HBV infection. Data from patients with HBV-related chronic hepatitis (n = 159), cirrhosis (n = 99) and HCC (n = 107), and healthy controls (n = 151) were analyzed. Serum PTX3 concentration was measured by immunoassay. Area under the receiver operating characteristic curve (AUC) was applied to assess diagnostic accuracy. PTX3 levels were significantly higher in HBV patients than in healthy controls (P < 0.001) and in HCC than in chronic hepatitis (P < 0.001) or cirrhosis patients (P < 0.001). PTX3 was an independent risk factor of HCC [odds ratio (OR) 1.617, P < 0.001] and could distinguish HCC in chronic HBV infection [cutoff 9.231 ng/mL, AUC 0.929 with 95% confidence interval (CI) of 0.898–0.953], including α-fetoprotein (AFP) negative [cutoff 8.985 ng/mL, AUC (95%CI) 0.947 (0.908–0.973)] and early-stage HCC [cutoff 9.359 ng/mL, AUC (95%CI) 0.920 (0.885–0.947)]. Combination of PTX3 with AFP improved the discrimination of early HCC from chronic HBV infection [AUC (95%CI) 0.948 (0.918–0.970)]. In short, PTX3 measurement could identify HCC, including AFP-negative and early-stage HCC, in chronic HBV infection. [ABSTRACT FROM AUTHOR]

Background. Hepatectomy remains one of the most effective treatments for patients with hepatocellular carcinoma (HCC); however, it can lead to serious complications. Irisin, a key regulator of energy metabolism, is secreted into the circulation by shedding of the extracellular portion of the fibronectin type III domain-containing 5 (FNDC5). We have shown that irisin administration alleviates liver ischemia-reperfusion injury in mice. However, the role of preoperative irisin levels in HCC patients who underwent hepatectomy remained unknown. The purpose of this study was to determine how irisin expression changes in HCC and to explore the relationship between preoperative serum irisin levels and complications after hepatectomy. Methods. FNDC5/irisin expression data in HCC were extracted from The Cancer Genome Atlas (TCGA) dataset. A total of 219 participants, including 102 healthy controls and 117 HCC patients, were recruited in this study. All HCC patients underwent hepatectomy at the First Affiliated Hospital of the Xi'an Jiaotong University. Preoperative serum irisin levels were measured by ELISA. Postoperative complications were assessed using the comprehensive complication index (CCI) score. The Pearson rank correlation coefficient was computed to assess the correlation between preoperative serum irisin levels and postoperative CCI scores. Results. In TCGA dataset, FNDC5/irisin expression was downregulated in HCC tissues (P < 0.001). Similarly, serum irisin levels were decreased in HCC patients (P < 0.001). Low preoperative serum irisin levels were significantly correlated with high CCI scores after hepatectomy. Conclusions. Irisin may be a novel serum biomarker in the diagnosis of HCC and a predictor of complications after hepatectomy. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the racial disparities in the presentation, treatment and survival time of patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) between Chinese and other racial groups from the Surveillance, Epidemiology, and End Results (SEER) database between January 1st 2004, and December 31st 2013. Key covariates, including clinical presentation, treatment and survival time, were recorded and compared, demonstrating the racial differences. Kaplan-Meier analysis and Cox regression models were performed to identify these disparities in survival time. A total of 30,954 patients were identified in the SEER database. Among these, 27,767 (89.7%) had HCC and 3,187 (10.3%) had ICC. In the HCC cohort, Chinese patients had the highest survival time. Compared with the mortality risk of Chinese patients, the mortality risk of Other Asian, non-Hispanic white, Hispanic and African-American patients increased by 16.8, 35.1, 28.3 and 33.3%, respectively. Compared with other groups, Chinese patients were more likely to present with localized stage, and without vascular invasion, adjacent invasion and metastasis. In the ICC cohort, the Chinese group had improved survival time, compared with the other groups following univariate analysis, although no significant differences were observed between Chinese and Other Asian and Hispanic patients following adjusting for contributing factors. Furthermore, there was no significant differences in the presentation between the groups, which differed from the HCC analysis. In conclusion, race/ethnicity was a significant independent prognostic factor in the HCC cohort, whereas it was not significant in the ICC cohort. The synergistic effect of contributing factors, including demographic, socioeconomic, biological and treatment differences, caused the racial disparity observed in primary liver cancer survival time. [ABSTRACT FROM AUTHOR]

Highlights • A transcriptional factor Hes-1 in Notch signaling pathway and an inverted-CCAAT box binding protein ICBP90 are highly expressed in HCC. • The blocking of Notch pathway by a specific inhibitor DAPT prevents HCC cells at the G0/G1 to enter S and G2/M phases through attenuating ICBP90. • Hes-1 gene knockdown suppresses the HCC cell growth through the reduction of ICBP90, potentially applied as a target to treatment of HCC. Abstract The Notch signaling pathway plays a key role in cell proliferation and development that is closely related to an inverted CCAAT box binding protein (ICBP90), but little is known about whether there is a correlation between Notch signaling and ICBP90. The aim of the current study was to elucidate this. MTT assay and flow cytometry were used to determine the proliferation, cell cycle and apoptosis of HepG2 or Hepa1-6 cells treated by N -[ N -(3,5-difluorophenacetyl)- L -alanyl]- S -phenylglycine t-butyl ester (DAPT), a specific inhibitor of the Notch pathway. RT-PCR, Western Blot and in situ immunofluorescence staining were employed to examine expression of ICBP90 in the cells. DAPT caused inhibition of the activation of the Notch signaling pathway, followed by preventing the cells at the G0/G1 phases to enter S and G2/M phases. ICBP90 and Hes-1 proteins were highly expressed in the untreated cells. The reduced levels of Notch intracellular domain (NICD) protein were observed in the DAPT-treated cells, thereby bringing about the down-regulation of ICBP90 with the increment of the DAPT dose. Consistent with this, knockdown of the Hes-1 gene, which encodes a critical transcriptional factor in the Notch pathway, also led to the attenuation of ICBP90. On the contrary, Jagged-1, a Notch ligand, facilitated ICBP90 production. Adriamycin could result in the reduction of ICBP90, which was not accompanied with the alteration of Hes-1. ICBP90 was almost fully distributed within the nuclei, but Hes-1 was visible within both the cytoplasm and nuclei. Our novel findings strongly indicate that inactivation of the Notch signaling pathway impedes hepatocellular carcinoma progress via reduction of ICBP90. [ABSTRACT FROM AUTHOR]

Whether and how garlic-derived S -allylmercaptocysteine (SAMC) inhibits hepatocellular carcinoma (HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) in HCC progression and the anti-HCC mechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients (66.7% of 48 patients) and its over-expression only correlated with the over-expression of β -catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. In vivo administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of SAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface. [ABSTRACT FROM AUTHOR]

Background and objective: Upregulated T-cell immunoglobulin and mucin domain containing molecule-3 (Tim-3) in hepatitis B virus (HBV)-specific CD8+ T-cells contributes to CD8+ T-cell exhaustion during chronic HBV infection. The membrane-bound Tim-3 can be cleaved from the cell surface by sheddase, yielding soluble Tim-3 (sTim-3). This study investigated serum sTim-3 levels in patients with chronic HBV infection of various liver diseases. Methods: Serum sTim-3 levels were quantitatively determined in 288 patients with chronic HBV infection of various liver diseases. The sTim-3 levels were analyzed in relation to liver diseases including HBV-related hepatocellular carcinoma (HCC) and overall survival of HCC patients. Results: Serum sTim-3 levels in the patients with chronic HBV infection were significantly elevated compared with healthy controls (P [ABSTRACT FROM AUTHOR]

The neutrophil to lymphocyte ratio (NLR), a simple marker of inflammation, has recently been showed to predict tumor recurrence in hepatocellular carcinoma (HCC) patients after hepatic resection or liver transplantation. However, whether it can be used to predict HCC development in cirrhotic patients remained unknown. The aim of this study was to evaluate the predictive value of the preoperative NLR for the development of HCC in cirrhotic patients who underwent splenectomy. A total of 230 HBV-associated cirrhotic patients who underwent splenectomy in our hospital from January 2000 to December 2012 were included in this study. Detailed clinical data included patients’ general characteristics, laboratory tests and imaging studies, surgical procedures and complications. Information on patients’ follow-up data was also obtained. We found that 38 (16.52%) patients developed HCC after splenectomy during the follow-up period. An elevated preoperative NLR was associated with increased risk of developing HCC in cirrhotic patients after splenectomy. The optimal cutoff value of NLR for HCC development was 2.27. In patients who developed HCC during the follow-up period, NLR scores showed no predictive value in overall survival after splenectomy. However, NLR scores appeared to have a much better predictive value in overall survival in patients who did not develop HCC. In conclusion, cirrhotic patients who underwent splenectomy remain at a relatively high risk of developing HCC, and an elevated preoperative NLR is associated with HCC development in cirrhotic patients who underwent splenectomy for hypersplenism. [ABSTRACT FROM AUTHOR]

Objectives: Surgical resection remains a controversial treatment for hepatocellular carcinoma (HCC) within different Barcelona Clinic Liver Cancer (BCLC) stages. The objective of this study was to evaluate the long-term outcome of patients undergoing surgical resection (SR) compared to non-surgical treatments across different BCLC stages. Patients and methods: One thousand four hundred forty-three HCC patients within BCLC 0, A, B and C stages were identified. Overall survival was compared by log-rank test among patients within different BCLC stages and among patients receiving different treatments (SR vs locoregional therapy [LRT] vs best supportive care). Propensity score matching analysis was introduced to mitigate the confounding biases between the groups. Results: The median survival time of the patients diminished from early, intermediate to advanced BCLC stages (BCLC 0-A 43 [range 0-100] months vs BCLC B 32 [range 0-100] months vs BCLC C 27 [range 0-90] months, all p<0.05). Patients undergoing SR presented with better liver function and more favorable tumor status and, consequently, displayed significant better overall survival than patients receiving LRT or best supportive care at different BCLC stages. In adjusted cohort after propensity score matching, patients who were surgically treated consistently had more favorable outcome than those who were non-curatively treated across different BCLC stages (median survival [range]: BCLC stage B: resection 45 [0-100] months vs LRT 36 [0-81] months, p=0.002; BCLC stage C: resection 39 [3-77] months vs LRT 27 [0-54] months, p=0.003). Conclusion: Surgical resection should be considered as a radical treatment for selected HCC patients regardless of the BCLC stages when appropriate. [ABSTRACT FROM AUTHOR]

Background/Aims: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related death. Critical roles for long non-coding RNAs (lncRNAs) have recently been demonstrated for a variety of cancers, including hepatocellular carcinoma. However, the effect and mechanism of lncRNAs in HCC tumorigenesis and chemoresistance have not been extensively characterized. Methods: In the current study, we have identified a HCC-expressed lncRNA termed as HANR (HCC associated long non-coding RNA). We identified HANR by microarray analysis and validated its up-regulated expression by quantitative PCR. RNA pull-down and pathway analyses were conducted to evaluate physical and functional interactions with HANR. In vivo experiments were performed to assess tumorigenesis and increase of chemoresistance. In addition, the HANR expression in HCC specimens was detected by FISH. Xenograft and orthotopic mice model was constructed to observe the effect of HANR on tumorigenesis and chemoresistance in vivo. Results: HANR was demonstrated to be up-regulated in HCC patients and HCC cell lines. Increased HANR expression in HCC predicted short survival of patients. Knock-down of HANR markedly retarded cell proliferation, suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity to doxorubicin, while overexpression of HANR showed the opposite effects. It was found that HANR bind to GSKIP for regulating the phosphorylation of GSK3ß in HCC. Conclusion: Our results demonstrate that HANR contributes to the development of HCC and is a promising therapeutic target for chemosensitization of HCC cells to doxorubicin, which may represent a promising therapeutic target in the future. [ABSTRACT FROM AUTHOR]

The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. The present study aims to evaluate the role of age on treatments and outcome of HCC patients. 1530 patients firstly diagnosed with HCC were retrospectively included and classified as older (≥65 years, n = 318, 21%) and younger patients (<65 years, n = 1212, 79%). The two groups were compared with clinical characteristics, tumor burden, Barcelona Clinics Liver Cancer (BCLC) stage, treatments and long-term prognosis. Elderly patients were more HCV infected, had more diabetes, poorer performance status, and were less aggressively treated. The proportion of HCC within BCLC stage 0-A, B or C was similar between the two groups, but elderly patients were more presented with BCLC stage D. The overall survival of older patients was poorer compared to younger patients before and after propensity score matching. However, elderly patients were less often effectively treated with surgery and loco-regional therapies across different BCLC stages. After stratified by BCLC stages or treatments, older patients showed comparable long-term outcome to younger patients. Performance status, BCLC stages and effective treatments, rather than age, was independent factors determining prognosis in the whole cohort and only elderly patients by multivariate analysis. In conclusion, older could have comparable survival to younger patients within the same tumor stage or after similar treatments. Thus, equally active treatments should be encouraged to elderly patients. [ABSTRACT FROM AUTHOR]

Background: Serum lens culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3%) has been widely used for HCC diagnosis and follow-up surveillance as tumor serologic marker. However, the prognostic value of high pre-treatment serum AFP-L3% in patients with hepatocellular carcinoma (HCC) remains controversial. We therefore conduct a meta-analysis to assess the relationship between high pre-treatment serum AFP-L3% and clinical outcome of HCC. Methods: Eligible studies were identified through systematic literature searches. A meta-analysis of fifteen studies (4,465 patients) was carried out to evaluate the association between high pre-treatment serum AFP-L3% and overall survival (OS) and disease-free survival (DFS) in HCC patients. Sensitivity and subgroup analyses were also conducted in this meta-analysis. Results: Our analysis results showed that high pre-treatment serum AFP-L3% implied poor OS (HR: 1.65, 95%CI: 1.45–1.89 p<0.00001) and DFS (HR: 1.80, 95% CI: 1.49–2.17 p<0.00001) of HCC. Subgroup analysis revealed that there was association between pre-treatment serum AFP-L3% and endpoint (OS and DFS) in low AFP concentration HCC patients (HR: 1.96, 95% CI: 1.24–3.10, p = 0.004; HR: 2.53, 95% CI: 1.09–5.89, p = 0.03, respectively). Conclusion: The current evidence suggests that high pre-treatment serum AFP-L3% levels indicated a poor prognosis for patients with HCC and AFP-L3% may have significant prognostic value in HCC patients with low AFP concentration. [ABSTRACT FROM AUTHOR]

Background and Objectives: Cigarette smoking is a potential risk factor for hepatocellular carcinoma (HCC) initiation, partially through interaction with hepatitis B virus (HBV). We examined the hypothesis that cigarette smoking might be associated with HBV-related HCC recurrence and patient survival after curative surgery. Patients and Methods: Data of 302 patients with HBV infection who had undergone curative resection for HCC were prospectively collected from 2008 to 2011. Smoking status and smoking quantity (pack-years, PY) were asked at admission. Factors affecting recurrence-free survival (RFS) were examined. RFS and liver-specific mortality (LSM) stratified by risk factors were compared with log-rank test. Results: 109 were current smokers. Current smokers were not different from non-smokers in tumor burden and surgical procedure. Univariate and multivariate analysis identified that heavy smoking (PY ≥20) was the most significant factor associated with HBV-related HCC recurrence after curative surgical resection (p = 0.001), followed by anti-HBV treatment (p<0.01), current smoking (p = 0.028), surgical margin <1 cm (p = 0.048) and blood transfusion >600 ml (p = 0.028). The median RFS in non-smokers, ex-smokers and current smokers was 34 months, 24 months and 26 months, respectively (p = 0.033). Current smokers had significantly worse RFS rate and increased 5-year cumulative LSM than non-smokers (p = 0.024, and p<0.001, respectively). Heavy smokers had significantly worse RFS than non- and light smokers (0

Purpose: Hepatocellular carcinoma (HCC) rarely occurs in children and adolescents and has been reported to be highly hepatitis B related more than 10 years ago. However, after global vaccination for hepatitis B virus (HBV), the characteristics and outcome of pediatric HCC remain undefined. Methods: Patients with HCC admitted from 2004 to 2010 were retrospectively reviewed in a large tertiary hospital. Results: 45 (1.97 %) pediatric HCC were diagnosed (age ≤18 years), with predominantly male patients (93.3 %). 32 (71.1 %) children were HBV positive, 30 of whom had vertical transmission from their mothers. HBV positivity was associated with liver cirrhosis and portal vein invasion, and thus compromised survival. Advanced disease prevented surgical resection due to large tumor size (>10 cm, 66.7 %), early metastasis (24.4 %), bilateral involvement (57.8 %) and portal vein invasion (46.7 %). The median survival for resectable, transarterial chemotherapy and embolization and untreated patients was 28.6, 4 and 5 months, respectively ( p < 0.001). Patients with distal metastasis had significantly poorer survival rate than those without metastasis ( p < 0.001). Conclusion: Screening of children whose mothers are HBV carriers is important in early detection of pediatric HCC. HBV-associated HCC in pediatric patients, especially in endemic areas, should be detected earlier for more resectability and improvement of surgical prognosis. [ABSTRACT FROM AUTHOR]

p57 is a multifunctional protein involved in the regulation of tumor formation and development; however, the biological role of p57 in the pathogenesis of hepatocellular carcinoma (HCC) is poorly understood. To explore the role of p57 in the development of HCC, we examined p57 messenger RNA (mRNA) and protein levels in HCC tissues and adjacent non-cancerous tissues by immunohistochemistry, real-time polymerase chain reaction and western blot analysis. Moreover, we generated stable p57 knockdown HCC cell lines to investigate the impact of p57 downregulation on the growth and invasion of HCC in vitro and in vivo. Our results showed that p57 mRNA and protein levels were significantly decreased in human HCC tissues. In addition, this reduction in p57 expression was associated with increased tumor size, more advanced TNM stages, the presence of capsule invasion and extrahepatic metastasis and decreased overall survival time. In human HCC cell lines, p57 downregulation increased the expression of cyclin D1 and CDK2 and enhanced the activities of CDK4/cyclin D1 and CDK2/cyclin E complexes, resulting in increased cellular proliferation and growth of xenografts. Furthermore, p57 downregulation accelerated the invasion of HCC cells in vitro and in vivo by controlling the activity of LIMK1. In conclusion, the downregulation of p57 accelerates the growth and invasion of HCC, indicating that p57 is an important tumor suppressor in HCC. Based on these findings, p57 may be a potential target for HCC prevention and therapy. [ABSTRACT FROM AUTHOR]

Abstract Background There is a strong correlation between liver fibrosis and postoperative morbidity after hepatectomy in hepatocellular carcinoma (HCC) patients. The aim of this study was to evaluate which noninvasive fibrosis index (gamma-glutamyl transpeptidase to platelet ratio [GPR], aspartate aminotransferase to platelet ratio index, fibrosis-4 index, or Forns index) was best able to predict complications in patients undergoing hepatectomy for HCC. Materials and methods This retrospective analysis included 275 patients who underwent hepatectomy for HCC from January 2008 to December 2012. Postoperative mortality was defined as death within 90 d after surgery. Complications were grouped into seven grades on the basis of the modified Clavien classification, and major postoperative complications were defined as grade 3 or above. The influence of noninvasive fibrosis indices on postoperative outcomes was assessed by receiver operating characteristic analysis. The primary outcomes were overall complications and major complications, estimated by univariate and multivariate analysis. Results Patients with HCC undergoing anatomical liver resection in the authors' department were evaluated for this study. Finally, 275 patients who underwent minor liver resection (≤2 liver segments) were included. Of these, 231 (84%) were male. The multivariate analysis indicated that the GPR index was not only independently associated with overall complications (hazard ratio, 2.692; 95% confidence interval [CI], 1.626-4.250; P < 0.001) but also independently predictive of major complications (hazard ratio, 1.143; 95% CI, 1.046-1.249; P = 0.03). The areas under the receiver operating characteristic curve for predicting overall complications and major complications for the GPR index were 0.704 (95% CI, 0.643-0.765; P < 0.001) and 0.752 (95% CI, 0.638-0.865; P < 0.001), respectively. Conclusions The data suggested that the GPR index could be a promising predictor of overall postoperative complications and major complications after minor hepatectomy for HCC. [ABSTRACT FROM AUTHOR]

Chemotherapy resistance represents a major obstacle in the treatment of patients with hepatocellular carcinoma (HCC). The purpose of this study was to investigate the anti-cancer effect of MEL-pep, a novel analog of the natural antibacterial peptide melittin (MEL), on human 5-fluorouracil-resistant HCC cells (BEL-7402/5-FU) and to clarify the molecular mechanisms involved in these effects. We found that MEL-pep inhibited the proliferation of BEL-7402/5-FU cells and reversed 5-FU resistance in vitro . MEL-pep directly bound to BEL-7402/5-FU cells and disrupted the cell membrane. P-glycoprotein (P-gp) plays an important role in the development of resistance to anticancer drugs. We found that MEL-pep inhibited P-gp expression and increased the intracellular accumulation of the P-gp substrate rhodamine-123 in BEL-7402/5-FU cells. Additionally, the phosphorylation of Akt and NF-κB/p65 nuclear translocation was all inhibited by MEL-pep. Insulin ­ like growth factor I, a phosphatidylinositol 3 kinase(PI3K) /protein kinase B(AKT) agonist, reversed MEL-pep induced P-gp suppression. Therefore, MEL-pep inhibited P-gp expression by deactivating the PI3K/Akt signaling pathway. Finally, in a BEL-7402/5-FU cell-derived xenograft tumor model in mice, we found that the intratumoral administration of MEL-pep inhibited tumor growth in a dose-dependent manner. Thus, MEL-pep could be a promising candidate in the treatment of chemotherapy resistant HCC. [ABSTRACT FROM AUTHOR]

Autophagy plays a dual role in many types of cancer, such as hepatocellular carcinoma (HCC). Autophagy seems to be inhibited and functions as a tumor-suppression mechanism in the "inflammation-carcinogenesis" pathway of the liver, including hepatitis B virus and hepatitis C virus, alcoholic steatohepatitis and non-alcoholic steatohepatitis related HCC. However, in established tumors, autophagy plays a tumor-promoting role. Because of the varied function of autophagy in HCC, we hypothesized p62 as a marker to evaluate the autophagic level. Moreover, autophagy is critical in antigen presentation and homeostasis of immune cells and tumor microenvironment. Understanding the intricate relationships of autophagy, inflammation, and immunity provides us with new insights into HCC immunotherapy. [ABSTRACT FROM AUTHOR]

Sex affects the risk, treatment responses and outcome of many types of cancers. The mechanism of gender disparity in development of hepatocellular carcinoma (HCC) remains obscure. Sex-determining region on Y chromosome (SRY) was overexpressed in approximate 84% male patient HCC. Moreover, we are the first to generate a liver-specific transgenic (TG) murine model with overexpression of the male specific gene SRY. Subject to a single intraperitoneal injection N-nitrosodiethylamine (DEN) at day 14, TG and wildtype (WT) mice of both genders were sacrificed at different time points (6-13.5 months). Overexpression of SRY in male TG and ectopic expression of SRY in female TG livers promoted DEN-induced hepatocarcinogenesis compared to age- and sex-matched WT. This accelerated tumorigenesis in TG of both genders was a consequence of increased injury and inflammation, fibrosis, and compensatory enhancement in hepatocytes proliferation secondary to activation of downstream targets Sox9 and platelet-derived growth factor receptor α (PDGFRα)/phosphoinositide 3-kinase (PI3K)/Akt and c-myc/CyclinD1. In conclusion, activation of SRY and its downstream Sox9 and PDGFRα pathways are commonly involved in male hepatocarcinogenesis, which provides novel insights into gender disparity and sex-specific therapeutic strategies of HCC. [ABSTRACT FROM AUTHOR]

Lymphotoxin-β receptor (LTβR) signaling is involved in hepatitis B virus (HBV) infection, hepatitis and liver carcinogenesis. However, the potential association between LTBR polymorphisms and HBV infection remains unclear. This study investigated the associations between LTBR polymorphisms and chronic HBV infection and HBV-related hepatocellular carcinoma (HCC). The study included 409 patients with chronic HBV infection, 73 HBV infection resolvers, and 197 healthy controls. Two polymorphisms rs12354 and rs3759333 were selected and genotyped by polymerase chain reaction-ligase detection reaction method. The frequencies of rs12354 genotype GT and allele T in HBV infection resolvers were significantly higher than those in patients with chronic HBV infection and healthy controls (genotype GT: 38.4% vs. 22.2% and 38.4% vs. 20.8%, P = 0.004 and P = 0.004, respectively; allele T: 20.5% vs. 13.1% and 20.5% vs. 12.9%, P = 0.017 and P = 0.028, respectively). The frequencies of rs3759333 genotypes and alleles between HBV patients, HBV infection resolvers and healthy controls had no statistical difference. The genotype and allele frequencies of rs12354 and rs3759333 had no statistical differences between chronic hepatitis B and HBV-related HCC patients. The serum LTβR levels and the overall survival rate between HBV-related HCC patients carrying different rs12354 and rs3759333 genotypes had no statistical differences. These results suggest that the LTBR rs12354 polymorphism might be associated with the spontaneous resolution of HBV infection. Additional studies with large sample size are needed to confirm and extend these findings. [ABSTRACT FROM AUTHOR]