Identification of core genes and outcomes in hepatocellular carcinoma by bioinformatics analysis.

Hepatocellular carcinoma (HCC) is the most common malignant liver disease in the world. However, the mechanistic relationships among various genes and signaling pathways are still largely unclear. In this study, we aimed to elucidate potential core candidate genes and pathways in HCC. The expression profiles GSE14520, GSE25097, GSE29721, and GSE62232, which cover 606 tumor and 550 nontumour samples, were downloaded from the Gene Expression Omnibus (GEO) database. Furthermore, HCC RNA-seq datasets were also downloaded from the Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were filtered using R software, and we performed gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis using the online databases DAVID 6.8 and KOBAS 3.0. Furthermore, the protein-protein interaction (PPI) network complex of these DEGs was constructed by Cytoscape software, the molecular complex detection (MCODE) plug-in and the online database STRING. First, a total of 173 DEGs (41 upregulated and 132 downregulated) were identified that were aberrantly expressed in both the GEO and TCGA datasets. Second, GO analysis revealed that most of the DEGs were significantly enriched in extracellular exosomes, cytosol, extracellular region, and extracellular space. Signaling pathway analysis indicated that the DEGs had common pathways in metabolism-related pathways, cell cycle, and biological oxidations. Third, 146 nodes were identified from the DEG PPI network complex, and two important modules with a high degree were detected using the MCODE plug-in. In addition, 10 core genes were identified, TOP2A, NDC80, FOXM1, HMMR, KNTC1, PTTG1, FEN1, RFC4, SMC4, and PRC1. Finally, Kaplan-Meier analysis of overall survival and correlation analysis were applied to these genes. The abovementioned findings indicate that the identified core genes and pathways in this bioinformatics analysis could significantly enrich our understanding of the development and recurrence of HCC; furthermore, these candidate genes and pathways could be therapeutic targets for HCC treatment.

The prognostic value of microvascular invasion in early-intermediate stage hepatocelluar carcinoma: a propensity score matching analysis.

BACKGROUND: Microvascular invasion (MVI) is well established as a negative prognostic factor for hepatocelluar carcinoma (HCC). However, its prognostic value in different subgroups of Barcelona Clinical Liver Cancer (BCLC) stages remains to be elucidated. METHODS: Four hundred fifty-eight MVI-negative and 204 MVI-positive patients who underwent hepatectomy were retrospectively analyzed. After propensity score matching (PSM) analysis, 187 pairs of matched patients were generated. Long-term survival was compared by the Kaplan-Meier method. RESULTS: Patients with MVI commonly had more advanced tumors. All the patients with MVI had significantly worse survival rate compared to the patients without MVI before and after PSM(p < 0.001). In the subgroup analysis, BCLC stage A HCC patients without MVI had better prognosis than those with MVI before and after PSM (p < 0.001 and p = 0.024). For BCLC stage B HCCs, long-term survival was significantly better for patients without MVI before PSM(p = 0.001). However, the overall survival (OS) rate was comparable between both groups after PSM (p = 0.682), although MVI-positive group had a higher rate of recurrence (p = 0.011).. Surgery type, satellite lesions, tumor size, and serum ALT level were statistically significant factors associated with survival in MVI-positive group. Tumor number, tumor size and neutrophil to lymphocyte ratio (NLR) were predictors of survival in MVI-negative group. CONCLUSIONS: Its prognostic value in different subgroups of BCLC stages differed. MVI is an independent predictor of prognosis in patients with BCLC stage A. For BCLC stage B HCCs, MVI-positive group had poor prognosis through more advanced HCCs.

The Prognostic Prediction Role of Preoperative Serum Albumin Level in Patients with Intahepatic Cholangiocarcinoma Following Hepatectomy.

BACKGROUND: There is little information regarding the role of preoperative serum albumin (ALB) in intrahepatic cholangiocarcinoma (ICC) patients who underwent liver resection. METHODS: Clinicopathological characteristics and survival rate of 91 ICC patients who underwent surgery between 2009 and 2013 were included in this study. The optimal cut-off for ALB were determined by plotting the receiver operating characteristics curves of ALB in predicting overall survival (OS) and utilizing the Youden index. Long-term outcome was calculated by Kaplan-meire method. RESULTS: The pathological characteristics were similar in both groups. The 1- and 3-year disease-free survival (DFS) rates between the high ALB group and the lower ALB group were 62.7 vs. 25.5% and 27.0 vs. 11.1% respectively (p < 0.001). The 1- and 3-year OS rates between the high ALB group and the lower ALB group were 78.4 vs. 57.5% and 42.6 vs. 6.7% respectively (p < 0.001). The ALB level as continuous variable in multivariate analysis remained a favorable factor for DFS and OS (p < 0.05). Furthermore, ALB could distinguish the prognoses in non-cirrhotic patients. Multivariate analysis showed other pathological risk factors like lymph node involvement, positive surgical margin, satellite lesions, and carbohydrate antigen 19-9 were associated with DFS and OS (p < 0.05 for all). CONCLUSIONS: A higher preoperative serum ALB level is associated with better long-term survival in ICC patients.

The Impact of Tumor Differentiation on the Prognosis of HBV-Associated Solitary Hepatocellular Carcinoma Following Hepatectomy: A Propensity Score Matching Analysis.

AIM: The role of tumor differentiation in the prognosis of hepatocellular carcinoma (HCC) after hepatectomy remains controversial. The present study aimed to classify the impact of tumor differentiation on solitary hepatitis B viral (HBV)-associated HCC using propensity score matching analysis. METHODS: Between January 2009 and March 2015, the data of 721 HCC patients in West China Hospital were prospectively collected and analyzed. Propensity matching analysis was applied to overcome the imbalance in baseline characteristics. Survival analysis was performed using the Kaplan-Meier method. Risk factors were identified by the Cox proportional hazards model. RESULTS: All HCC patients were classified into the moderately well-differentiated HCCs group (group A, n = 442, 61.3%) or poorly differentiated HCCs group (group B, n = 279, 38.7%). Patients with poorly differentiated HCCs commonly had a larger tumor size, more advanced tumors, and a higher alpha-fetoprotein (AFP) level. Patients with poorly differentiated HCCs had a poorer recurrence-free survival and overall survival before and after propensity score matching analysis. Poorly differentiated tumors, positive serum hepatitis B viral e antigen, positive hepatitis B virus deoxyribonucleic acid load, tumor size, microvascular invasion, and AFP > 400 ng/ml were risk factors of a poor outcome. CONCLUSIONS: Our propensity model provided strong evidence that a poorly differentiated tumor had a negative impact on the recurrence and long-term survival of solitary HBV-associated HCCs after curative hepatectomy. Antiviral therapy might improve their prognosis.

Short- and Long-term Outcomes between Young and Older HCC Patients Exceeding The Milan Criteria after Hepatectomy.

AIM: The objective of this study was to evaluate short- and long-term survival after surgical treatment between young and older hepatocellular carcinoma (HCC) patients beyond the Milan criteria. MATERIAL AND METHODS: One hundred fifty-seven HCC patients (≤ 55 years old) were categorized into group A, and one hundred fifty-eight HCC patients (> 55 years old) were categorized into group B. Postoperative complications and overall survival were retrospectively analyzed. RESULTS: Older HCC patients had a higher rate of delayed extubation after surgery and suffered more complications after surgery, especially major complications. Intraoperative blood transfusion, liver fibrosis/cirrhosis and delayed extubation were risk factors related to postoperative complications. Microvascular invasion (MVI), tumor diameter, postoperative alpha-fetoprotein and the presence of satellites were independent risk factors for long-term survival. Young patients had more advanced tumors. Overall survival rates at 1, 3 and 5-years were 78.1%, 45.1% and 27.4% for young patients, respectively, and 86.5%, 57.5% and 42.4% for older patients, respectively (p = 0.007). CONCLUSION: The category A group had poorer tumor characteristics and worse prognoses than the category B group.

Genetic variants in cell death pathway genes and HBV-related hepatocellular carcinoma among a Chinese Han population.

Cell death pathway plays an important role in apoptosis, and corruption of this signaling pathway has been shown to participate in carcinogenesis. We aimed at determining whether genetic variants in CASP8, CASP10 and CFLAR influence the development and clinical outcomes of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). A hospital-based case-control study, including 600 HCC cases and 600 HBsAg positive controls without HCC, was conducted to assess the relationship between 11 tagging SNPs in CASP8, CASP10 and CFLAR and HBV-related HCC risk and prognosis in a Chinese Han population. Among the 11 polymorphisms, only CASP8 rs3834129 (-652 6N ins/del) modified HCC risk. Compared with CASP8 -652 insins genotype, the deldel (adjusted OR 0.717, 95% CI 0.553-0.930) and insdel (adjusted OR 0.731, 95% CI 0.554-0.964) genotypes had a significantly decreased HCC risk. Furthermore, this polymorphism was significantly associated with decreased portal vein tumor thrombosis (adjusted OR 0.554; P = 0.044) and reduced postoperative recurrence (adjusted OR 0.356; P < 0.001) of resected HCC. In addition, the multivariate analysis showed that the -652 6N ins/del polymorphism was significantly associated with improved overall survival and recurrence-free survival of resected HCC patients. The expression levels of CASP8 in HCC tumor tissues were significantly lower than those in paracancerous liver tissues, although no significant association between -652 6N ins/del genotypes and the expression levels of CASP8 were observed in these tissues. These results suggest that the CASP8 -652 6N ins/del polymorphism may play a protective role in the development, progression, and survival of HBV-related HCC among the Chinese Han population.

Alpha fetoprotein changes predict hepatocellular carcinoma survival beyond the Milan criteria after hepatectomy.

BACKGROUND: Assessing the outcomes of surgeries for hepatocellular carcinoma (HCC) patients who exceed the Milan criteria is necessary. Some studies have demonstrated that preoperative or postoperative alpha fetoprotein (AFP) can predict HCC patients' prognoses. METHODS: A total of 280 HCC patients who were positive for AFP and received curative resection were retrospectively analyzed. The patients were classified into three groups according to their preoperative and postoperative AFP levels (group A: normalized AFP; group B: AFP decreases >50%, but continued abnormality; and group C: AFP decreases <50%). Disease-free survival and overall survival rates were analyzed using the Kaplan-Meier method. The factors associated with AFP changes were evaluated by logistic regression. RESULTS: AFP dynamic changes were independently associated with disease-free survival and overall survival rates. Group A had better 3- and 5-y survivals than groups B or C (58.7% and 39.5% versus 31.3% and 14.9% versus 17.1% and 8.8%, P < 0.001). Preoperative AFP, tumor differentiation, tumor diameter, microvascular invasion, and satellite nodules remained significant risk factors that were associated with AFP changes. Furthermore, in group A, the disappearances of AFP within and beyond 8 wk resulted in similar overall survival rates (P > 0.05). Among those with HCC recurrence, the patients treated with resurgery or radiofrequency ablation achieved the best recurrence to death survivals. Those treated with transcatheter arterial chemoembolization achieved the next best survivals. CONCLUSIONS: AFP changes predicted the prognoses of patients with HCC beyond the predictions of the Milan criteria. Preoperative AFP (>400 ng/mL), tumor differentiation, tumor diameter, and satellite nodules were the risk factors related to AFP normalization. The regular follow-up and early detection of recurrent HCCs that are suitable for curative therapies, such as resurgery and radiofrequency ablation, might improve the prognoses. Other therapies, such as transcatheter arterial chemoembolization, might also be effective.

Liver resection versus liver resection plus TACE for patients with hepatocellular carcinoma beyond Milan criteria.

BACKGROUND: The recurrence of patients with hepatocellular carcinoma (HCC) beyond the Milan criteria after liver resection (LR) is common. This study aimed to clarify whether LR plus postoperative adjuvant transcatheter arterial chemoembolization (TACE) could improve the outcomes of patients with HCC beyond the Milan criteria after LR. METHODS: A total of 754 consecutive patients with HCC beyond the Milan criteria who received LR alone (n = 459) or LR + TACE (n = 295) were included. A propensity scoring matched model (PSM) was used to adjust for the baseline differences between the groups. RESULTS: The 1, 3, and 5-y recurrence-free survival (76.7%, 40.4%, and 30.8%, respectively, for the LR-alone group versus 78.3%, 50.5%, and 46.2%, respectively, for the LR + TACE group; P = 0.004) and overall survival (94.1%, 58.3%, and 36.3%, respectively, for the LR-alone group versus 95.3%, 71.3%, and 54.9%, respectively, for the LR + TACE group; P < 0.001) rates of patients who underwent LR alone were much lower than in the LR + TACE group. Multivariate Cox proportional hazards regression analysis showed that LR alone was an independent risk factor for postoperative recurrence and poor long-term survival. After one-to-one PSM, 284 patients who underwent LR alone and 284 patients who underwent LR + TACE were selected for further analyses. Similar results were observed in the PSM model. CONCLUSIONS: This study showed that LR + TACE may be beneficial for patients with HCC beyond the Milan criteria. Postoperative adjuvant TACE should be considered to patients with HCC beyond the Milan criteria.

Splenectomy before adult liver transplantation: a retrospective study.

BACKGROUND: A considerable number of patients with portal hypertension (PHT) have to undergo splenectomy because they do not meet the requirements for liver transplantation (LT) or cannot find a suitable liver donor. However, it is not known whether pre-transplantation splenectomy may create occult difficulties for patients who require LT in future. METHODS: We analyzed 1059 consecutive patients who underwent adult liver transplantation (ADLT). Patients with pre-transplantation splenectomy Sp(+) and without splenectomy Sp(-) were compared using a propensity score analysis to create the best match between groups. RESULTS: There were no differences between patients in group Sp(+) and group Sp(-) with respect to the main post-operative infections (12.20% vs. 15.85%, P = 0.455), and the incidence of major complications (6.10% vs. 10.98%, P = 0.264). The post-operative platelet count was significantly higher in group Sp(+) (P = 0.041), while group Sp(-) had a higher rate of post-operative thrombocytopenia (91.46% vs. 74.39%, P = 0.006) and early allograft dysfunction (EAD) (23.20% vs. 10.98%, P = 0.038). The 5-year overall survival rates were similar in groups Sp(-) and Sp(+) (69.7% vs. 67.6%, P = 0.701). CONCLUSIONS: Compared with Sp(-), the risk of infection and post-operative complications in group Sp(+) was not increased, while group Sp(-) had a higher rate of post-operative EAD. Moreover, pre-transplantation splenectomy is very effective for the prevention of thrombocytopenia after LT. Pre-transplantation splenectomy is recommended in cases with risky PHT patients without appropriate source of liver for LT.

Microvascular invasion patterns affect survival in hepatocellular carcinoma patients after second hepatectomy.

BACKGROUND: Microvascular invasion (MVI) is an important risk factor for survival of patients with hepatocellular carcinoma (HCC) after hepatectomy. However, its impact on patients with recurrent HCC who receive a second hepatectomy is unknown. METHODS: We enrolled 167 patients with HCC who underwent a second hepatectomy because of intrahepatic recurrences. We compared the patients' demographic, tumor, and pathologic characteristics with 766 cases of original hepatectomy. We analyzed the possible risk factors for survival after the first and second hepatectomies and the influence of different MVI patterns on patients' survival after the second hepatectomy. RESULTS: The median overall survival was comparable between the first and second hepatectomy groups, 34 (3-84) mo versus 27 (3-57) mo, P = 0.09. For patients who underwent a first hepatectomy, the presence of macro-VI or MVI, an early recurrence pattern, and a total tumor diameter >5 cm were independent risk factors. For survival after the second hepatectomy, MVI patterns that were positive-positive or negative-positive and a total recurrent tumor diameter >5 cm were significant risk factors for survival. CONCLUSIONS: A second hepatectomy provides satisfying survival for patients with intrahepatic recurrence of HCC after the initial operation. Different MVI patterns affect survival after the second hepatectomy. Because MVI represents the biological behavior of HCC, we place a high premium on the clinical value of MVI after each hepatectomy.

Liver transplantation for hepatolithiasis: Is terminal hepatolithiasis suitable for liver transplantation?

Hepatolithiasis, originally as oriental cholangiohepatitis, especially prevails in Asia, but globalization and intercontinental migration have also converted the endemic disease dynamics around the world. Characterized by its high incidence of ineffective treatment and recurrence, hepatolithiasis, always, poses a therapeutic challenge to global doctors. Although the improved surgical and non-surgical techniques have evolved over the past decade, incomplete clearance and recurrence of calculi are always so common and disease-related mortality from liver failure and concurrent cholangiocarcinoma still exists in the treatment of hepatolithiasis. In the late stage of hepatolithiasis, is it suitable for liver transplantation (LT)? Herein, we propose a comprehensive review and analysis of the LTx currently in potential use to treat hepatolithiasis. In our subjective opinion, and as is objective from the literatures so far, also given the strict indications, LT remains one of the definitive treatments for terminal hepatolithiasis.

Prognostic value of the platelet to lymphocyte ratio change in liver cancer.

BACKGROUND: There is limited evidence concerning the postoperative platelet to lymphocyte ratio change (ΔPLR) in relation to the prognosis of hepatocellular carcinoma (HCC). This study was designed to evaluate the prognostic value of ΔPLR in patients with hepatitis B virus (HBV)-related small HCC who underwent liver resection. MATERIALS AND METHODS: We retrospectively reviewed 219 patients with HBV-related small HCC who underwent liver resection between February 2007 and April 2013. The patients were divided into two groups as follows: group A (ΔPLR ≥2.875, n = 94) and group B (ΔPLR <2.875, n = 125), according to receiver operating characteristic analysis. Demographic, clinical, and follow-up data were analyzed, and multivariate analysis was used to identify prognostic factors. RESULTS: The 1-, 3-, and 5-y overall survival (OS) rates were 90.5%, 72.3%, and 42.1%, respectively, in group A and 98.1%, 89.5%, and 86.4%, respectively, in group B (P < 0.001). Correspondingly, the 1-, 3-, and 5-y recurrence-free survival (RFS) rates were 57.5%, 36.1%, and 22.8%, respectively, in group A and 84.3%, 62.4%, and 55.4%, respectively, in group B (P < 0.001). Multivariate analysis showed that ΔPLR was an independent prognostic factor for both OS (P < 0.001, hazard ratio = 5.452, 95% confidence interval 2.592-11.467) and RFS (P < 0.001, hazard ratio = 2.191, 95% confidence interval 1.4611-3.288). CONCLUSIONS: ΔPLR was an independent prognostic factor for OS and RFS in patients with HBV-related small HCC who underwent liver resection.

Upper abdominal shape as a risk factor of extended operation time and severe postoperative complications in HCC hepatectomy through subcostal incision.

BACKGROUND: Subcostal incision is the most widely used approach in open surgery for patients with hepatocellular carcinoma (HCC). Body shape is recognised to be a factor influencing the difficulty of surgery; however, the exact impact of the increased difficulty on the patients' operation as well as the outcome has not been analysed. In this study, we retrospectively studied the possible influence of patients' body shape, tumour burden and varied surgical methods on the operation procedure and postoperative complications. METHODS: From January 2009 to December 2013, 651 patients with HCC were included in the study. We studied the patients' sex, age, body mass index, upper abdominal body shape described by the depth-to-width ratio for the trunk at the celiac axis on CT/MRI, Child-Pugh classification, tumour burden and a different liver dissection method before the surgery and used a regression model for analysis. RESULTS: Prolonged operation time is associated with advanced tumour stage, large CA ratio, previous abdominal surgery, selective hepatic vascular occlusion and dissecting with Cavitron ultrasonic surgical aspirator rather than clamp crushing. Surgical blood loss is associated with operation time, liver function and a different liver dissection method. The incidence of severe postoperative complication was 17.5% (114/651) and was associated with larger CA ratio, Child-Pugh stage B liver function and greater blood loss. CONCLUSIONS: Large upper abdominal shape is a risk factor of both prolonged operation time and severe postoperative complication. CA ratio combined with liver function and surgical blood loss has an acceptable power to predict severe postoperative complications.

Neutrophil to lymphocyte ratio changes predict small hepatocellular carcinoma survival.

BACKGROUND: There is limited information available concerning the delta neutrophil to lymphocyte ratio (ΔNLR) in hepatocellular carcinoma (HCC). The present study was designed to evaluate the predictive value of dynamic change of NLR in patients who undergo curative resection for small HCC. METHODS: A retrospective cohort study was performed to analyze 189 patients with small HCC who underwent curative resection between February 2007 and March 2012. Patient data were retrieved from our prospectively maintained database. Patients were divided into two groups: group A (NLR increased, n = 80) and group B (NLR decreased, n = 109). Demographic and clinical data, overall survival (OS), and recurrence-free survival (RFS) were statistically compared and a multivariate analysis was used to identify prognostic factors. RESULTS: The 1, 3, and 5-y OS in group A was 92.7, 70.0, and 53.0%, respectively, and 96.2, 87.5, and 75.9%, respectively, for group B (P = 0.003); The corresponding 1, 3, and 5-y RFS was 58.7, 37.9, 21.8, and 81.2%, 58.5% and 53.8% for groups A and B, respectively (P <0.001). Multivariate analysis suggested that ΔNLR was an independent prognostic factor for both OS (P = 0.004, Hazard Ratio (HR) = 2.637, 95% confidence interval (CI) 1.356-5.128) and RFS (P <0.001, HR = 2.372, 95% CI 1.563-3.601). CONCLUSIONS: Increased NLR, but not high preoperative NLR or postoperative NLR, helps to predict worse OS and RFS in patients with small HCC who underwent curative resection.

Thirty-five consecutive pediatric living donor liver transplantation: experiences and lessons learned from a single center.

BACKGROUND/AIMS: In the last 10 years, the early patient outcome of liver transplantation in children have significantly improved. Now the overall outcomes of pediatric LT are promising. METHODOLOGY: In this study, we review the outcome of all pediatric liver transplants performed at our center and analyze our experiences with pediatric liver transplant. Of the 34 liver transplant recipients, 26 were highly urgent (19.7%). RESULTS: Actuarial patient survival rates at 6, 12, and 36 months was 82.9%, 79.8% and 72.2%, respectively. Indications for liver transplant were biliary atresia (n = 22), Wilson's disease (n = 4), glycogen storage disease (n = 3), portal vein cavernous transformation (PVCT) (n = 3), fulminant liver failure (n = 1), and cryptogenic cirrhosis (n = 1). The main complications were surgical complications (including biliary complications, portal vein or arterial complications, intestinal perforation, postoperative bleeding, of which 20% required reoperation) and infections. Cyclosporine was the primary immunosuppressive agent used in 70.6% of patients, with a 26.5% incidence of acute allograft rejection within the first six months. One children underwent re-transplant as a result of hepatic artery thrombosis. Nine children died during followup. They were related to portal vein thrombosis (one), chronic rejection (one), sepsis (one), post-transplant lymphoproliferative disease (one) and so on. CONCLUSIONS: The overall outcomes of pediatric liver transplantation at our center are promising. Advances in post-transplant care and monitoring of the recipients, technical refinements enable these results.

Short-term and long-term outcomes of surgical treatment for HCC within Milan criteria with cirrhotic portal hypertension.

BACKGROUND/AIMS: To compare and assess the outcomes of liver resection, radiofrequency ablation and liver transplantation for patients with hepatocellular carcinoma (HCC) within Milan criteria and cirrhotic portal hypertension. METHODOLOGY: 248 patients with HCC within Milan criteria and cirrhotic portal hypertension who underwent surgical treatments (liver resection, radiofrequency ablation and liver transplantation were reviewed in this study. Patients were divided into three groups according to different surgical strategies: RST Group, RFA Group and LT Group. Pre- and intra-operative parameters were statistically analyzed. Postoperative outcomes including Hematological data and tumor data, complications, long-term survival rates and recurrence-free survival rates were compared. RESULTS: The incidence of postoperative complications that were classified according to Clavien-Dido Classification were 16.22% for RST Group, 9.09% for RFA Group and 53.85% for LT Group. The 1-, 2- and 3-year recurrence-free survival rate of three groups were 88%, 74%, 68% for RST Group, 60%, 39%, 35% for RFA Group and 97%, 89%, 87% for LT Group, respectively. CONCLUSION: Although the postoperative recurrence rate following RFA was higher than that of RST and LT, the long-term survival rates of three managements for patients with HCC within Milan criteria and portal hypertension were similar.

[Clinical significance of hepatitis B virus S gene mutation for recurrence of hepatitis B after liver transplantation].

OBJECTIVE: To examine the incidence of hepatitis B virus (HBV) S gene mutation in recipients with recurrent HBV infection after liver transplantation (LT) and to evaluate the clinical significance of these mutants. METHODS: Two-hundred-and-ninety-nine patients who received LT for HBV-related liver diseases in single centre were enrolled in the study and followed up. Serum HBV DNA was amplified by fluorescence quantitative polymerase chain reaction, and HBV-S gene mutation was detected by Sanger's enzymatic method. RESULTS: Twelve of the 299 patients developed recurrent HBV after LT, and 2 of these 12 carried a mutant of the HBV-S gene (incidence rate of 16.67%). One of the patients had T126I and G145A mutations, and the other had a M 133L mutation. Cox regression modelling identified the risk factors of HBV recurrence after LT as HBV-YMDD mutants (P =0.01), HBV-S mutants (P =0.03) and compliance decrease (P =0.03). CONCLUSION: HBV-S mutants may contribute to recurrence of HBV after LT, and the mechanism should be addressed in future studies.

Repaglinide restrains HCC development and progression by targeting FOXO3/lumican/p53 axis.

PURPOSE: The recent focus on the roles of N-linked glycoproteins in carcinogenesis across various malignancies has prompted our exploration of aberrantly expressed glycoproteins responsible for HCC progression and potential therapeutic strategy. METHODS: Mass spectrometry was applied to initially identify abnormally expressed glycoproteins in HCC, which was further assessed by immunohistochemistry (IHC) staining. The role of selected glycoprotein on HCC development and underlying mechanism was systematically investigated by colony formation, mouse xenograft, RNA-sequencing and western blot assays, etc. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to explore potential transcription factors (TFs) of selected glycoprotein. The regulation of repaglinide (RPG) on expression of lumican and downstream effectors was assessed by western blot and IHC, while its impact on malignant phenotypes of HCC was explored through in vitro and in vivo analyses, including a murine NASH-HCC model established using western diet and carbon tetrachloride (CCl4). RESULTS: Lumican exhibited upregulation in both serum and tumor tissue, with elevated expression associated with an inferior prognosis in HCC patients. Knockdown of lumican resulted in significantly reduced growth of HCC in vitro and in vivo. Mechanically, lumican promoted HCC malignant phenotypes by inhibiting the p53/p21 signaling pathway. Forkhead Box O3 (FOXO3) was identified as the TF of lumican that transcriptionally enhanced its expression. Without silencing FOXO3, RPG blocked the binding of FOXO3 to the promoter region of lumican, thereby inhibiting the activation of lumican/p53/p21 axis. Mice treated with RPG developed fewer and smaller HCCs than those in the control group at 24 weeks after establishment. CONCLUSION: Our results indicate that RPG prevented the development and progression of HCC via alteration of FOXO3/lumican/p53 axis.

Genetic variants of p21 and p27 and hepatocellular cancer risk in a Chinese Han population: a case-control study.

The p21 (Cip1/CDKN1A) and p27 (Kip1/CDKN1B) are members of the Cip/Kip family of cyclin-dependent kinase inhibitors, which can arrest cell proliferation and serve as tumour suppressors. We hypothesized that genetic variants in p21 and p27 may modify individual susceptibility to hepatocellular carcinoma (HCC). To test this hypothesis, we evaluated the associations of the polymorphisms of Ser31Arg and C+20T in p21 and C-79T and Gly109Val in p27, as well as their combinations, with HCC risk in a case-control study of 476 HCC cases and 526 cancer-free controls in a Chinese population. The matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry method was performed to detect these polymorphisms. We found that the variant genotypes of p21 Ser31Arg and p27 C-79T were individually associated with a significantly increased risk of HCC, but no associations were observed for other variant genotypes. Moreover, the combined variant genotypes of the four loci were associated with a significantly increased HCC risk (adjusted OR = 2.24, 95% CI = 1.72, 2.91 among subjects carrying 3 or more variant alleles), especially among HbsAg-positive individuals (adjusted OR = 3.09, 95% CI = 1.86, 5.14). Furthermore, the combined variant genotypes of the four loci (carrying three or more variant alleles) increased a 1.93-fold (95% CI = 1.20, 3.09) and 1.76-fold (95% CI = 1.17, 2.64) risk of HCC among smokers and nonsmokers. The variant genotypes of the two genes in this study have negative correlation with the clinicopathologicals observed. These results suggest that p21 polymorphisms individually or in combination with p27 polymorphisms increases risk of HCC, particularly among HbsAg-positive individuals.

Association of a p73 exon 2 G4C14-to-A4T14 polymorphism with risk of hepatocellular carcinoma in a Chinese population.

P73, a p53 homolog, has some p53-like activities and plays an important role in modulating cell cycle, apoptosis, and DNA repair. A potentially functional dinucleotide polymorphism, G4C14-to-A4T14, has been identified in the 5' untranslated region of exon 2 of the p73 gene, which may theoretically form a stem-loop structure and affect gene expression. We hypothesized that genetic variants in p73 may modify individual susceptibility to hepatocellular carcinoma (HCC). To test this hypothesis that these two common variants play a role in HCC susceptibility, we conducted a hospital-based case-control study of 476 HCC patients and 526 cancer-free controls in a Chinese population. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry method was performed to detect these polymorphisms. The results showed that the genotype and allele frequencies of the p73 G4C14-A4T14 did not differ significantly between the HCC patients and the control group (all P values are above 0.05). However, with stratification analysis by age, sex, smoking status, drinking status, HBV carrier state, and family history of cancer, we found that the variant genotypes (GC/AT + AT/AT) of the p73 G4C14-A4T14 was associated with a significant increased risk of HCC among HbsAg-positive individuals (adjusted OR = 2.19, 95 % CI = 1.25-3.83) and among women (adjusted OR = 2.62, 95 % CI = 1.47, 4.66). These results suggest that the p73 G4C14-to-A4T14 dinucleotide polymorphism may play a role in the development of chronic HBV-infected HCC in the Chinese population, especially among women.