Safety and efficacy of interventional embolization in cirrhotic patients with refractory hepatic encephalopathy associated with spontaneous portosystemic shunts.

This study aimed to assess the safety and efficacy of interventional embolization in cirrhotic patients with refractory hepatic encephalopathy (HE) associated with large spontaneous portosystemic shunts (SPSS). Inverse probability of treatment weighting (IPTW) was employed to minimize potential bias. A total of 123 patients were included in this study (34 in the embolization group and 89 in the control group). In the unadjusted cohort, the embolization group demonstrated significantly better liver function, a larger total area of SPSS, and a higher percentage of patients with serum ammonia levels > 60 µmol/L and the presence of hepatocellular carcinoma (HCC) (all P < 0.05). In the IPTW cohort, baseline characteristics were comparable between the two groups (all P > 0.05). Patients in the embolization group exhibited significantly longer HE-free survival compared to the control group in both the unadjusted and IPTW cohorts (both P < 0.05). Subsequent subgroup analyses indicated that patients with serum ammonia level > 60 µmol/L, hepatopetal flow within the portal trunk, the presence of solitary SPSS, a baseline HE grade of II, and the absence of HCC at baseline showed statistically significant benefit from embolization treatment (all P < 0.05). No early procedural complications were observed in the embolization group. The incidence of long-term postoperative complications was comparable to that in the control group (all P > 0.05). Hence, interventional embolization appears to be a safe and effective treatment modality for cirrhotic patients with refractory HE associated with large SPSS. However, the benefits of embolization were discernible only in a specific subset of patients.

External validation of the modified CTP score based on ammonia to predict survival in patients with cirrhosis after TIPS placement.

This study aimed to perform the first external validation of the modified Child-Turcotte-Pugh score based on plasma ammonia (aCTP) and compare it with other risk scoring systems to predict survival in patients with cirrhosis after transjugular intrahepatic portosystemic shunt (TIPS) placement. We retrospectively reviewed 473 patients from three cohorts between January 2016 and June 2022 and compared the aCTP score with the Child-Turcotte-Pugh (CTP) score, albumin-bilirubin (ALBI), model for end-stage liver disease (MELD) and sodium MELD (MELD-Na) in predicting transplant-free survival by the concordance index (C-index), area under the receiver operating characteristic curve, calibration plot, and decision curve analysis (DCA) curve. The median follow-up time was 29 months, during which a total of 62 (20.74%) patients died or underwent liver transplantation. The survival curves for the three aCTP grades differed significantly. Patients with aCTP grade C had a shorter expected lifespan than patients with aCTP grades A and B (P < 0.0001). The aCTP score showed the best discriminative performance using the C-index compared with other scores at each time point during follow-up, it also showed better calibration in the calibration plot and the lowest Brier scores, and it also showed a higher net benefit than the other scores in the DCA curve. The aCTP score outperformed the other risk scores in predicting survival after TIPS placement in patients with cirrhosis and may be useful for risk stratification and survival prediction.

Interventional embolisation for patients with cirrhosis and recurrent or persistent hepatic encephalopathy related to spontaneous portosystemic shunts: protocol for a prospective, non-randomised controlled study.

INTRODUCTION: The presence of spontaneous portosystemic shunts (SPSS) has been identified to be associated with hepatic encephalopathy (HE) in patients with cirrhosis. Nevertheless, the role of interventional embolisation in managing such patients remains poorly defined. Consequently, this prospective controlled study aims to assess the efficacy and safety of interventional embolisation as a therapeutic approach for patients with cirrhosis and recurrent or persistent HE related to SPSS. METHODS AND ANALYSIS: Cirrhotic patients diagnosed with recurrent or persistent HE associated with SPSS will be recruited for this study, and assigned to either the interventional embolisation group or the standard medical treatment group. The efficacy endpoints encompass the evaluation of postoperative alleviation of HE symptoms and the incidence of overt HE recurrence during the follow-up period, as well as the duration and frequency of hospitalisations for HE, alterations in liver function and volume, and overall survival. The safety endpoints encompass both immediate and long-term postoperative complications. ETHICS AND DISSEMINATION: This study will be conducted in strict adherence to the principles of good clinical practice and the guidelines outlined in the Declaration of Helsinki. Ethical approval for the trial has been obtained from the Ethics Committee of Mengchao Hepatobiliary Hospital of Fujian Medical University (2023_013_02). Written informed consent will be obtained from all the participants by the treating physician for each patient prior to their enrolment. The documented informed consent forms will be retained as part of the clinical trial records for future reference. The study findings will be disseminated through publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300072189.

RNA Methyltransferase FTSJ3 Regulates the Type I Interferon Pathway to Promote Hepatocellular Carcinoma Immune Evasion.

Immunotherapies such as immune checkpoint blockade have achieved remarkable success in treating cancer. Unfortunately, response rates have been limited in multiple cancers including hepatocellular carcinoma (HCC). The critical function of epigenetics in tumor immune evasion and antitumor immunity supports harnessing epigenetic regulators as a potential strategy to enhance the efficacy of immunotherapy. Here, we discovered a tumor-promoting function of FTSJ3, an RNA 2'-O-methyltransferase, in HCC by suppressing antitumor immune responses. FTSJ3 was upregulated in hepatocellular carcinoma, and high FTSJ3 expression correlated with reduced patient survival. Deletion of FTSJ3 blocked HCC growth and induced robust antitumor immune responses. Mechanistically, FTSJ3 suppressed double-stranded RNA (dsRNA)-induced IFNß signaling in a 2'-O-methyltransferase manner. Deletion of RNA sensors in HCC cells or systemic knockout of type I IFN receptor IFNAR in mice rescued the in vivo tumor growth defect caused by FTSJ3 deficiency, indicating that FTSJ3 deletion suppresses tumor growth by activating the RNA sensor-mediated type I IFN pathway. Furthermore, FTSJ3 deletion significantly enhanced the efficacy of programmed cell death protein 1 (PD-1) immune checkpoint blockade. The combination of FTSJ3 deficiency and anti-PD-1 antibody treatment effectively eradicated tumors and increased the survival time. In conclusion, this study reveals an epigenetic mechanism of tumor immune evasion and, importantly, suggests FTSJ3-targeting therapies as potential approach to overcome immunotherapy resistance in patients with HCC. SIGNIFICANCE: Hepatocellular carcinoma cells use 2'-O-methylation catalyzed by FTSJ3 for immune evasion by suppressing abnormal dsRNA-mediated type I IFN responses, providing a potential target to activate antitumor immunity and enhance immunotherapy efficacy.

Hypoxia induces hepatocellular carcinoma metastasis via the HIF-1α/METTL16/lnc-CSMD1-7/RBFOX2 axis.

Hypoxic microenvironment is clinically associated with metastasis and poor prognosis of numerous cancers. The mechanisms by which intratumoral hypoxia regulates metastasis are not fully understood. Our study identifies a downregulation of Lnc-CSMD1-7 in hepatocellular carcinoma (HCC) and correlated with poor prognosis of HCC patients. Lnc-CSMD1-7 negatively regulated HCC cell migration and invasion in vitro and suppressed lung metastasis in vivo. Mechanistically, Lnc-CSMD1-7 directly binds to RBFOX2, thereby affecting RBFOX2-regulated alternative splicing in epithelial and mesenchymal-specific events. More importantly, hypoxic microenvironment and m6A methylation mediate the downregulation of Lnc-CSMD1-7 expression. Specifically, hypoxia transcriptionally upregulates the expression of the m6A methyltransferase METTL16 via HIF-1α, and METTL16 directly binds to Lnc-CSMD1-7 and downregulates the RNA stability of Lnc-CSMD1-7 via m6A methylation, ultimately promoting HCC metastasis. Our findings highlight the regulatory function of the METTL16/Lnc-CSMD1-7/RBFOX2 axis in modulating hypoxia-induced HCC progression, which may provide potential prognostic and therapeutic targets for HCC treatment.

LncRNA TIALD contributes to hepatocellular carcinoma metastasis via inducing AURKA lysosomal degradation.

The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in RNA modification landscape and responsible for the deposition of m6A in a few transcripts. AURKA (aurora kinase A) has been confirmed as an oncogene in cancer development including hepatocellular carcinoma (HCC). Nevertheless, it remains unclear whether METTL16 mediated m6A modification of lncRNAs can regulate AURKA activation in cancer progression. Here we aimed to investigate the functional links between lncRNAs and the m6A modification in AURKA signaling and HCC progression. Here we show that LncRNA TIALD (transcript that induced AURKA Lysosomal degradation) was down-regulated in HCC tissues by METTL16 mediated m6A methylation to facilitate its RNA degradation, and correlates with poor prognosis. Functional assays reveal that TIALD inhibits HCC metastasis both in vitro and in vivo. Mechanistically, TIALD directly interacts with AURKA and facilitate its degradation through the lysosomal pathway to inhibited EMT and metastasis of HCC. AURKA's specific inhibitor alisertib exerts effective therapeutic effect on liver cancer with low TIALD expression, which might provide a new insight into HCC therapy. Our study uncovers a negative functional loop of METTL16-TIALD-AURKA axis, and identifies a new mechanism for METTL16 mediated m6A-induced decay of TIALD on AURKA signaling in HCC progression, which may provide potential prognostic and therapeutic targets for HCC.

Prevalence, clinical characteristics, and outcomes of spontaneous portosystemic shunt in patients with hepatitis B-related cirrhosis: A multicenter study from China.

BACKGROUND: The impact of spontaneous portosystemic shunt (SPSS) on decompensated events and mortality for patients with hepatitis B-related cirrhosis remains poorly investigated. AIMS: To evaluate the prevalence, clinical characteristics, and outcomes of SPSS among patients with hepatitis B-related cirrhosis. METHODS: Patients who were diagnosed with hepatitis B-related cirrhosis were retrospectively recruited. All eligible patients were classified into SPSS and non-SPSS groups and their clinical characteristics and outcomes were compared and analyzed. RESULTS: Of the 1282 patients included in this study, SPSS was identified in 488 patients (38.1%). SPSS group had more severe liver function impairment, higher prevalence and severity of esophageal and gastric varices (EGV), and a higher prevalence of EGV bleeding (EGVB), portal vein thrombosis (PVT), hepatic encephalopathy (HE), ascites, and hepatocellular carcinoma (HCC, all P<0.05). During the follow-up period, SPSS group experienced a significantly higher incidence of EGVB, PVT, and HE (all P<0.05); however, there was no significant difference in the incidence of ascites, HCC, and mortality between the two groups (all P>0.05). CONCLUSION: With hepatitis B-related cirrhosis, SPSS was common and characterized by severe liver damage and a high prevalence of decompensated events. Moreover, patients with SPSS had higher risks of EGVB, PVT, and HE.

Hepatic venous pressure gradient evaluates the Scheuer stage of liver fibrosis by transjugular liver biopsy: a multicenter study.

BACKGROUND: Hepatic venous pressure gradient (HVPG) is the criterion for assessing sinusoidal portal hypertension. Using HVPG to assess the degree of liver fibrosis by transjugular liver biopsy (TJLB) is still being explored, as no data has been shown that portal hypertension may already be present in patients with advanced hepatic fibrosis (Scheuer stage ≥ S3). The objective of this study was to observe whether portal hypertension exists before progressing to cirrhosis (Scheuer stage = S4). METHODS: Fifty patients who underwent TJLB and HVPG were enrolled. The correlation between Scheuer stage and HVPG was analyzed using the Pearson correlation coefficient, and the ROC curve predicted the diagnostic value of HVPG in patients with hepatic fibrosis. RESULTS: The Scheuer stage and HVPG significantly correlated (r = 0.654, p < 0.001). The AUC of HVPG in predicting advanced liver fibrosis was 0.896, and of cirrhosis was 0.810. There were 45 patients with portal hypertension (HVPG> 5 mmHg), 12 with S3, 29 with S4; There were 42 patients with CSPH (HVPG≥ 10 mmHg), 11 with S3, and 29 with S4. CONCLUSION: HVPG is valuable in evaluating the Scheuer stage of liver fibrosis in patients with TJLB. Portal hypertension might already exist before the progression to cirrhosis in some patients.

Spontaneous portosystemic shunts outside the esophago-gastric region: Prevalence, clinical characteristics, and impact on mortality in cirrhotic patients: A systematic review and meta-analysis.

BACKGROUND: Spontaneous portosystemic shunt (SPSS) other than esophago-gastric varices is one of the consequences of cirrhosis-induced portal hypertension (PHT), but its role is not fully understood. Therefore, we conducted a systematic review and meta-analysis to determine the prevalence and clinical characteristics of SPSS (excluding esophago-gastric varices) and its impact on mortality in patients with cirrhosis. METHODS: Eligible studies were identified from MedLine, PubMed, Embase, Web of Science, and Cochrane Library between Jan 1, 1980 and Sep 30, 2022. Outcome indicators were SPSS prevalence, liver function, decompensated events, and overall survival (OS). RESULTS: Totally, 2015 studies were reviewed, of which 19 studies recruiting 6884 patients were included. On pooled analysis, the prevalence of SPSS was 34.2% (26.6%∼42.1%). SPSS patients had significantly higher Child-Pugh scores and grades and Model for End-stage Liver Disease scores (all P<0.05). Moreover, SPSS patients experienced a higher incidence of decompensated events, including hepatic encephalopathy, portal vein thrombosis, and hepatorenal syndrome (all P<0.05). Additionally, SPSS patients had significantly shorter OS than the non-SPSS group (P<0.05). CONCLUSIONS: In patients with cirrhosis, SPSS outside the esophago-gastric region is common, characterized by severe impairment of liver function, high rates of decompensated events, including HE, PVT, and hepatorenal syndrome, as well as a high mortality rate.

Emergent Transjugular Intrahepatic Portosystemic Shunt Creation for Acute Gastric Variceal Bleeding in Patients with Hepatocellular Carcinoma.

A total of 42 cirrhotic patients (mean age, 51.7 years ± 10.8; 38 men) with hepatocellular carcinoma who underwent emergent transjugular intrahepatic portosystemic shunt (TIPS) creation for controlling acute gastric variceal bleeding (GVB) were included in this multicenter retrospective study. Of these, 37 (88.1%) patients underwent emergent TIPS creation as the first-line treatment to control acute GVB. Five (11.9%) patients underwent emergent TIPS creation as a rescue/salvage treatment to control acute GVB after emergent endoscopic therapy and pharmacotherapy. Emergent TIPS creation was technically successful in 40 (95.2%) patients. Two (4.8%) patients had severe and moderate procedural adverse events. The median follow-up duration was 16.9 months (range, 0.1-100.8 months). Failure to control acute bleeding and failure to prevent rebleeding occurred in 8 (19.0%) patients during follow-up. Eighteen (42.9%) patients died during follow-up. Three (7.1%) patients had shunt dysfunction during follow-up. Overt hepatic encephalopathy occurred in 6 (14.3%) patients during follow-up.

Splenic vein embolization as a feasible treatment for patients with hepatic encephalopathy related to large spontaneous splenorenal shunts.

INTRODUCTION AND OBJECTIVES: Although splenic vein embolization (SVE) has been performed for the management of patients with hepatic encephalopathy (HE) related to large spontaneous splenorenal shunts (SSRS) in recent years, its role remains poorly defined. In this study, we aimed to explore the safety and efficacy of SVE for HE patients with large SSRS. MATERIALS AND METHODS: Data from cirrhotic patients who were confirmed to have recurrent or persistent HE related to large SSRS and underwent SVE from January 2017 to April 2021 were retrospectively collected and analyzed at our center. The primary endpoints were the change of HE severity at 1 week after embolization and the recurrence of HE during the follow-up period. The secondary endpoints were procedure-related complications and changes in laboratory indicators and hepatic function (Child-Pugh score/grade and model for end-stage liver disease score). RESULTS: Of the eight cirrhotic patients included in the study, six were diagnosed with recurrent HE, and the others were diagnosed with persistent HE. Embolization success was achieved for all patients (100%), and no immediate procedure-related complications, de novo occurrence, or aggravation of symptoms related to portal hypertension were observed during the long-term follow-up. HE status was assessed at 1 week after embolization. The results demonstrated that the symptoms were mitigated in three patients and resolved completely in five patients. During the follow-up period, all patients were free of HE within 1 month after embolization, but one patient experienced the recurrence of HE within 6 months and another one experienced the recurrence of HE within 1 year. Compared with the preoperative parameters, the Child-Pugh score and grade were significantly improved at 1 week and 1 month after embolization (all P<0.05), and the serum ammonia level was significantly lower at 1 month after embolization (P<0.05). CONCLUSIONS: SVE could be considered as a feasible treatment for patients with HE related to large SSRS, but further validation is required.

Efficacy and safety of endovascular brachytherapy combined with transarterial chemoembolization for the treatment of hepatocellular carcinoma patients with type III or IV portal vein tumor thrombosis.

BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of endovascular brachytherapy (EVBT) combined with transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC) complicated with type III OR IV portal vein tumor thrombosis (PVTT) and to further analyze the prognostic predictors for the patients with HCC and PVTT. METHODS: We retrospectively analyzed the medical records of 54 patients who were diagnosed with HCC complicated with type III or IV PVTT and received EVBT combined with modified TACE treatment from January 2017 to June 2019. Adverse events, treatment response, overall survival (OS), progression-free survival (PFS), and stent patency were analysed to evaluate the efficacy and safety of this treatment. The independent prognostic predictors of OS were also statistically analyzed by the cox regression model. RESULTS: No adverse events occurred in the enrolled patients receiving EVBT combined with TACE treatment. The objective response and disease control rates were 42.6% and 96.3% respectively within 4 weeks after the treatment. The median OS and PFS were 209 days and 138 days, respectively. Cumulative stent patency rate was 70.4% at the last follow-up. AFP ≥ 400 ng/ml, ECOG PS > 1, Child Pugh grade B, and non-hemihepatic HCC were independent risk predictors to evaluate the OS of HCC patient with type III or IV PVTT. CONCLUSIONS: EVBT combined with TACE was a relatively effective and safe strategy to treat HCC patients with type III or IV PVTT.

Transjugular Intrahepatic Portosystemic Shunt Creation for the Prevention of Gastric Variceal Rebleeding in Patients with Hepatocellular Carcinoma: A Multicenter Retrospective Study.

PURPOSE: To evaluate the effectiveness and safety of transjugular intrahepatic portosystemic shunt (TIPS) creation for the prevention of gastric variceal rebleeding in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This multicenter retrospective study included 126 cirrhotic patients (mean age, 54.1 ± 10.2 years; 110 men) with HCC who underwent TIPS creation for the prevention of gastric variceal rebleeding. Of these, 110 (87.3%) patients had gastroesophageal varices and 16 (12.7%) patients had isolated gastric varices. Thirty-five (27.8%) patients had portal vein tumor thrombus. RESULTS: TIPS creation was technically successful in 124 (98.4%) patients. Rebleeding occurred in 26 (20.6%) patients during the follow-up period. The 6-week and 1-year actuarial probabilities of patients remaining free of rebleeding were 98.3% ± 1.2% and 81.2% ± 3.9%, respectively. Forty-nine (38.8%) patients died during the follow-up period. The 6-week and 1-year actuarial probabilities of survival were 98.4 ± 1.1% and 65.6 ± 4.4%, respectively. Two (1.6%) patients had major procedure-related complications, including acute liver failure (n = 1) and intra-abdominal bleeding (n = 1). Thirty-three (26.2%) patients had at least 1 episode of overt hepatic encephalopathy during the follow-up period. Shunt dysfunction occurred in 15 (11.9%) patients after a median follow-up time of 11.4 months (range, 1.4-41.3 months). Lung metastasis occurred in 3 (2.4%) patients, 3.9-32.9 months after TIPS creation. CONCLUSIONS: TIPS creation may be effective and safe for the prevention of gastric variceal rebleeding in patients with HCC.

Meta-Analysis of Postoperative Adjuvant Hepatic Artery Infusion Chemotherapy Versus Surgical Resection Alone for Hepatocellular Carcinoma.

BACKGROUND: To systematically identify the long-term efficacy of postoperative adjuvant hepatic artery infusion chemotherapy (HAIC) for patients with hepatocellular carcinoma (HCC). METHODS: PubMed, MedLine, Embase, the Cochrane Library, and Web of Science were searched to collect the eligible studies up to March 31, 2021, that compared the surgical resection (SR) versus SR+HAIC for HCC patients. The endpoints were overall survival (OS) rates and disease-free survival (DFS) rates, and the effect size was determined by hazard ratio (HR) with 95% CI. RESULTS: A total of 12 studies (two randomized controlled trials (RCTs) and 10 non-RCTs) including 1,333 patients were eligible for this meta-analysis. The pooled results showed that OS and DFS rates in the SR+HAIC group were both better than those in the SR alone group (HR = 0.56, 95% CI = 0.41-0.77, p < 0.001; HR = 0.66, 95% CI = 0.55-0.78, p < 0.001, respectively). Furthermore, the subgroup analysis showed that patients would benefit from SR+HAIC regardless of chemotherapy regimens and courses (all p < 0.05), and patients with microvascular or macrovascular invasion would also benefit more from SR+HAIC in terms of OS and DFS (all p < 0.05). CONCLUSION: Postoperative adjuvant HAIC could improve the long-term prognosis of HCC patients, especially for those with microvascular or macrovascular invasion, regardless of chemotherapy regimens and courses, but it deserves further validation.

The chemokine receptor CCR10 promotes inflammation-driven hepatocarcinogenesis via PI3K/Akt pathway activation.

G-protein-coupled receptor (GPCR)-related proteins are dysregulated and the GPCR CC-chemokine receptor 10 (CCR10) is significantly upregulated in inflammation-driven HCC. However, CCR10's role in inflammation-driven hepatocarcinogenesis remains unknown. The aim of this study was to evaluate the role of CCR10 in inflammation-driven hepatocarcinogenesis. Via a targeted gene expression microarray screening alterations in GPCR family gene expression, we found CCR10 to be significantly upregulated in hepatocytes isolated from inflammation-driven human HCC tumors and matching paracancerous tissues. Tetrachloromethane (CCl4)-induced and diethylnitrosamine (DEN)-induced murine models of inflammatory hepatocarcinogenesis displayed significant hepatocellular TNF and CCR10 upregulation. Exogenous TNF applied to HepG2 and LO2 cell lines as well as wild-type (WT) mice significantly upregulated hepatocellular CCR10 expression, Akt phosphorylation, PCNA expression, and hepatocellular proliferation. Additionally, exogenous TNF significantly upregulated secretion of the natural CCR10 ligand-agonist CCL28 from both cell lines. Transgenic CCR10-knockout (CCR10 KO) in DEN-treated mice significantly increased hepatocellular apoptosis levels and significantly lowered compensatory hepatocellular proliferation but did not affect upstream TNF expression. In addition, DEN-treated CCR10 KO mice showed a significantly lower liver weight/body weight ratio, significantly lower liver tumor incidence, and significantly smaller tumors. Moreover, exogenous CCR10 expression significantly raised xenograft tumor growth in Balb/c nude mice. In vitro, CCR10 transfection or CCL28 treatment in HepG2 and LO2 cell lines significantly increased Akt phosphorylation, PCNA expression, and cell proliferation, while CCR10 silencing or Akt inhibition produced the opposite effects. In vivo, hepatocytes isolated from HCC tumor tissue and matching paracancerous tissue in DEN-treated CCR10 KO mice showed significantly lower Akt phosphorylation and PCNA expression relative to WT hepatocytes. In conclusion, inflammation-induced TNF promotes hepatocellular CCR10 expression and downstream PI3K/Akt-mediated hepatocarcinogenesis. CCR10 appears to function as a linkage between TNF stimulation and downstream PI3K/Akt pathway activation and shows promise as a potential therapeutic target for inflammation-driven HCC.

HMGA1 participates in MHCC97H cell proliferation and invasion through the ILK/Akt/GSK3ß signaling pathway.

Hepatocellular carcinoma (HCC) is one of the major causes of cancer­related mortality, and the prognosis of HCC patients is unsatisfactory. It is known that the occurrence and development of HCC involves numerous genes, as well as various steps and stages in the pathological process. High mobility group AT­hook 1 (HMGA1) and integrin­linked kinase (ILK) may be overexpressed in HCC and may serve important roles in the development of cancer; however, the relationship between HMGA1 and ILK in HCC has not been examined. The present study demonstrated that inhibition of HMGA1 expression significantly decreased the levels of expression of ILK and the downstream elements phosphorylated (p)­Akt, p­glycogen synthase kinase 3ß (GSK3ß), matrix metalloproteinase (MMP)2, MMP9, CyclinD1 and c­Myc. Transfection with an ILK expression vector was able to recover the decreased expression of these downstream genes, and affected cell proliferation and apoptosis. In addition, results from Transwell and wound­healing experiments indicated that HMGA1 participates cell invasion and migration through the ILK/Akt/GSK3ß pathway. The present study aimed to improve our understanding about the regulatory pathway involved in HCC and provides the basis for exploring HMGA1 inhibition as a therapy for patients with HCC and a new treatment strategy to prevent the development of HCC.

Down-regulation of UBC9 increases the sensitivity of hepatocellular carcinoma to doxorubicin.

UBC9 is an E2-conjugating enzyme that is required for SUMOylation and has been implicated in regulating several critical cellular pathways. UBC9 is overexpressed in certain tumors, such as lung adenocarcinoma, ovarian carcinoma and melanoma, which implies that it has special clinical significance. However, the role of UBC9 in Hepatocellular carcinoma (HCC) drug responsiveness is not clear. In this study, we investigated the clinicopathological significance of UBC9 in HCC and investigated the mechanism of UBC9-mediated chemosensitivity to doxorubicin (DOX) in hepatocellular carcinoma cells. We found that relative to adjacent normal tissues, UBC9 was markedly overexpressed in HCC, which closely correlated with tumor size, tumor microsatellite formation, and tumor encapsulation. Our results also showed that down-regulation of UBC9 by shRNA reduced the expression of Bcl-2 and Bcl-xl and increased the expression of cleaved-Caspase3, which is a proapoptotic protein. These changes were associated with reduced apoptosis in response to DOX. Furthermore, we observed a mechanism involving modulation of the P38 and ERK1/2 signaling pathways. Together, our results indicate that down-regulation of UBC9 sensitizes cells to anticancer drugs, is possibly associated with the regulation of ERK1/2 and P38 activation and interacts with the intrinsic apoptosis pathway. Thus, knockdown of UBC9 may have a tumor suppressor effect and UBC9 could be a potential target for the treatment of HCC cancer.

Downregulation of UBC9 promotes apoptosis of activated human LX-2 hepatic stellate cells by suppressing the canonical NF-κB signaling pathway.

UBC9, the only known E2-conjugating enzyme involved in SUMOylation, is a key regulator in fibrosis. However, the roles of UBC9 in liver fibrosis remain unclear. Therefore, in this study, we investigated the roles of UBC9 in HSC apoptosis and liver fibrogenesis. Our results showed that the UBC9 levels in activated LX-2 cells, HepG2 and SMMC-7721 were increased compared with LO2, and the expression of UBC9 in activated LX-2 cells, HepG2 and SMMC-7721 were no significant differences. The expression of UBC9 was effectively down-regulated by the UBC9-shRNA plasmid, and this effect was accompanied by the attenuated expression of the myofibroblast markers smooth muscle actin (α-SMA) and Collagen I. Downregulation of UBC9 also promotes activated HSCs apoptosis by up-regulating cell apoptosis-related proteins. Further, knockdown of UBC9 in activated HSCs inhibited cell viability and caused cell cycle arrest in the G2 phase. Moreover, knockdown of UBC9 suppressed the activation of NF-κB signaling pathways. In conclusion, these results demonstrated that down-regulation of UBC9 expression induced activated LX-2 cell apoptosis and promoted cells to return to a quiescent state by inhibiting the NF-κB signaling pathway. These results provide novel mechanistic insights for the anti-fibrotic effect of UBC9.

Association of HLA-DRB1 gene polymorphisms with hepatocellular carcinoma risk: a meta-analysis.

INTRODUCTION: The study aimed to assess the association between human leukocyte antigen (HLA)-DRB1 allele polymorphisms and hepatocellular carcinoma (HCC) susceptibility. EVIDENCE ACQUISITION: Relevant case-control studies on HLA-DRB1 allele correlation with HCC risk published between 2000 and 2015 were searched and retrieved in literature database. The odds ratio (OR) with its 95% confidence interval (CI) were employed to calculate the strength of association. Total 16 articles including 2208 HCC patients and 3028 relevant controls were finally screened out. EVIDENCE SYNTHESIS: A total of 12 case-control studies including 2030 HCC patients and 2817 relevant controls were screened out. Thirteen alleles (HLA-DRB1 *01, *03, *04, *07, *08, *09, *10, *11, *12, *13, *14, *15, and *16) were reported. Overall, we found that HLA-DRB1 *1 and *11 allele polymorphisms were significantly associated with decreased the HCC risk (*1: OR=0.53, 95% CI: 0.29-0.96, P=0.04; *11: OR=0.58, 95% CI: 0.38-0.88, P=0.010); while *12 and *14 allele polymorphisms were significantly associated with increased the HCC risk (*12: OR=1.49, 95% CI: 1.08-2.07, P=0.02; *14: OR=1.89, 95% CI: 1.27-2.82, P=0.002) in a fixed-effect model. However, other HLA-DRB1 allele polymorphisms were not associated with HCC susceptibility (P>0.05). CONCLUSIONS: HLA-DRB1 *1 and *11 allele polymorphisms were protective factors, *12 and *14 allele polymorphisms were risk factors for HCC development. Future large-scale studies with more ethnicities are still needed.

Ki-67 as a prognostic marker in early-stage non-small cell lung cancer in Asian patients: a meta-analysis of published studies involving 32 studies.

BACKGROUND: Despite the large number of published papers analyzing the prognostic role of Ki-67 in NSCLC, it is still not considered an established factor for routine use in clinical practice. The present meta-analysis summarizes and analyses the associations between Ki-67 expression and clinical outcome in NSCLC patients. METHODS: PubMed, Cochrane, and Embase databases were searched systematically using identical search strategies. The impacts of Ki-67 expression on survival in patients with NSCLC and NSCLC subtypes were evaluated. Furthermore, the association between Ki-67 expression and the clinicopathological features of NSCLC were evaluated. RESULTS: In total, 32 studies from 30 articles met the inclusion criteria, involving 5600 patients. Meta-analysis results suggested that high Ki-67 expression was negatively associated with overall survival (OS; HR = 1.59, 95 % CI 1.35-1.88, P < 0.001) and disease-free survival (DFS; HR = 2.21, 95 % CI 1.43-3.42, P < 0.001) in NSCLC patients. Analysis of the different subgroups of NSCLC suggested that the negative association between high Ki-67 expression and OS and DFS in Asian NSCLC patients was stronger than that in non-Asian NSCLC patients, particularly in early-stage (Stage I-II) adenocarcinoma (ADC) patients. Additionally, while high expression was more common in males, smokers, and those with poorer differentiation, there was no correlation between high Ki-67 expression and age or lymph node status. Importantly, significant correlations between high Ki-67 expression and clinicopathological features (males, higher tumor stage, poor differentiation) were seen only in Asian NSCLC patients. CONCLUSIONS: The present meta-analysis indicated that elevated Ki-67 expression was associated with a poorer outcome in NSCLC patients, particularly in early-stage Asian ADC patients. Studies with larger numbers of patients are needed to validate our findings.