Overexpression of transcription factor 3 drives hepatocarcinoma development by enhancing cell proliferation via activating Wnt signaling pathway.

BACKGROUND: Transcription factor 3 (TCF3) plays pivotal roles in embryonic development, stem cell maintenance and carcinogenesis. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. This study aimed to analyze the correlation between TCF3 expression and clinicopathological features of HCC, and further explore the underlying mechanism in HCC progression. METHODS: The expression of TCF3 was collected from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) HCC datasets, and further confirmed by immunostaining and Western blotting assays. The correlation between TCF3 expression and the clinicopathological features was evaluated. Bioinformatical analysis and in vitro experiments were conducted to explore the potential role of TCF3 in HCC development. RESULTS: Both the mRNA and protein levels of TCF3 were significantly higher in HCC tumor tissues compared to tumor adjacent tissues (P < 0.001 and P < 0.01). Analysis based on TCGA datasets showed that TCF3 was positively correlated with tumor clinical stage and grade, and patients with high TCF3 expression had shorter overall survival (P = 0.012), disease-specific survival (P = 0.022) and progression-free survival (P = 0.013). Similarly, the immunostaining results revealed that the high expression of TCF3 was closely correlated with tumor size (P = 0.001) and TNM stage (P = 0.002), and TCF3 was an independent risk factor of HCC. In vitro study exhibited that TCF3 knockdown dramatically suppressed cancer cell proliferation, and the underlying mechanism might be that the silencing of TCF3 reduced the expression of critical regulating proteins towards cell cycle and proteins involved in Wnt signaling pathways. CONCLUSIONS: TCF3 expression is significantly elevated in HCC and positively associated with the tumor size and TNM stage, as well as poor prognosis of HCC patients. The mechanism might be that TCF3 promotes cancer cell proliferation via activating Wnt signaling pathway.

Integrating transcriptomes and somatic mutations to identify RNA methylation regulators as a prognostic marker in hepatocellular carcinoma.

BACKGROUND: RNA methylation modifying plays an important role in the occurrence and progression of a range of human cancers including hepatocellular carcinoma (HCC), which is characterized by a mass of genetic and epigenetic alterations. However, the treatment targeting these alterations is limited. METHODS: We used comprehensive bioinformatics analysis to analyze the correlation between cancer-associated RNA methylation regulators and HCC malignant features in network datasets. RESULTS: We identified two HCC subgroups (cluster 1 and 2), which had clearly distinct clinicopathological, biofunctional and prognostic characteristics, by consensus clustering. The cluster 2 subgroup correlated with malignancy of the primary tumor, higher tumor stage, higher histopathological grade and higher frequency of TP53 mutation, as well as with shorter survival when compared with cluster 1. Gene enrichment indicated that the cluster 2 correlated to the tumor malignancy signaling and biological processes. Based on these findings, an 11-gene risk signature was built, which not only was an independent prognostic marker but also had an excellent power to predict the tumor features. CONCLUSIONS: Our study indicated that RNA methylation regulators are vital for HCC malignant progression and provide an important evidence for RNA methylation, methylation regulators are actionable targets for anticancer drug discovery.

IL-27 is elevated in sepsis with acute hepatic injury and promotes hepatic damage and inflammation in the CLP model.

BACKGROUND: Immuno-inflammation plays an important role in the pathophysiological process of sepsis-associated acute hepatic injury (AHI). Interleukin 27 (IL-27) is an important inflammatory regulator; however, its role in this condition is not clear. METHODS: The clinical data and IL-27 serum levels in sepsis patients with or without AHI were analysed. Classical caecal ligation puncture (CLP) models were established in wild-type (WT) and IL-27 receptor (WSX-1)-deficient (IL-27R-/-) mice. In addition, exogenous IL-27 was injected into these mice, and the levels of IL-27, IL-6, and tumour necrosis factor alpha (TNF-α) in the serum and liver were then measured by enzyme-linked immunoassay (ELISA), quantitative PCR, and Western blotting. The severity of liver damage was evaluated by haematoxylin and eosin staining of liver tissue, TUNEL assay and evaluation of alanine aminotransferase (ALT) and aspartate transaminase (AST) serum levels. Furthermore, the effects of IL-27 on the levels of phosphorylated c-Jun N-terminal kinase (JNK) in macrophages were assessed by Western blotting, and the effects of IL-27 on the expression of IL-6 and TNF-α in macrophages were assessed by ELISA. RESULTS: IL-27 was elevated in sepsis patients with acute hepatic injury, which correlated with the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHEII) scores, Sequential Organ Failure Assessment (SOFA) scores, and procalcitonin, C-reactive protein, IL-6, and TNF-α expression. In the CLP-WT group, IL-27 was highly expressed in the serum and liver, which correlated with the elevated content of ALT, AST, TNF-α, IL-6, and p-JNK in the serum and liver and the pathological injury of the liver. In CLP-IL-27R-/- group, however, the levels of ALT, AST, TNF-α, IL-6, and p-JNK in the serum and liver and the pathological injury of the liver were decreased. Treatment with exogenous IL-27 led to a further increase in these cytokines in WT mice after CLP. IL-27 treatment and lipopolysaccharide stimulation in vitro increased the expression of p-JNK, IL-6, and TNF-α in macrophages, and these changes were decreased by a JNK signalling pathway inhibitor. CONCLUSION: IL-27 is elevated in sepsis patients, especially those with acute hepatic injury. In addition, IL-27 can promote inflammatory reactions in the CLP-induced hepatic injury mice model.

Outcomes of adult patients adopting small-for-size grafts in living donor liver transplantation: A systematic review and meta-analysis.

BACKGROUND: Small-for-size graft (SFSG) has emerged as one of the very contentions in adult-to-adult living donor liver transplantation (LDLT) as a certain graft size is related to recipients' prognosis. Graft-to-recipient weight ratio (GRWR) ≥0.8% was considered as a threshold to conduct LDLT. However, this also has been challenged over decades as a result of technique refinements. For a better understanding of SFSG in practice, we conducted this meta-analysis to compare the perioperative outcomes and long-term outcomes between patients adopting the grafts with a lower volume (GRWR < 0.8%, SFSG group) and sufficient volume (GRWR ≥ 0.8%, non-SFSG group) in adult-to-adult LDLT. DATA SOURCES: The studies comparing recipients adopting graft with a GRWR < 0.8% and ≥ 0.8% were searched by three authors independently in PubMed, Web of Science, Embase, the Cochrane Library, MEDLINE and Google Scholar databases until September 2018 and data were analyzed by RevMan 5.3.5. RESULTS: Sixteen studies with a total of 3272 subjects were included in this meta-analysis. In terms of small-for-size syndrome (SFSS), no significant difference was found in subjects enrolled after year 2010 (before 2010, OR=3.00, 95% CI: 1.69-5.35, P = 0.0002; after 2010, OR=1.23, 95% CI: 0.79-1.90, P = 0.36; P for interaction: 0.02). There was no significant difference in operative duration, blood loss, cold ischemia time, biliary complications, acute rejection, postoperative bleeding, hospitalization time, perioperative mortality, and 1-, 3- and 5-year overall survival rates between two groups. CONCLUSIONS: This meta-analysis suggested that adopting SFSG in adult LDLT has comparable outcomes to those with non-SFSG counterparts since 2010.

IL-37b suppresses epithelial mesenchymal transition in hepatocellular carcinoma by inhibiting IL-6/STAT3 signaling.

BACKGROUND: Interleukin-37b (IL-37b), a vital negative regulator of the innate immune system, has been reported to be a tumor inhibitor in different type of cancers. However, little is known about the relationship between IL-37b and hepatocellular carcinoma (HCC). The present study aimed to investigate the potential roles of IL-37b in HCC progression. METHODS: Subjects (n = 237) were recruited, and serum IL-37b was measured using ELISA. The tumor-suppressive capacity and underlying mechanisms of IL-37b in HCC were investigated in vitro and in vivo. RESULTS: Compared to healthy controls, serum IL-37b levels were elevated in chronic hepatitis B (CHB) patients but decreased significantly in HBV-HCC patients, especially for those with portal venous tumor thrombus. Low level serum IL-37b in HBV-HCC patients correlated with high HCC stage and poor overall survival and disease-free survival. In vitro and in vivo, recombinant human IL-37b inhibited proliferation and metastasis in HCC cells. Furthermore, IL-37b inhibited epithelial mesenchymal transition in HCC cells in vitro by downregulating IL-6, pSTAT3 (Y705), N-cadherin, and vimentin expression and by upregulating E-cadherin expression. These effects were partially reversed by transfection of adenovirus encoding human IL-6. CONCLUSIONS: IL-37b inhibits HCC growth, metastasis and epithelial mesenchymal transition by regulating IL-6/STAT3 signaling. Serum IL-37b may be a biomarker for HBV-HCC and its staging.

Standard liver weight model in adult deceased donors with fatty liver: A prospective cohort study.

BACKGROUND: Standard liver weight (SLW) is frequently used in deceased donor liver transplantation to avoid size mismatches with the recipient. However, some deceased donors (DDs) have fatty liver (FL). A few studies have reported that FL could impact liver size. To the best of our knowledge, there are no relevant SLW models for predicting liver size. AIM: To demonstrate the relationship between FL and total liver weight (TLW) in detail and present a related SLW formula. METHODS: We prospectively enrolled 212 adult DDs from West China Hospital of Sichuan University from June 2019 to February 2021, recorded their basic information, such as sex, age, body height (BH) and body weight (BW), and performed abdominal ultrasound (US) and pathological biopsy (PB). The chi-square test and kappa consistency score were used to assess the consistency in terms of FL diagnosed by US relative to PB. Simple linear regression analysis was used to explore the variables related to TLW. Multiple linear regression analysis was used to formulate SLW models, and the root mean standard error and interclass correlation coefficient were used to test the fitting efficiency and accuracy of the model, respectively. Furthermore, the optimal formula was compared with previous formulas. RESULTS: Approximately 28.8% of DDs had FL. US had a high diagnostic ability (sensitivity and specificity were 86.2% and 92.9%, respectively; kappa value was 0.70, P < 0.001) for livers with more than a 5% fatty change. Simple linear regression analysis showed that sex (R2, 0.226; P < 0.001), BH (R2, 0.241; P < 0.001), BW (R2, 0.441; P < 0.001), BMI (R2, 0.224; P < 0.001), BSA (R2, 0.454; P < 0.001) and FL (R2, 0.130; P < 0.001) significantly impacted TLW. In addition, multiple linear regression analysis showed that there was no significant difference in liver weight between the DDs with no steatosis and those with steatosis within 5%. Furthermore, in the context of hepatic steatosis, TLW increased positively (non-linear); compared with the TLW of the non-FL group, the TLW of the groups with hepatic steatosis within 5%, between 5% and 20% and more than 20% increased by 0 g, 90 g, and 340 g, respectively. A novel formula, namely, -348.6 + (110.7 x Sex [0 = Female, 1 = Male]) + 958.0 x BSA + (179.8 x FLUS [0 = No, 1 = Yes]), where FL was diagnosed by US, was more convenient and accurate than any other formula for predicting SLW. CONCLUSION: FL is positively correlated with TLW. The novel formula deduced using sex, BSA and FLUS is the optimal formula for predicting SLW in adult DDs.

Resveratrol preconditioning protects hepatocytes against hepatic ischemia reperfusion injury via Toll-like receptor 4/nuclear factor-κB signaling pathway in vitro and in vivo.

The purpose of this study was to investigate the protective effect of resveratrol against hepatic ischemia reperfusion injury (HIRI) and explore the potential underlying mechanism. Resveratrol-pretreated BRL-3A (rat liver) cells and rats underwent hypoxia/reoxygenation and hepatic ischemia/reperfusion, respectively. BRL-3A cell damage was evaluated, and the mRNA and protein expression of related signal molecules was assessed in cell model. The protein expression of related signal molecules was also assessed in rat model. Inflammatory cytokines levels were determined in the cell supernatant and rat serum while rat liver function and hepatocyte apoptosis were assessed. The results revealed that resveratrol significantly enhanced cell viability, inhibited cell apoptosis, and decreased levels of lactate dehydrogenase (LDH) and production of tumor necrosis factor-α (TNF-α) and interleukin-(IL)-1ß in the cell supernatant. In addition, resveratrol ameliorated elevated Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB, and the depressed inhibitor of NF-κB (IκB)-α caused by hypoxia/reoxygenation stimulation in BRL-3A cells. Moreover, resveratrol inhibited the translocation of NF-κB p65 after the stimulation of hypoxia/reoxygenation in BRL-3A cells. In vivo assays revealed that resveratrol reduced levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and liver pathological changes, while it alleviated hepatocyte apoptosis, negatively mediated the production of TNF-α and IL-1ß in serum, and reversed TLR4/NF-κB signaling pathway caused by hepatic ischemia/reperfusion stimulation in liver tissues. The results indicate that resveratrol protected hepatocytes against HIRI, which may be mediated in part via the TLR4/NF-κB signaling pathway.