SRY is a Key Mediator of Sexual Dimorphism in Hepatic Ischemia/Reperfusion Injury.

OBJECTIVES: To identify the role and mechanism of a male specific gene, SRY, in I/R-induced hepatic injury. BACKGROUND: Males are more vulnerable to I/R injury than females. However, the mechanism of these sex-based differences remains poorly defined. METHODS: Clinicopathologic data of patients who underwent hepatic resection were identified from an international multi-institutional database. Liver specific SRY TG mice were generated, and subjected to I/R insult with their littermate WT controls in vivo. In vitro experiments were performed by treating primary hepatocytes from TG and WT mice with hypoxia/reoxygen-ation stimulation. RESULTS: Clinical data showed that postoperative aminotransferase level, incidence of overall morbidity and liver failure were markedly higher among 1267 male versus 508 female patients who underwent hepatic resection. SRY was dramatically upregulated during hepatic I/R injury. Overexpression of SRY in male TG mice and ectopic expression of SRY in female TG mice exacerbated liver I/R injury compared with WTs as manifested by increased inflammatory reaction, oxidative stress and cell death in vivo and in vitro. Mechanistically, SRY interacts with Glycogen synthase kinase-3ß (GSK-3ß) and ß-catenin, and promotes phosphorylation and degradation of ß-catenin, leading to suppression of the downstream FOXOs, and activation of NF-κBand TLR4 signaling. Furthermore, activation of ß-catenin almost completely reversed the SRYoverexpression-mediated exacerbation of hepatic I/R damage. CONCLUSIONS: SRY is a novel hepatic I/R mediator that promotes hepatic inflammatory reaction, oxidative stress and cell necrosis via inhibiting Wnt/ß-catenin signaling, which accounts for the sex-based disparity in hepatic I/R injuries.

Liver fibrosis promotes immune escape in hepatocellular carcinoma via GOLM1-mediated PD-L1 upregulation.

Immune checkpoint blockade is considered a breakthrough in cancer treatment. However, with the low response rates and therapeutic resistance of patients with hepatocellular carcinoma (HCC), the challenges facing the application of this treatment are tremendous. Liver fibrosis is a key driver of tumor immune escape, the underlying mechanism has never been clarified. This study sought to explore the role of liver fibrosis in regulating tumor-infiltrating lymphocytes (TILs) and inducing tumor immunosuppression. Ninety-nine fixed HCC tissue samples were used to analyze the association between liver fibrosis and immune escape using immunohistochemistry. In HCC patients, low FIB-4 values and high CD8+ T cell infiltration were correlated with prolonged survival. Elevated expression of immune checkpoints and attenuated antitumor immunity were observed in CCl4-induced mice liver fibrosis models and human fibrotic livers compared to control group. GOLM1 levels were increased in livers of patients with fibrosis and mice in response to CCl4-induced liver fibrosis. CD8+ T cell infiltrations were significantly decreased and PD-L1 expression was significantly increased in tumor tissues from hepatocyte-specific GOLM1 transgenic mice (Alb/GOLM1 mice) inducing chemical carcinogenesis compared to their corresponding control WT mice. GOLM1 induced PD-L1 expression via EGFR pathway activation. EGFR inhibitors, especially together with anti-PD-L1 therapy, improved the efficacy of immunotherapy in HCC. These findings illustrate the importance of liver fibrosis-induced immunosuppression as a tumor-promoting mechanism. GOLM1, which is highly upregulated in the fibrotic liver, regulates tumor microenvironmental immune escape via the EGFR/PD-L1 signaling pathway. EGFR blockade may bolster the efficacy of immune checkpoint inhibitors for HCC treatment.

Serum GP73 predicts posthepatectomy outcomes in patients with hepatocellular carcinoma.

BACKGROUND AND AIMS: Serum GP73 is a useful biomarker in assessing hepatic fibrosis degree. The aim of this study was to evaluate the predictive value of serum GP73 level for posthepatectomy short-term outcomes in hepatocellular carcinoma (HCC) patients. METHODS: A total of 280 patients undergoing liver resection for HCC between October 2015 and April 2018 were included in this study. Detailed preoperative clinicopathological data were collected and GP73 levels in serum obtained the day before hepatectomy were examined. Receiver operating characteristic (ROC) analysis was used to calculate the optimal cutoff of GP73, and independent risk factors for postoperative outcomes was assessed by logistic regression model. RESULTS: The mean GP73 level in patients was 111.8 ± 153.3 ng/mL. Serum GP73 levels were correlated with the METAVIR fibrosis score. Overall complications occurred in 145 patients and major complications developed in 29 patients. ROC analysis demonstrated that the predictive power of serum GP73 for postoperative outcomes was greater than the Child-Pugh score, ALBI score, FIB-4 index and APRI score. The optimal value of serum GP73 to predict overall complications and major complications was 80.9 and 79.2 respectively. Serum GP73 levels were independent factors affecting the incidence of overall complications (odds ratio [OR], 3.996; 95% CI 2.152-7.421; P < 0.001) and major complications (OR, 4.970; 95% CI 1.654-14.934; P = 0.004) by multivariate analysis. CONCLUSION: Serum GP73 is a useful tool to stratify HCC patients and to predict short-term outcomes after hepatectomy.

Gamma-glutamyl transpeptidase to platelet ratio predicts short-term outcomes in hepatocellular carcinoma patients undergoing minor liver resection.

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.

Activation of SRY accounts for male-specific hepatocarcinogenesis: Implication in gender disparity of hepatocellular carcinoma.

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.