Microwave ablation provides better survival than liver resection for hepatocellular carcinoma in patients with borderline liver function: application of ALBI score to patient selection.

BACKGROUND: Studies comparing microwave ablation (MWA) and liver resection are lacking. This study evaluates the survival of patients with hepatocellular carcinoma (HCC) treated with liver resection or MWA and the role of Albumin-Bilirubin (ALBI) score in patient selection for treatments. METHODS: This is a retrospective analysis of patients who received curative liver resection or MWA for HCC. Propensity score matching was used at a 1:1 ratio. The value of ALBI grade for patient selection was evaluated. Overall and disease-free survival were compared between two groups. RESULTS: Of the 442 patients underwent MWA or liver resection for HCC during the study period, 63 patients received MWA and 379 patients received liver resection. Propensity scoring matching analysis resulted in 63 matched pairs for further analysis. Subgroup analysis according to the ALBI grade was performed. Liver resection offered better overall and disease-free survivals in patients with ALBI grade 1. MWA provided a significantly better overall survival (p = 0.025) and a trend towards better disease-free survival (p = 0.39) in patients with ALBI grade 2 or 3. CONCLUSIONS: Liver resection offered superior disease-free survival to MWA in patients with HCC. The ALBI grade could identify patients with worse liver function who might gain survival advantage from MWA.

Histone Deacetylase HDAC8 Promotes Insulin Resistance and ß-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma.

The growing epidemic of obesity, which causes nonalcoholic fatty liver disease (NAFLD) and the more severe phenotype nonalcoholic steatohepatitis (NASH), has paralleled the increasing incidence of hepatocellular carcinoma (HCC). Accumulating evidence demonstrates that overnutrition and metabolic pathways can trigger modifications of DNA and histones via deregulation of chromatin modifiers, resulting in aberrant transcriptional activity. However, the epigenetic regulation of HCC development in NAFLD remains obscure. Here, we uncover key epigenetic regulators using both dietary and genetic obesity-promoted HCC models through quantitative expression profiling and characterize the oncogenic activities of histone deacetylase HDAC8 in NAFLD-associated hepatocarcinogenesis. HDAC8 is directly upregulated by the lipogenic transcription factor SREBP-1 where they are coexpressed in dietary obesity models of NASH and HCC. Lentiviral-mediated HDAC8 attenuation in vivo reversed insulin resistance and reduced NAFLD-associated tumorigenicity. HDAC8 modulation by genetic and pharmacologic approaches inhibited p53/p21-mediated apoptosis and G2-M phase cell-cycle arrest and stimulated ß-catenin-dependent cell proliferation. Mechanistically, HDAC8 physically interacted with the chromatin modifier EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3 lysine 27 trimethylation. In human NAFLD-associated HCC, levels of SREBP-1, HDAC8, EZH2, H4 deacetylation, H3K27me3, and active ß-catenin were all correlated positively in tumors compared with nontumor tissues. Overall, our findings show how HDAC8 drives NAFLD-associated hepatocarcinogenesis, offering a novel epigenetic target to prevent or treat HCC in obese patients.

Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives ß-catenin/T cell factor-dependent hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. It is more prevalent in men than women. Related to this, recent genetic studies have revealed a causal role for androgen receptor (AR) in hepatocarcinogenesis, but the underlying molecular mechanism remains unclear. Here, we used genome-wide location and functional analyses to identify a critical mediator of AR signaling - cell cycle-related kinase (CCRK) - that drives hepatocarcinogenesis via a signaling pathway dependent on ß-catenin and T cell factor (TCF). Ligand-bound AR activated CCRK transcription and protein expression via direct binding to the androgen-responsive element of the CCRK promoter in human HCC cell lines. In vitro analyses showed that CCRK was critical in human cell lines for AR-induced cell cycle progression, hepatocellular proliferation, and malignant transformation. Ectopic expression of CCRK in immortalized human liver cells activated ß-catenin/TCF signaling to stimulate cell cycle progression and to induce tumor formation, as shown in both xenograft and orthotopic models. Conversely, knockdown of CCRK decreased HCC cell growth, and this could be rescued by constitutively active ß-catenin or TCF. In primary human HCC tissue samples, AR, CCRK, and ß-catenin were concordantly overexpressed in the tumor cells. Furthermore, CCRK overexpression correlated with the tumor staging and poor overall survival of patients. Our results reveal a direct AR transcriptional target, CCRK, that promotes hepatocarcinogenesis through the upregulation of ß-catenin/TCF signaling.