Background: KDM5C is a histone H3K4-specific demethylase, which has multiple biological functions during development and disease. However, the role of KDM5C in intrahepatic cholangiocarcinoma (ICC) remains unknown. Methods: Expression levels of KDM5C in ICC patients were determined by qRT-PCR, western blotting and immunohistochemical assay. The functions of KDM5C in cell proliferation and invasion were determined in human ICC cells and mouse xenograft model using KDM5C overexpression and knockdown strategies in vivo. RNA-seq analysis was applied to investigate the transcriptional program of KDM5C. In addition, ChIP-qPCR was used to determine the regulation of FASN by KDM5C. Results: Here, we show that KDM5C was downregulated in human ICC, where its diminished expression was associated with poor prognosis. ICC cell proliferation and invasion were inhibited by KDM5C overexpression. Moreover, KDM5C suppressed ICC proliferation and metastasis in vivo. RNA-sequencing showed that KDM5C inhibits key signal pathways of cell proliferation, cell invasion and fatty acid metabolism. ChIP-qPCR revealed that overexpression of KDM5C led to the reduction of H3K4me3 on the promoter and the corresponding downregulation of the expression of FASN, which represents the major target gene of KDM5C to mediate the proliferation and invasion of ICC cells. Conclusions: Our results revealed the role of KDM5C as a novel tumor suppressor in ICC largely by repressing FASN-mediated lipid acid metabolism and thus KDM5C may contribute to the pathogenesis of ICC.
Our data suggests that a sterile glove pouch could enhance exposure in surgical field, which results in decrease in blood loss and procedure time. More studies with large sample size, large tumor size, and longer follow-up are needed.
Background: Intrahepatic cholangiocarcinoma (ICC) caused by chronic hepatitis B virus (HBV) infection has become prominent. Prospectively stratifying postoperative risk factors is a challenging task.
Methods:We retrospectively assessed the relationship between serum gamma-glutamyl transpeptidase (GGT) concentration and postoperative outcomes in 107 subjects with HBV-associated ICC. Cox proportionate hazard models and subgroup analyses were used to test the hypothesis with adjustment for potential confounders.Results: Serum GGT concentration was negatively correlated with postoperative outcomes. For a 1-standard deviation (per-SD) (117 μ/L) increase of serum GGT concentration, the relative risk (RR) for overall survival (OS) and time to recurrence (TTR) were 1.72 [95% confidence interval (CI), 1.37 to 2.16] and 1.53 (95% CI, 1.22 to 1.91), respectively. In addition, the RRs of middle and top tertiles of GGT for death were 1.81 (95% CI, 0.98 to 3.32) and 3.56 (95% CI, 1.97 to 6.42), respectively (P for trend <0.001).Similarly, the RRs for recurrence of the corresponding tertiles were 1.70 (95% CI, 0.93 to 3.10) and 3.27 (95% CI, 1.77 to 6.06), respectively (P for trend =0.002). In our study, the negative correlation between serum GGT levels and OS did not differ significantly between groups stratified by age, sex, HBV DNA level, carbohydrate antigen 19-9 (CA19-9) level and liver resection type (all P for interaction >0.05); however, there was a significant interactive effect of serum GGT and adjuvant chemotherapy on OS (RR =0.64 vs. 1.77, P for interaction =0.04).Conclusions: High serum GGT concentration is associated with an increased risk of postoperative death and tumor recurrence in patients with HBV-associated ICC. However, this relationship became less significant with the implementation of adjuvant chemotherapy.
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