Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
Department of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
PLoS One. 2018 Oct 24;13(10):e0206261. doi: 10.1371/journal.pone.0206261. eCollection 2018.
Trimethylation of histone H3K36 (H3K36me3), an epigenetic marker of transcription-associated histone modification and stem cell regulation, is expressed in a variety of human cancers. This study elucidated the prognostic significance of H3K36me3 in patients with resectable hepatocellular carcinoma (HCC).
Expression of H3K36me3 was retrospectively evaluated through immunohistochemistry in 152 surgically resected primary HCCs.
In nontumorous liver parenchyma, H3K36Me3 was detected in bile ducts but not in hepatocytes. H3K36me3 was positive in 104 (68.4%) of the HCCs. Positivity for H3K36me3 was associated with high level of serum α-fetoprotein (>200 ng/mL, P = 0.0148), high tumor grade (P = 0.0017), and high tumor stage (P = 0.0008). Patients with H3K36me3-positive tumors were more likely to have lower 5-year disease-free survival and 5-year overall survival than those with H3K36me3-negative tumors (P = 0.0484 and P = 0.0213, respectively). Multivariate analysis showed that H3K36me3 positivity was an independent predictor of high tumor grade (P = 0.0475) and high tumor stage (P = 0.0114) and thus contributed to poor prognosis. Furthermore, H3K36me3 positivity was significantly correlated with the expression of biliary markers cytokeratin 19 (CK19) and hepatocyte nuclear factor 1β (HNF1β) (P < 0.0001 and P = 0.0005, respectively). Combinatorial analysis revealed that CK19 and HNF1β expression individually exerted additive prognostic adverse effects on HCCs with H3K36me3 positivity.
Our study indicates that H3K36me3 positivity is associated with the expression of biliary markers and is a crucial predictor of poor prognosis in resectable HCC.
组蛋白 H3K36 三甲基化（H3K36me3）是转录相关组蛋白修饰和干细胞调控的表观遗传标记，在多种人类癌症中表达。本研究阐明了 H3K36me3 在可切除肝细胞癌（HCC）患者中的预后意义。
通过免疫组织化学方法对 152 例手术切除的原发性 HCC 进行了 H3K36me3 的表达回顾性评估。
在非肿瘤性肝实质中，H3K36Me3 存在于胆管中，而不存在于肝细胞中。在 104 例 HCC 中 H3K36me3 为阳性。H3K36me3 阳性与血清 α-胎蛋白水平较高（>200ng/ml，P=0.0148）、肿瘤分级较高（P=0.0017）和肿瘤分期较高（P=0.0008）相关。H3K36me3 阳性肿瘤患者的 5 年无病生存率和总生存率均低于 H3K36me3 阴性肿瘤患者（P=0.0484 和 P=0.0213）。多因素分析显示，H3K36me3 阳性是肿瘤分级高（P=0.0475）和肿瘤分期高（P=0.0114）的独立预测因子，因此导致预后不良。此外，H3K36me3 阳性与胆管标记物细胞角蛋白 19（CK19）和肝细胞核因子 1β（HNF1β）的表达显著相关（P<0.0001 和 P=0.0005）。组合分析表明，CK19 和 HNF1β 的表达单独对 H3K36me3 阳性的 HCC 具有相加的预后不良影响。
本研究表明，H3K36me3 阳性与胆管标记物的表达相关，是可切除 HCC 患者预后不良的关键预测因子。
