Department of Hepatology, Qilu Hospital of Shandong University.
Institute of Hepatology, Shandong University.
Tohoku J Exp Med. 2020 Dec;252(4):297-307. doi: 10.1620/tjem.252.297.
Wnt1-inducible signaling pathway protein 1 (WISP1) regulates cell proliferation, differentiation, adhesion, migration and survival. Abnormal WISP1 expression is associated with the carcinogenesis of hepatocellular carcinoma (HCC). Aberrant DNA methylation is one of the major epigenetic alterations in HCC. However, the methylation status of the WISP1 promoter is still unclear. We therefore aimed to determine the methylation status of the WISP1 promoter and evaluate its clinical value in HCC. The study enrolled 251 participants, including 123 participants with HCC, 90 participants with chronic hepatitis B (CHB) and 38 healthy controls (HCs). WISP1 methylation status, mRNA levels and plasma soluble WISP1 were detected by methylation-specific polymerase chain reaction (MSP), quantitative real-time PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. We found that the methylation frequency of WISP1 in patients with HCC was significantly lower than that in patients with CHB and HCs, while the relative expression levels of WISP1 mRNA were markedly higher in patients with HCC than in patients with CHB and HCs. Furthermore, the plasma soluble WISP1 in patients with HCC was obviously lower than in that in patients with CHB and HCs. Alpha-fetoprotein (AFP) is a widely recognized biomarker to diagnose HCC which lacks enough sensitivity and specificity. WISP1 promoter methylation status combined with AFP significantly improved the diagnostic ability in discriminating HCC from CHB compared with AFP or WISP1 methylation status alone. In conclusion, hypomethylation of the WISP1 gene promoter may serve as a noninvasive biomarker for detecting HBV-associated HCC.
Wnt1 诱导信号通路蛋白 1（WISP1）调节细胞增殖、分化、黏附、迁移和存活。异常的 WISP1 表达与肝细胞癌（HCC）的发生有关。异常的 DNA 甲基化是 HCC 中主要的表观遗传改变之一。然而，WISP1 启动子的甲基化状态仍不清楚。因此，我们旨在确定 WISP1 启动子的甲基化状态，并评估其在 HCC 中的临床价值。本研究纳入了 251 名参与者，包括 123 名 HCC 患者、90 名慢性乙型肝炎（CHB）患者和 38 名健康对照者（HCs）。采用甲基化特异性聚合酶链反应（MSP）、实时定量 PCR（RT-qPCR）和酶联免疫吸附试验（ELISA）分别检测 WISP1 甲基化状态、mRNA 水平和血浆可溶性 WISP1。我们发现 HCC 患者的 WISP1 甲基化频率明显低于 CHB 患者和 HCs，而 HCC 患者的 WISP1 mRNA 相对表达水平明显高于 CHB 患者和 HCs。此外，HCC 患者的血浆可溶性 WISP1 明显低于 CHB 患者和 HCs。甲胎蛋白（AFP）是一种广泛认可的诊断 HCC 的生物标志物，但缺乏足够的灵敏度和特异性。与 AFP 或 WISP1 甲基化状态单独相比，WISP1 启动子甲基化状态联合 AFP 显著提高了鉴别 HCC 与 CHB 的诊断能力。总之，WISP1 基因启动子的低甲基化可能作为一种非侵入性生物标志物，用于检测与 HBV 相关的 HCC。
