DNA Methylation of Cannabinoid Receptor Interacting Protein 1 Promotes Pathogenesis of Intrahepatic Cholangiocarcinoma Through Suppressing Parkin-Dependent Pyruvate Kinase M2 Ubiquitination
DNA Methylation of Cannabinoid Receptor Interacting Protein 1 Promotes Pathogenesis of Intrahepatic Cholangiocarcinoma Through Suppressing Parkin-Dependent Pyruvate Kinase M2 Ubiquitination
复制标题
大麻素受体相互作用蛋白 1 的 DNA 甲基化通过抑制 Parkin 依赖性丙酮酸激酶 M2 泛素化促进肝内胆管癌的发病机制
DOI：
10.1002/hep.31561
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发表时间：
2021-03-25
期刊：
影响因子：
13.5
通讯作者：
Wu, Jian
中科院分区：
文献类型：
--
作者：
Chen, Diyu;Wu, Hao;Wu, Jian
背景和目的甲基化景观对于维持某些肿瘤中大麻素受体相互作用蛋白 1 (CNRIP1) 的沉默非常重要。然而，CNRIP1在肝内胆管癌（ICC）中的作用仍不清楚。 方法和结果在我们的研究中，我们发现CNRIP1在ICC组织中下调，并且CNRIP1的低表达与ICC患者3年总生存和无瘤生存的不良预后显着相关。通过研究基因组 DNA 甲基化谱，我们发现了一个名为 CNRIP1 MS-2（CNRIP1 甲基化位点-2）的 CpG 岛位点，该位点有助于 CNRIP1 的下调。此外，CNRIP1 MS-2的甲基化水平与ICC的病理分级、转移和肿瘤淋巴结转移分类相关。值得注意的是，我们观察到 CNRIP1 通过抑制丙酮酸激酶 M2 (PKM2) 的活性来抑制肿瘤细胞迁移、侵袭和增殖。 CNRIP1 的持续过度表达抑制了小鼠异种移植模型中的体内肿瘤生长。还发现 CNRIP1 过表达激活 Parkin（一种 E3 泛素连接酶），导致 ICC 细胞中 PKM2 的蛋白降解。结论我们确定 CNRIP1 在 ICC 中充当假定的肿瘤抑制因子，这表明 CNRIP1 可以作为预测 ICC 患者肿瘤复发的候选生物标志物。此外，这些发现强调了针对 CNRIP1/Parkin/PKM2 通路治疗 ICC 的潜在治疗方法。
Background and Aims Methylation landscape is important for maintaining the silence of cannabinoid receptor-interacting protein 1 (CNRIP1) in some tumors. However, the role of CNRIP1 in intrahepatic cholangiocarcinoma (ICC) remains poorly defined.Approach and Results In our study, we showed that CNRIP1 was down-regulated in ICC tissues, and low expression of CNRIP1 was significantly associated with poor prognosis of patients with ICC in 3-year overall survival and tumor-free survival. Investigating the genomic DNA methylation profile, we disclosed a CpG island site named CNRIP1 MS-2 (CNRIP1 methylation site-2) that contributes to the down-regulation of CNRIP1. In addition, the methylation level of CNRIP1 MS-2 was correlated to the pathological grade, metastasis, and tumor-node-metastasis classification in ICC. Notably, we observed that CNRIP1 suppressed tumor cell migration, invasion, and proliferation by inhibiting the activity of pyruvate kinase M2 (PKM2). Sustained overexpression of CNRIP1 suppressed the in vivo tumor growth in a mouse xenograft model. It was also found that CNRIP1 overexpression activated Parkin (an E3 ubiquitin ligase), which resulted in the protein degradation of PKM2 in ICC cells.Conclusions We identified that CNRIP1 acted as a putative tumor suppressor in ICC, which suggested that CNRIP1 could be a candidate biomarker for predicting tumor recurrence in patients with ICC. Furthermore, these findings highlight a potential therapeutic approach in targeting the CNRIP1/Parkin/PKM2 pathway for the treatment of ICC.