Key Laboratory on Living Donor Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Department of Hepatobiliary Surgery, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.
Biomed Res Int. 2023 Sep 22;2023:5491682. doi: 10.1155/2023/5491682. eCollection 2023.
COTE1 was recently described as an oncogene in hepatocellular carcinoma and gastric cancer. However, the roles of COTE1 in intrahepatic cholangiocarcinoma (ICC) are little known. Our study is aimed at clarifying novel functions of COTE1 in ICC progression, including proliferation, invasion, and autophagy. By using quantitative real-time PCR, immunohistochemistry staining, and western blotting, we found that COTE1 expression was frequently upregulated in ICC tissues, compared to paracarcinoma tissues. High COTE1 expression was significantly correlated with aggressive clinical features and predicted poor prognosis of ICC patients. Functional experiments revealed that ectopic COTE1 expression promoted ICC cell proliferation, colony formation, cellular invasion, migration, and in vivo tumorigenicity; in contrast, COTE1 knockdown resulted in the opposite effects. At molecular mechanism in vitro and vivo, our study revealed that COTE1 overexpression suppressed autophagy via Beclin1 transcription inhibition; conversely, COTE1 silencing facilitated autophagy through promoting Beclin1 expression. Furthermore, the suppression of COTE1 knockdown on cellular growth and invasion was rescued/aggravated by Beclin1 inhibition/accumulation. Our data, for the first time, illustrate that COTE1 is an oncogene in ICC pathogenesis, and the ectopic COTE1 expression promotes ICC proliferation and invasion via Beclin1-dependent autophagy inhibition.
COTE1 最近被描述为肝癌和胃癌的癌基因。然而，COTE1 在肝内胆管癌（ICC）中的作用知之甚少。我们的研究旨在阐明 COTE1 在 ICC 进展中的新功能，包括增殖、侵袭和自噬。通过使用定量实时 PCR、免疫组织化学染色和 Western blot，我们发现 COTE1 在 ICC 组织中经常上调，与癌旁组织相比。COTE1 高表达与侵袭性临床特征显著相关，并预测 ICC 患者的预后不良。功能实验表明，异位 COTE1 表达促进 ICC 细胞增殖、集落形成、细胞侵袭、迁移和体内致瘤性；相反，COTE1 敲低导致相反的效果。在体外和体内的分子机制研究中，我们揭示了 COTE1 通过 Beclin1 转录抑制抑制自噬；相反，COTE1 沉默通过促进 Beclin1 表达促进自噬。此外，通过 Beclin1 抑制/积累，可挽救/加重 COTE1 敲低对细胞生长和侵袭的抑制作用。我们的数据首次表明，COTE1 是 ICC 发病机制中的癌基因，异位 COTE1 表达通过 Beclin1 依赖性自噬抑制促进 ICC 增殖和侵袭。
