Serine/threonine kinase TBK1 promotes cholangiocarcinoma progression via direct regulation of β-catenin

癌症研究 生物 癌变 坦克结合激酶1 激酶 癌症 蛋白激酶A 细胞生物学 细胞周期蛋白依赖激酶2 遗传学
作者
Chongqing Gao,Zhen-Zhen Chu,Di Zhang,Jing Wang,Xing-Yan Zhou,Junru Wu,Hui Yuan,Yuchuan Jiang,Dong Chen,Ji‐chun Zhang,Nan Yao,Kaiyun Chen,Jian Hong
出处
期刊:Oncogene [Springer Nature]
卷期号:42 (18): 1492-1507 被引量:8
标识
DOI:10.1038/s41388-023-02651-4
摘要

Abstract Cholangiocarcinoma (CCA) is a highly heterogeneous and metastatic malignancy with a poor prognosis even after curative hepatectomy. Studies exploring its pathogenesis and identifying effective therapeutic targets are urgently needed. In this study, we found that TANK-binding kinase 1 (TBK1), a serine/threonine-protein kinase, showed a dynamic increase during the different stages of murine spontaneous CCA carcinogenesis (hyperplasia, dysplasia, and CCA). TBK1 was upregulated in human tissues, including intrahepatic ( n = 182) and extrahepatic ( n = 40) CCA tissues, compared with nontumor tissues, and the elevated expression of TBK1 was positively correlated with larger tumour diameter, lymph node metastasis, and advanced TNM stage. Functional studies indicated that TBK1 promoted CCA growth and metastasis both in vitro and in vivo. TBK1 directly interacts with β-catenin, promoting its phosphorylation at the S552 site and its nuclear translocation, which further activates EMT-related transcriptional reprogramming. GSK-8612, a TBK1 inhibitor or a kinase-inactivating mutation, effectively suppresses the above processes. In addition, we found that low-density lipoprotein receptor (LDLR), which mediates the endocytosis of cholesterol, was upregulated in CCA. Therefore, we designed a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting TBK1 (Cho-TBK1-HDO), which could accumulate in CCA cells via LDLR, reduce the TBK1 mRNA level and inhibit intrahepatic metastasis of CCA. Besides, in the experimental group of 182 ICC patients, high TBK1 expression combined with high nuclear β-catenin expression predicted a worse prognosis. In summary, TBK1 might serve as a potential prognostic biomarker and therapeutic target for patients with CCA.
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