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

by Selleckchem | Sep 04 2023

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.

Comments:

The study you described focuses on the role of TANK-binding kinase 1 (TBK1) in cholangiocarcinoma (CCA), a highly heterogeneous and metastatic malignancy with a poor prognosis. The researchers investigated the expression and function of TBK1 in both mouse models and human CCA tissues.

The study found that TBK1 expression increased dynamically during different stages of murine spontaneous CCA development, including hyperplasia, dysplasia, and CCA. Similarly, TBK1 was upregulated in human intrahepatic and extrahepatic CCA tissues compared to non-tumor tissues. The elevated expression of TBK1 was associated with larger tumor diameter, lymph node metastasis, and advanced TNM stage, indicating its potential as a prognostic biomarker.

Functional studies demonstrated that TBK1 promoted CCA growth and metastasis both in vitro and in vivo. The researchers discovered that TBK1 directly interacted with β-catenin, a protein involved in cell adhesion and signaling pathways. This interaction resulted in the phosphorylation of β-catenin at the S552 site and its subsequent translocation into the nucleus. Once in the nucleus, β-catenin activated EMT (epithelial-mesenchymal transition)-related transcriptional reprogramming, a process associated with increased invasiveness and metastasis.

To explore potential therapeutic strategies, the researchers used GSK-8612, a TBK1 inhibitor, and a kinase-inactivating mutation to suppress TBK1 activity. Both approaches effectively inhibited CCA growth and metastasis in experimental models.

In addition to TBK1, the study also identified an upregulation of low-density lipoprotein receptor (LDLR) in CCA. LDLR is responsible for the endocytosis of cholesterol. Leveraging this finding, the researchers designed a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide (Cho-TBK1-HDO) that targeted TBK1. This construct could specifically accumulate in CCA cells via LDLR-mediated endocytosis, resulting in a reduction of TBK1 mRNA levels and inhibition of intrahepatic metastasis.

Furthermore, in the group of 182 patients with intrahepatic cholangiocarcinoma (ICC), high expression of TBK1 combined with high nuclear β-catenin expression predicted a worse prognosis.

Overall, the study suggests that TBK1 may serve as a potential prognostic biomarker and therapeutic target for patients with cholangiocarcinoma. Inhibition of TBK1 activity using inhibitors or targeted oligonucleotides could potentially suppress CCA growth and metastasis. However, further research and clinical validation are necessary to fully understand the potential of TBK1 as a therapeutic target in CCA.