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

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.

Exploring the role of innate immunity in Cholangiocarcinoma: implications for prognosis, immune infiltration, and tumor metastasis

“…This activation enhances the immunogenicity of the tumor cells 36 . Furthermore, studies have demonstrated that the serine/threonine kinase TBK1 can promote cholangiocarcinoma progression by directly regulating β-catenin phosphorylation 37 .…”

The Complex of p-Tyr42 RhoA and p-p65/RelA in Response to LPS Regulates the Expression of Phosphoglycerate Kinase 1

“…As si-PGK1 reduced β-catenin (Figure 6E), we hypothesized that the PGK1 expressed through NF-κB and p-Tyr42 RhoA could stabilize β-catenin through phosphorylation. Recently, it was reported that chitinase 3-like 1 (Chi3l1) binds to CD44 and induces the phosphorylation of β-catenin at Ser552 by Akt in glioblastomas [28] and TANK-binding kinase 1 (TBK1) in cholangiocarcinomas [29], leading to its nuclear translocation. Additionally, PKA phosphorylates β-catenin at Ser675, preventing ubiquitination and consequently promoting the stabilization of β-catenin [30].…”

A DNA/RNA heteroduplex oligonucleotide coupling asparagine depletion restricts FGFR2 fusion-driven intrahepatic cholangiocarcinoma

“…Histology and immunohistochemistry were performed as previously described. 64 The related antibody information is listed in Table S2 . Images were acquired by an Olympus BX51 Fluorescence Microscope (Tokyo, Japan).…”