A PLCB1-PI3K-AKT Signaling Axis Activates EMT to Promote Cholangiocarcinoma Progression.

Abstract

As a member of the phospholipase family, phospholipase C beta 1 (<i>PLCB1</i>) is involved in phospholipid hydrolysis and is frequently upregulated in human cancer. However, little is known about the role of PLCB1 in cholangiocarcinoma (CCA). In this study, we uncover a role for <i>PLCB1</i> in CCA progression and identify the underlying mechanisms. Both human CCA tissues and CCA cell lines expressed high levels of PLCB1. PLCB1 promoted tumor development and growth in various CCA mouse models, including transposon-based tumorigenesis models. PLCB1 activated PI3K/AKT signaling to induce CCA cells to undergo epithelial-to-mesenchymal transition (EMT). Mechanistically, PABPC1 interacted with PLCB1 and PI3K to amplify PLCB1-mediated EMT via PI3K/AKT/GSK3β/Snail signaling. Ectopic PLCB1 induced resistance to treatment with gemcitabine combined with cisplatin, which could be reversed by the AKT inhibitor MK2206. <i>PLCB1</i> expression was regulated by miR-26b-5p through direct interaction with <i>PLCB1</i> 3'UTR. Collectively, these data identify a PLCB1-PI3K-AKT signaling axis vital for CCA development and EMT, suggesting that AKT can be used as a therapeutic target to overcome chemotherapy resistance in CCA patients with high PLCB1 expression. SIGNIFICANCE: <i>PLCB1</i> functions as an oncogenic driver in cholangiocarcinoma development that confers an actionable therapeutic vulnerability to AKT inhibition.