Gastroenterology Chongqing University Tang Liling and other teams discover potential therapeutic targets for intrahepatic cholangiocarcinoma

Aberrant activation of iNatureYAP is associated with intrahepatic cholangiocarcinoma (iCCA)
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TEAD-mediated transcriptional regulation is a major signaling event downstream of YAP
.

The role of Wnt/β-Catenin signaling in cholangiocarcinogenesis remains undetermined
.

On April 27, 2022, Tang Liling of Chongqing University, Chen Xin of UCSF/University of Hawaii, and Diego F.
Calvisi of University of Regensburg published a joint communication online in Gastroenterology (IF=23) entitled "β-Catenin sustains and is required for YES-associated protein oncogenic activity in cholangiocarcinoma”, which found that TEAD factors are required for YAP-dependent iCCA development
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However, transcriptional activation of TEADs does not fully recapitulate the activity of YAP in promoting cholangiocarcinogenesis
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Notably, β-Catenin physically interacts with YAP in human and mouse iCCA
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Ctnnb1 ablation strongly inhibits human iCCA cell growth and Yap-dependent cholangiocarcinogenesis
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Furthermore, RNASeq analysis revealed that YAP/TAZ regulates a group of genes that significantly overlap with those controlled by β-Catenin
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Importantly, activated/non-phosphorylated β-Catenin was detected in more than 80% of human iCCAs
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In conclusion, this study found that YAP induces cholangiocarcinogenesis through TEAD-dependent transcriptional activation and interaction with β-Catenin
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β-Catenin binds to YAP in iCCA and is required for full YAP transcriptional activity, revealing functional crosstalk between YAP and β-Catenin pathways in cholangiocarcinogenesis
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Cholangiocarcinoma (CCA) is a highly heterogeneous hepatobiliary malignancy characterized by cholangiocellular differentiation
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They can be subdivided into three subtypes based on anatomical location: intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA)
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iCCA is the second most common primary liver tumor after hepatocellular carcinoma (HCC), accounting for approximately 10-15% of all hepatobiliary malignancies
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The incidence of iCCA is on the rise globally
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With limited therapeutic options, there is an urgent need to discover signaling pathways in iCCA tumorigenesis to develop novel and effective therapies against this lethal malignancy
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Hippo is a tumor suppressor pathway that is inactivated in multiple tumor types including iCCA
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YES-associated protein (YAP) acts as a transcriptional coactivator downstream of Hippo
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YAP exerts its functions primarily by interacting with transcription factors and other proteins containing TEA domains (TEADs)
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Structurally, YAP is a multi-domain protein with an N-terminal proline-rich domain, a TEAD-binding domain (TBD), a WW domain, an SH3-binding motif, a transcriptional activation domain (TAD), and a C - Terminal PDZ binding motif
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TBD and TAD are essential for YAP transcriptional activity, while other domains mediate YAP protein interactions
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 YAP is critical for cancer initiation, progression and metastasis
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Studies have shown that YAP nuclear expression is increased in human iCCA specimens, and that activated YAP levels are associated with poorer prognosis in iCCA patients
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The oncogenic role of YAP in cholangiocarcinogenesis has been further confirmed in vivo
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Indeed, co-expression of the activated forms of Akt (myr-Akt) and Yap (YapS127A) induced mouse iCCA formation (Akt/Yap)
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Schematic diagram of the article (picture from Gastroenterology) The Wnt/β-Catenin pathway is an evolutionarily conserved pathway that plays a key role in regulating liver homeostasis, regeneration and carcinogenesis
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Activated Wnt/β-Catenin is associated with the development of hepatoblastoma (HB) and HCC because gain-of-function (GOF) mutations in the CTNNB1 gene encoding β-Catenin occur in both tumor entities
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CTNNB1 mutations are uncommon in iCCA
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Several studies have reported activation of Wnt/β-Catenin signaling in human iCCA, while the exact function of this pathway in cholangiocarcinogenesis remains poorly understood
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Using the Akt/Yap-induced iCCA model, this study explored the molecular mechanisms by which YAP drives cholangiocarcinogenesis
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The data suggest that YAP induces iCCA development through TEAD-mediated transcriptional activation and crosstalk with β-Catenin
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