CRKL Enhances YAP Signaling through Binding and JNK/JUN Pathway Activation in Liver Cancer.

The Hippo pathway transducers yes-associated protein (YAP) and WW-domain containing transcription regulator 1 (WWTR1/TAZ) are key regulators of liver tumorigenesis, promoting tumor formation and progression. Although the first inhibitors are in clinical trials, targeting the relevant upstream regulators of YAP/TAZ activity could prove equally beneficial. To identify regulators of YAP/TAZ activity in hepatocarcinoma (HCC) cells, we carried out a proximity labelling approach (BioID) coupled with mass spectrometry.

Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication.

Introduction: The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell-cell communication of non-malignant liver cells.

SEPTIN10-mediated crosstalk between cytoskeletal networks controls mechanotransduction and oncogenic YAP/TAZ signaling.

The transcriptional co-activators of the Hippo pathway, YAP and TAZ, are regulated by mechanotransduction, which depends on dynamic actin cytoskeleton remodeling. Here, we identified SEPTIN10 as a novel cytoskeletal protein, which is transcriptionally regulated by YAP/TAZ and whose overexpression correlates with poor survival and vascular invasion in hepatocellular carcinoma (HCC) patients. Functional characterization demonstrated that SEPTIN10 promotes YAP/TAZ-dependent cell viability, migration and invasion of liver cancer cells.

Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in HCC.

Background And Aims: HCC is the most common primary liver tumor, with an increasing incidence worldwide. HCC is a heterogeneous malignancy and usually develops in a chronically injured liver. The NF-κB signaling network consists of a canonical and a noncanonical branch.

α-catenin interaction with YAP/FoxM1/TEAD-induced CEP55 supports liver cancer cell migration.

Background: Adherens junctions (AJs) facilitate cell-cell contact and contribute to cellular communication as well as signaling under physiological and pathological conditions. Aberrant expression of AJ proteins is frequently observed in human cancers; however, how these factors contribute to tumorigenesis is poorly understood. In addition, for some factors such as α-catenin contradicting data has been described.

HELLS Is Negatively Regulated by Wild-Type P53 in Liver Cancer by a Mechanism Involving P21 and FOXM1.

The major tumor suppressor P53 () acts primarily as a transcription factor by activating or repressing subsets of its numerous target genes, resulting in different cellular outcomes (e.g., cell cycle arrest, apoptosis and senescence).

Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma.

Background: Activation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma (iCCA); however, the expression pattern and the functional impact of its paralogue WW domain-containing transcription regulator 1 (WWTR1; synonym: TAZ) are not well described in different CCA subtypes.

Methods: Immunohistochemical analysis of YAP and TAZ in iCCA and extrahepatic CCA (eCCA) cohorts was performed. YAP/TAZ shuttling and their functional impact on CCA cell lines were investigated.

YAP-induced Ccl2 expression is associated with a switch in hepatic macrophage identity and vascular remodelling in liver cancer.

Background & Aim: The development of hepatocellular carcinoma (HCC) is associated with the formation of communication networks leading to the recruitment of disease-modifying macrophages. However, how oncogenes in tumour cells control paracrine communication is not fully understood.

Methods: Transgenic mice with liver-specific expression of the constitutively active yes-associated protein (YAP ) or an orthotopic implantation model served as tumour models.

Yes-associated protein (YAP) induces a secretome phenotype and transcriptionally regulates plasminogen activator Inhibitor-1 (PAI-1) expression in hepatocarcinogenesis.

Background: Overexpression and nuclear enrichment of the oncogene yes-associated protein (YAP) cause tumor initiation and support tumor progression in human hepatocellular carcinoma (HCC) via cell autonomous mechanisms. However, how YAP expression in tumor cells affects intercellular communication within the tumor microenvironment is not well understood.

Methods: To investigate how tumor cell-derived YAP is changing the paracrine communication network between tumor cells and non-neoplastic cells in hepatocarcinogenesis, the expression and secretion of cytokines, growth factors and chemokines were analyzed in transgenic mice with liver-specific and inducible expression of constitutively active YAP (YAP).

YAP Orchestrates Heterotypic Endothelial Cell Communication via HGF/c-MET Signaling in Liver Tumorigenesis.

The oncogene yes-associated protein (YAP) controls liver tumor initiation and progression via cell extrinsic functions by creating a tumor-supporting environment in conjunction with cell autonomous mechanisms. However, how YAP controls organization of the microenvironment and in particular the vascular niche, which contributes to liver disease and hepatocarcinogenesis, is poorly understood. To investigate heterotypic cell communication, we dissected murine and human liver endothelial cell (EC) populations into liver sinusoidal endothelial cells (LSEC) and continuous endothelial cells (CEC) through histomorphological and molecular characterization.

TAZ target gene ITGAV regulates invasion and feeds back positively on YAP and TAZ in liver cancer cells.

The Hippo pathway effectors yes-associated protein (YAP) and WW domain containing transcription regulator 1 (TAZ/WWTR1) support tumor initiation and progression in various cancer entities including hepatocellular carcinoma (HCC). However, to which extent YAP and TAZ contribute to liver tumorigenesis via common and exclusive molecular mechanisms is poorly understood. RNAinterference (RNAi) experiments illustrate that YAP and TAZ individually support HCC cell viability and migration, while for invasion additive effects were observed.

YAP-dependent induction of UHMK1 supports nuclear enrichment of the oncogene MYBL2 and proliferation in liver cancer cells.

The oncogene yes-associated protein (YAP) is a key modifier of liver homeostasis and regulates mitosis in hepatocytes as well as in malignantly transformed cells. However, the question of how YAP supports cell proliferation in hepatocellular carcinoma (HCC) is not well understood. Here we identified U2AF momology motif kinase 1 (UHMK1) as a direct transcriptional target of YAP and the transcription factor forkhead box M1 (FOXM1), which supports HCC cell proliferation but not migration.

Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness.

Unlabelled: The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the basolateral cell polarity complex protein scribble (Scrib) correlated with poor prognosis of HCC patients.

Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer.

Background & Aims: Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice.