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Activation of ?-catenin and Yap1 in human hepatoblastoma and induction of
hepatocarcinogenesis in mice
#MMPMID24837480
Tao J
; Calvisi DF
; Ranganathan S
; Cigliano A
; Zhou L
; Singh S
; Jiang L
; Fan B
; Terracciano L
; Armeanu-Ebinger S
; Ribback S
; Dombrowski F
; Evert M
; Chen X
; Monga SPS
Gastroenterology
2014[Sep]; 147
(3
): 690-701
PMID24837480
show ga
BACKGROUND & AIMS: Aberrant activation of ?-catenin and Yes-associated protein 1
(Yap1) signaling pathways have been associated with the development of multiple
tumor types. Yap functions as a transcriptional coactivator by interacting with
TEA domain DNA binding proteins. We investigated the interactions among these
pathways during hepatic tumorigenesis. METHODS: We used immunohistochemical
analysis to determine expression of ?-catenin and Yap1 in liver cancer specimens
collected from patients in Europe and the United States, consisting of 104
hepatocellular carcinoma, 62 intrahepatic cholangiocarcinoma, and 94
hepatoblastoma samples. We assessed ?-catenin and Yap1 signaling and interactions
in hepatoblastoma cell lines ((HuH6, HepG2, HepT1, HC-AFW1, HepG2, and HC-AFW1);
proteins were knocked down with small interfering RNAs, and effects on
proliferation and cell death were measured. Sleeping beauty-mediated hydrodynamic
transfection was used to overexpress constitutively active forms of ?-catenin
(?N90/?-catenin) and Yap1 (YapS127A) in livers of mice; tissues were collected,
and histological and immunohistochemical analyses were performed. RESULTS: We
observed nuclear localization of ?-catenin and Yap1 in 79% of hepatoblastoma
samples but not in most hepatocellular carcinoma or intrahepatic
cholangiocarcinoma samples. Yap1 and ?-catenin coprecipitated in hepatoblastoma
but not hepatocellular carcinoma cells. Small interfering RNA-mediated knockdown
of Yap1 or ?-catenin in hepatoblastoma cells reduced proliferation in an additive
manner. Knockdown of Yap1 reduced its ability to coactivate transcription with
?-catenin; ?-catenin inhibitors inactivated Yap1. Overexpression of
constitutively active forms of Yap1 and ?-catenin in mouse liver led to rapid
tumorigenesis, with 100% mortality by 11 weeks. Tumor cells expressed both
proteins, and human hepatoblastoma cells expressed common targets of their 2
signaling pathways. Yap1 binding of TEA domain factors was required for
tumorigenesis in mice. CONCLUSIONS: ?-catenin and the transcriptional regulator
Yap1 interact physically and are activated in most human hepatoblastoma tissues;
overexpression of activated forms of these proteins in livers of mice leads to
rapid tumor development. Further analysis of these mice will allow further
studies of these pathways in hepatoblastoma pathogenesis and could lead to the
identification of new therapeutic targets.
|Adaptor Proteins, Signal Transducing/genetics/*metabolism
[MESH]
free
free
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