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Transforming Growth Factor-β Promotes Liver Tumorigenesis in Mice via Up-regulation of Snail

 Hyuk Moon  ;  Hye-Lim Ju  ;  Sook In Chung  ;  Kyung Joo Cho  ;  Jung Woo Eun  ;  Suk Woo Nam  ;  Kwang-Hyub Han  ;  Diego F. Calvisi  ;  Simon Weonsang Ro 
 GASTROENTEROLOGY, Vol.153(5) : 1378-1391.e6, 2017 
Journal Title
Issue Date
Animals ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism* ; Carcinoma, Hepatocellular/pathology ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism* ; Cell Transformation, Neoplastic/pathology ; Gene Expression Regulation, Neoplastic ; Genes, myc ; Genes, ras ; Genetic Predisposition to Disease ; Hep G2 Cells ; Humans ; Liver/metabolism* ; Liver/pathology ; Liver Neoplasms, Experimental/genetics ; Liver Neoplasms, Experimental/metabolism* ; Liver Neoplasms, Experimental/pathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Protein-Serine-Threonine Kinases/deficiency ; Protein-Serine-Threonine Kinases/genetics ; RNA Interference ; Receptors, Transforming Growth Factor beta/deficiency ; Receptors, Transforming Growth Factor beta/genetics ; Signal Transduction ; Smad Proteins/genetics ; Smad Proteins/metabolism ; Snail Family Transcription Factors/genetics ; Snail Family Transcription Factors/metabolism* ; Time Factors ; Transfection ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism* ; Tumor Suppressor Protein p53/deficiency ; Tumor Suppressor Protein p53/genetics ; Up-Regulation
Liver Cancer ; Mouse Model ; Oncogene ; Signal Transduction
BACKGROUND & AIMS: Transforming growth factor beta (TGF-β) suppresses early stages of tumorigenesis, but also contributes to migration and metastasis of cancer cells. A large number of human tumors contain mutations that inactivate its receptors, or downstream proteins such as Smad transcription factors, indicating that the TGF-β signaling pathway prevents tumor growth. We investigated the effects of TGF-β inhibition on liver tumorigenesis in mice.

METHODS: C57BL/6 mice received hydrodynamic tail-vein injections of transposons encoding HRASG12V and a short hairpin RNA (shRNA) to down-regulate p53, or those encoding HRASG12V and MYC, or those encoding HRASG12V and TAZS89A, to induce liver tumor formation; mice were also given injections of transposons encoding SMAD7 or shRNA against SMAD2, SMAD3, SMAD4, or SNAI1 (Snail), with or without ectopic expression of Snail. Survival times were compared, and livers were weighted and examined for tumors. Liver tumor tissues were analyzed by quantitative reverse-transcription PCR, RNA sequencing, immunoblots, and immunohistochemistry. We analyzed gene expression levels in human hepatocellular carcinoma samples deposited in The Cancer Genome Atlas. A cell proliferation assay was performed using human liver cancer cell lines (HepG2 and Huh7) stably expressing Snail or shRNA against Snail.

RESULTS: TGF-β inhibition via overexpression of SMAD7 (or knockdown of SMAD2, SMAD3, or SMAD4) consistently reduced formation and growth of liver tumors in mice that expressed activated RAS plus shRNA against p53, or in mice that expressed activated RAS and TAZ. TGF-β signaling activated transcription of the Snail gene in liver tumors induced by HRASG12V and shRNA against p53, and by activated RAS and TAZ. Knockdown of Snail reduced liver tumor formation in both tumor models. Ectopic expression of Snail restored liver tumorigenesis suppressed by disruption of TGF-β signaling. In human hepatocellular carcinoma, Snail expression correlated with TGF-β activation. Ectopic expression of Snail increased cellular proliferation, whereas Snail knockdown led to reduced proliferation in human hepatocellular carcinoma cells.

CONCLUSIONS: In analyses of transgenic mice, we found TGF-β signaling to be required for formation of liver tumors upon expression of activated RAS and shRNA down-regulating p53, and upon expression of activated RAS and TAZ. Snail is the TGF-β target that is required for hepatic tumorigenesis in these models.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Ro, Simon Weonsang(노원상) ORCID logo https://orcid.org/0000-0003-2187-3698
Chung, Sook In(정숙인) ORCID logo https://orcid.org/0000-0002-7915-9203
Han, Kwang-Hyub(한광협) ORCID logo https://orcid.org/0000-0003-3960-6539
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