title: The transcription factor GLI1 mediates TGFβ1 driven EMT in hepatocellular carcinoma via a SNAI1-dependent mechanism.
abstract: The role of the epithelial-to-mesenchymal transition (EMT) during hepatocellular carcinoma (HCC) progression is well established, however the regulatory mechanisms modulating this phenomenon remain unclear. Here, we demonstrate that transcription factor glioma-associated oncogene 1 (GLI1) modulates EMT through direct up-regulation of SNAI1 and serves as a downstream effector of the transforming growth factor-β1 (TGFβ1) pathway, a well-known regulator of EMT in cancer cells. Overexpression of GLI1 increased proliferation, viability, migration, invasion, and colony formation by HCC cells. Conversely, GLI1 knockdown led to a decrease in all the above-mentioned cancer-associated phenotypes in HCC cells. Further analysis of GLI1 regulated cellular functions showed that this transcription factor is able to induce EMT and identified SNAI1 as a transcriptional target of GLI1 mediating this cellular effect in HCC cells. Moreover, we demonstrated that an intact GLI1-SNAI1 axis is required by TGFβ1 to induce EMT in these cells. Together, these findings define a novel cellular mechanism regulated by GLI1, which controls the growth and EMT phenotype in HCC.
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
authors.forename: Natalia B Rumie
authors.initials: NB
authors.lastname: Vittar
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Gai
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernandez-Barrena
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Moser
authors.forename: Chunling
authors.initials: C
authors.lastname: Hu
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.forename: Angela L
authors.initials: AL
authors.lastname: McCleary-Wheeler
authors.forename: Sherine F
authors.initials: SF
authors.lastname: Elsawa
authors.forename: Anne M
authors.initials: AM
authors.lastname: Vrabel
authors.forename: Abdirashid M
authors.initials: AM
authors.lastname: Shire
authors.forename: Andrea
authors.initials: A
authors.lastname: Comba
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.forename: Qingguang
authors.initials: Q
authors.lastname: Liu
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008856:Microscopy, Fluorescence / Q000379:methods; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000071676:Zinc Finger Protein GLI1