title: Six1 overexpression at early stages of HPV16-mediated transformation of human keratinocytes promotes differentiation resistance and EMT.
abstract: Previous studies in our laboratory discovered that SIX1 mRNA expression increased during in vitro progression of HPV16-immortalized human keratinocytes (HKc/HPV16) toward a differentiation-resistant (HKc/DR) phenotype. In this study, we explored the role of Six1 at early stages of HPV16-mediated transformation by overexpressing Six1 in HKc/HPV16. We found that Six1 overexpression in HKc/HPV16 increased cell proliferation and promoted cell migration and invasion by inducing epithelial-mesenchymal transition (EMT). Moreover, the overexpression of Six1 in HKc/HPV16 resulted in resistance to serum and calcium-induced differentiation, which is the hallmark of the HKc/DR phenotype. Activation of MAPK in HKc/HPV16 overexpressing Six1 is linked to resistance to calcium-induced differentiation. In conclusion, this study determined that Six1 overexpression resulted in differentiation resistance and promoted EMT at early stages of HPV16-mediated transformation of human keratinocytes.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Pirisi
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA. Electronic address: creekk@sccp.sc.edu.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Creek
mesh_terms: D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002465:Cell Movement; D049109:Cell Proliferation; D002472:Cell Transformation, Viral / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D052162:Human papillomavirus 16 / Q000472:pathogenicity*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D020935:MAP Kinase Signaling System; D012333:RNA, Messenger / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000821:virology
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; C099236:SIX1 protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: Cervical cancer; Differentiation resistance; Epithelial–mesenchymal transition; Human papillomavirus; MAPK; Six1