HPV16-transformed human keratinocytes depend on SIX1 expression for proliferation and HPV E6/E7 gene expression

The homeodomain transcription factor SIX1 plays a critical role in embryogenesis, is not expressed in normal adult tissue, but is expressed in many malignancies, including cervical cancer. SIX1 drives the progression of HPV16-immortalized human keratinocytes (HKc/HPV16) toward malignancy: HKc/HPV16...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2019-11, Vol.537, p.20-30
Main Authors: Hosseinipour, Maria, Wan, Fang, Altomare, Diego, Creek, Kim E., Pirisi, Lucia
Format: Article
Language:English
Subjects:
Cell Line
Cell Proliferation
Cell Transformation, Viral
Epithelial-Mesenchymal Transition
Gene Silencing
Homeodomain Proteins - metabolism
Host-Pathogen Interactions
HPV16
Human keratinocytes
Human papillomavirus
Human papillomavirus 16 - growth & development
Humans
Keratinocytes - virology
Oncogene Proteins, Viral - biosynthesis
Papillomavirus E7 Proteins - biosynthesis
Repressor Proteins - biosynthesis
Signal Transduction
SIX1
TGF-Beta
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Summary:The homeodomain transcription factor SIX1 plays a critical role in embryogenesis, is not expressed in normal adult tissue, but is expressed in many malignancies, including cervical cancer. SIX1 drives the progression of HPV16-immortalized human keratinocytes (HKc/HPV16) toward malignancy: HKc/HPV16 express high levels of SIX1 mRNA and protein; overexpression of SIX1 in HKc/HPV16 produces pre-malignant, differentiation-resistant lines (HKc/DR); SIX1 overexpression in HKc/DR induces tumorigenicity. In this paper, we explore the consequences of inhibition of SIX1 expression in premalignant HKc/DR. Only partial inhibition of SIX1 expression could be obtained in HKc/DR by RNA interference. Decreased SIX1 expression (up to 80%) in HKc/DR resulted in slower proliferation, decreased HPV16-E6/E7 mRNA levels, and increased p53 protein levels. Gene expression changes induced in HKc/DR by anti-SIX1 shRNA were indicative of mesenchymal-epithelial transition (MET) and changes in TGF-beta signaling. We conclude that HPV16-transformed cells depend on SIX1 for survival, HPV16 E6/E7 gene expression and epithelial-mesenchymal transition.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2019.08.009