Human papilloma virus-dependent HMGA1 expression is a relevant step in cervical carcinogenesis.
HMGA1 is a member of a small family of architectural transcription factors involved in the coordinate assembly of multiprotein complexes referred to as enhanceosomes. In addition to their role in cell proliferation, differentiation, and development, high-mobility group proteins of the A type (HMGA) family members behave as transforming protoncogenes either in vitro or in animal models. Recent reports indicated that HMGA1 might counteract p53 pathway and provided an interesting hint on the mechanisms determining HMGA's transforming potential. HMGA1 expression is deregulated in a very large array of human tumors, including cervical cancer, but very limited information is available on the molecular mechanisms leading to HMGA1 deregulation in cancer cells. Here, we report that HMGA1 expression is sustained by human papilloma virus (HPV) E6/E7 proteins in cervical cancer, as demonstrated by either E6/E7 overexpression or by repression through RNA interference. Knocking down HMGA1 expression by means of RNA interference, we also showed that it is involved in cell proliferation and contributes to p53 inactivation in this type of neoplasia. Finally, we show that HMGA1 is necessary for the full expression of HPV18 E6 and E7 oncoproteins thus establishing a positive autoregulatory loop between HPV E6/E7 and HMGA1 expression.
Mellone
Massimiliano
M
Department of Experimental Medicine, Sapienza University, Rome 00161, Italy.
Rinaldi
Christian
C
Massimi
Isabella
I
Petroni
Marialaura
M
Veschi
Veronica
V
Talora
Claudio
C
Truffa
Silvia
S
Stabile
Helena
H
Frati
Luigi
L
Screpanti
Isabella
I
Gulino
Alberto
A
Giannini
Giuseppe
G
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002472:Cell Transformation, Viral / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D025741:HMGA1a Protein / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000235:genetics* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D051881:Receptor, Notch1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology*
D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; C497761:NOTCH1 protein, human; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D025741:HMGA1a Protein