Down-regulation of microRNA-146a is associated with high-risk human papillomavirus infection and epidermal growth factor receptor overexpression in penile squamous cell carcinoma.
Dysregulation of host microRNA expression has been involved in the development and progression of human papillomavirus (HPV)-related tumors. Analysis of miR-146a expression in a series of 59 penile squamous cell carcinomas (PSCCs) showed that its levels were lower in high-risk HPV-positive than in HPV-negative PSCCs and inversely correlated with expression of epidermal growth factor receptor (EGFR), a known target for miR-146a. Analysis of genotype distribution for rs2910164, a common functional polymorphism of miR-146a, did not identify correlations with miR-146a levels and EGFR expression in PSCCs. In vitro experiments demonstrated that E6 of HPV type 16, but not low-risk HPV-6, down-regulated miR-146a in human foreskin keratinocytes and up-regulated EGFR. Ectopic expression of miR-146a decreased expression of EGFR and inhibited proliferation of keratinocytes and cervical carcinoma cells. EGFR is commonly overexpressed in penile cancer and in other squamous cell carcinomas. Molecular mechanisms leading to EGFR overexpression and activation are known for HPV-negative cancers and include amplification or mutations of the EGFR gene. The results of this study indicate that down-regulation of miR-146a may represent another mechanism of EGFR overexpression in PSCCs, which can be mediated by high-risk HPV E6 in HPV-related tumors.
Department of Molecular Medicine, University of Padova, I-35121 Padova, Italy.
Elektra
E
Peta
Department of Medicine, University of Padova, I-35121 Padova, Italy.
Rocco
R
Cappellesso
Department of Molecular Medicine, University of Padova, I-35121 Padova, Italy.
Giulia
G
Masi
Veneto Institute of Oncology IOV IRCCS, I-35128 Padova, Italy.
Alessandro
A
Sinigaglia
Department of Molecular Medicine, University of Padova, I-35121 Padova, Italy.
Marta
M
Trevisan
Department of Information Engineering, University of Padova, I-35121 Padova, Italy.
Angela
A
Grassi
Department of Information Engineering, University of Padova, I-35121 Padova, Italy.
Barbara
B
Di Camillo
Department of Medicine, University of Padova, I-35121 Padova, Italy.
Elisa
E
Vassarotto
Department of Medicine, University of Padova, I-35121 Padova, Italy.
Ambrogio
A
Fassina
Department of Molecular Medicine, University of Padova, I-35121 Padova, Italy.
Giorgio
G
Palù
Department of Molecular Medicine, University of Padova, I-35121 Padova, Italy. Electronic address: luisa.barzon@unipd.it.
Luisa
L
Barzon
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D010412:Penile Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology
D014408:Biomarkers, Tumor; C068651:E6 protein, Human papillomavirus type 16; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors
E6; Epidermal growth factor receptor; HPV-16; Human papillomavirus; MiR-146a; Penile squamous cell carcinoma