Human Papillomaviruses , p 16 INK 4 a and Akt expression in basal cell carcinoma

Background: The pathogenic role of beta-HPVs in non melanoma skin cancer (NMSC), is not still completely understood, and literature data indicate that they might be at least cofactors in the development of certain cutaneous squamous cell carcinomas. However, only few reports contain data on basal cell carcinoma (BCC). The HPVs interact with many cellular proteins altering their function or the expression levels, like the p16 and Akt. Our study aimed to determine the presence of different beta -HPV types and the expression of p16 and Akt in BCC, the commonest NMSC, in the normal appearing perilesional skin and in forehead swab of 37 immunocompetent patients. Methods: The expression of p16 and Akt, by immunohistochemistry, and the HPV DNA, by nested PCR, were investigated in each sample. Results: No correspondence of HPV types between BCC and swab samples was found, whereas a correspondence between perilesional skin and BCC was ascertained in the 16,7% of the patients. In BCC, 16 different types of beta HPV were found and the most frequent types were HPV107 (15,4%), HPV100 (11,5%) and HPV15 (11,5%) all belonging to the beta HPV species 2. Immunohistochemistry detected significant p16 expression in almost all tumor samples (94,3%) with the highest percentages (> 30%) of positive cells detected in 8 cases. A statistically significant (p = 0,012) increase of beta HPV presence was detected in p16 strongly positive samples, in particular of species 2. pAkt expression was detected in all tumor samples with only 2 cases showing rare positive cells, whereas Akt2 expression was found in 14 out of 35 BCC (40%); in particular in HPV positive samples overexpressing p16. Conclusions: Our data show that p16 and pAkt are over-expressed in BCC and that the high expression of p16 and of Akt2 isoform is often associated with the presence of beta-HPV species 2 (i.e. HPV 15). The association of these viruses with the up-regulation of p16 and Akt/PI3K pathway suggests that in a subtype of BCC these viruses may exert a role in the carcinogenesis or in other, still undefined, biological property of these tumors. If this particular type of BCC reflects a different biology it will remain undisclosed until further studies on a larger number of samples will be performed.

[1]  M. Pawlita,et al.  Seropositivity for human papillomavirus and incidence of subsequent squamous cell and basal cell carcinomas of the skin in patients with a previous nonmelanoma skin cancer , 2011, The British journal of dermatology.

[2]  M. Landthaler,et al.  Activation of the PI3K/AKT signalling pathway in non‐melanoma skin cancer is not mediated by oncogenic PIK3CA and AKT1 hotspot mutations , 2010, Experimental dermatology.

[3]  E. de Villiers,et al.  Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. , 2010, Virology.

[4]  A. Zaravinos,et al.  Viral DNA detection and RAS mutations in actinic keratosis and nonmelanoma skin cancers , 2010, The British journal of dermatology.

[5]  M. Meyerson,et al.  Somatic mutations are present in all members of the AKT family in endometrial carcinoma , 2009, British Journal of Cancer.

[6]  M. Karagas,et al.  Exposure profiles and human papillomavirus infection in skin cancer: an analysis of 25 genus beta-types in a population-based study. , 2008, The Journal of investigative dermatology.

[7]  V. Sondak,et al.  Measures of cutaneous human papillomavirus infection in normal tissues as biomarkers of HPV in corresponding nonmelanoma skin cancers , 2008, International journal of cancer.

[8]  P. Ismail,et al.  p16 gene expression in basal cell carcinoma. , 2008, Archives of medical research.

[9]  S. H. Lee,et al.  Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias , 2008, British Journal of Cancer.

[10]  K. Urabe,et al.  Significance of the expression of phosphorylated-STAT3, -Akt, and -ERK1/2 in several tumors of the epidermis. , 2007, Journal of dermatological science.

[11]  J. Dillner,et al.  Cutaneous human papillomaviruses found in sun-exposed skin: Beta-papillomavirus species 2 predominates in squamous cell carcinoma. , 2007, The Journal of infectious diseases.

[12]  H. Pfister,et al.  Cutaneous human papillomaviruses down-regulate AKT1, whereas AKT2 up-regulation and activation associates with tumors. , 2007, Cancer research.

[13]  M. Birnbaum,et al.  AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation* , 2007, Journal of Biological Chemistry.

[14]  James T. Elder,et al.  Differential ErbB1 signaling in squamous cell versus basal cell carcinoma of the skin. , 2007, The American journal of pathology.

[15]  A. Alonso,et al.  Phylogeny and evolution of papillomaviruses based on the E1 and E2 proteins , 2007, Virus Genes.

[16]  Alexandros Stamatakis,et al.  Multiple evolutionary mechanisms drive papillomavirus diversification. , 2007, Molecular biology and evolution.

[17]  D. Giannarelli,et al.  Molecular analyses and prognostic relevance of HPV in head and neck tumours. , 2007, Oncology reports.

[18]  G. Orth.  Genetics of epidermodysplasia verruciformis: Insights into host defense against papillomaviruses. , 2006, Seminars in immunology.

[19]  C. Clavel,et al.  P16 is overexpressed in cutaneous carcinomas located on sun-exposed areas. , 2006, European journal of dermatology : EJD.

[20]  Jung Young Lee,et al.  Mutational Analysis of AKT1, AKT2 and AKT3 Genes in Common Human Carcinomas , 2006, Oncology.

[21]  D. McCance,et al.  Human papillomavirus type 16 E7 up-regulates AKT activity through the retinoblastoma protein. , 2006, Cancer research.

[22]  L. Mariani,et al.  Immunohistochemical expression of p16INK4a is predictive of HR-HPV infection in cervical low-grade lesions , 2006, Modern Pathology.

[23]  P. Fuchs,et al.  Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8. , 2005, Cancer research.

[24]  A. Venuti,et al.  Presence of HPV in head and neck tumours: high prevalence in tonsillar localization. , 2004, Journal of experimental & clinical cancer research : CR.

[25]  G. Landberg,et al.  Retinoblastoma protein function and p16INK4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16INK4a expression and infiltrative behavior , 2004, Modern Pathology.

[26]  Claude Fauquet,et al.  Classification of papillomaviruses. , 2004, Virology.

[27]  K. Nishioka,et al.  Enhanced expression of p16 in seborrhoeic keratosis; a lesion of accumulated senescent epidermal cells in G1 arrest , 2003, The British journal of dermatology.

[28]  G. Landberg,et al.  Invade or proliferate? Two contrasting events in malignant behavior governed by p16(INK4a) and an intact Rb pathway illustrated by a model system of basal cell carcinoma. , 2003, Cancer research.

[29]  H. Hausen.  Papillomaviruses and cancer: from basic studies to clinical application , 2002, Nature Reviews Cancer.

[30]  T. Ochiya,et al.  Enhanced skin carcinogenesis in cyclin D1-conditional transgenic mice: cyclin D1 alters keratinocyte response to calcium-induced terminal differentiation. , 2002, Cancer research.

[31]  O. Stål,et al.  Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients , 2002, British Journal of Cancer.

[32]  E. Kay,et al.  p53 codon 72 polymorphism and human papillomavirus associated skin cancer , 2001, Journal of clinical pathology.

[33]  M. von Knebel Doeberitz,et al.  Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri , 2001, International journal of cancer.

[34]  J. McGregor,et al.  Human papillomavirus infection and non‐melanoma skin cancer in immunosuppressed and immunocompetent individuals , 2000, Journal of medical virology.

[35]  B. Hansson,et al.  A broad range of human papillomavirus types detected with a general PCR method suitable for analysis of cutaneous tumours and normal skin. , 1999, The Journal of general virology.

[36]  C. Meijer,et al.  A general primer GP5+/GP6(+)-mediated PCR-enzyme immunoassay method for rapid detection of 14 high-risk and 6 low-risk human papillomavirus genotypes in cervical scrapings , 1997, Journal of clinical microbiology.

[37]  C. Sherr.  Cancer Cell Cycles , 1996, Science.

[38]  H. Smits,et al.  Nested PCR approach for detection and typing of epidermodysplasia verruciformis-associated human papillomavirus types in cutaneous cancers from renal transplant recipients , 1995, Journal of clinical microbiology.

[39]  A. Robles,et al.  Overexpression of cyclin D1 in mouse skin carcinogenesis. , 1993, Oncogene.

[40]  K. Mullis,et al.  Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. , 1988, Science.

[41]  B. Thiers.  Human Papillomavirus Infection and Incidence of Squamous Cell and Basal Cell Carcinomas of the Skin , 2007 .

[42]  A. Green,et al.  Case-control study in a subtropical Australian population to assess the relation between non-melanoma skin cancer and epidermodysplasia verruciformis human papillomavirus DNA in plucked eyebrow hairs. The Nambour Skin Cancer Prevention Study Group. , 2000, International journal of cancer.

[43]  M. Herlyn,et al.  In Human Squamous Carcinomas Antisense Cyclin D1 Induces Apoptosis and Tumor Shrinkage Updated Version Cited Articles Citing Articles E-mail Alerts Antisense Cyclin D1 Induces Apoptosis and Tumor Shrinkage in Human Squamous Carcinomas , 2022 .