| Abstract |
Human Papilloma Viruses (HPVs) are small double-stranded DNA viruses, which
comprise a family of more than 130 genotypes. HPVs occur worldwide and induce a broad
spectrum of benign and malignant epithelial lesions in humans. Although HPV infection is
considered as a sexual transmitted infection, HPVs may also be transmitted by other nonsexual
routes including vertical transmission, autoinoculation and heteroinoculation, and,
possibly, indirect transmission via fomites. Recent studies suggest that perinatal infection and
autoinoculation or heteroinoculation may be much more likely than originally thought. It has
been found that vertical HPV transmission from HPV positive mothers to their infants results
in persistent infection in their first 3 years of life. Neonatal infections seem to be caused
predominantly by HPV types 16 and 18 in the genital area as well as in buccal cavity.
However, it is still unclear how frequently perinatal infections progress to clinical lesions.
HPVs can be classified into cutaneous or mucosal types according to their site of
infection. Cutaneous HPV types infect the squamous epithelium of the skin and produce
benign skin warts including common warts, plantar warts and flat warts. Mucosal HPV types
infect the mucous membranes of the cervix, the upper respiratory tract and esophagus and
have been considered as the principal etiologic factors of the development of cervical
intraepithelial neoplasia and cervical carcinoma. However, although the presence of ‘high
risk’ HPV types is proposed as a virtually necessary cause of primary epithelial cells
immortalization, in vitro experiments have shown that HPV infection alone is not sufficient
to engender a full tumorigenic conversion of cervical tissue. This is illustrated by the rare
occurrence of cancer compared with the wide distribution of HPV infection worldwide and
the long latency of HPV-induced cervical neoplasia. Additional environmental and genetic
factors, such as the activation of host cellular oncogenes are likely to be involved in the
persistence and progression of HPV infection to cervical cancer.
The family of ras oncogenes consists of three well-characterized genes, Harvey
(H)-ras, Kirsten(K)-ras and Neuroblastoma (N)-ras, genes that encode for a 21 kDa (p21)
protein with GTPase activity which participates in cellular signal transduction.
Overexpression of the ras oncogenes has also been suggested to play an important role in
carcinogenesis and has been implicated in several human cancers including breast, colon,
head and neck, bladder and lung. The purpose of this study was to evaluate the quantitative
and qualitative changes of expression of the ras family oncogenes in women with normal
cervix, with cervical intraepithelial neoplasia (CIN) and with cervical cancer and to
investigate their relationship with HPV infection. The expression of ras mRNA levels was
examined using reverse transcriptase polymerase chain reaction (RT-PCR). In addition, we
studied the incidence of point mutations in codon 12 of each ras gene using polymerase chain
reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. HPV
detection and typing was performed using PCR with general and specific primers. The
transcript levels for H-ras and N-ras were significantly higher in cancer cases compared to
normal cervical tissues and CIN lesions, while the transcript levels for K-ras were similar in
normal cervical tissue, CIN and cervical cancer. Among HPV positive patients, H-, K- and Nras
expression levels were higher in HPV 16/18-associated cases with cervical cancer.
Differences in ras mRNA expression between multiple HPV and single HPV infection were
also detected in patients with cervical cancer. Our findings indicate the expression pattern of
the three ras oncogenes in cervical tissue and the involvement of H- and N-ras upregulation
in the pathogenesis of cervical cancer. Our results support the hypothesis of a potential
interactive effect between high-risk’ HPV 16/18 and transcriptional activation of ras
oncogenes in cervical carcinogenesis. Further investigation is needed to determine the
influence of ras oncogenes activation on HPV persistence and progression.
We also determined the frequency of HPV infection in children with benign adenoid
or/and tonsillar hyperplasia. To date several researchers have evaluated the presence of HPV
DNA in children’s buccal cavity by studying oral swabs or washings of healthy children,
however data on HPV infection in biopsy specimens of tumor free oral mucosa are limited.
HPV DNA was detected using PCR with general primers and HPV typing was performed by
PCR by using specific primers. HPV DNA was detected in 9 (8.5%) of 106 specimens. HPV
16 was predominant, while HPV 11 was detected less frequently. The mean age of children
with HPV-positive specimens was lower than HPV-negative children. There was observed no
statistical important difference in the prevalence of HPV infection between adenoid and
tonsillar tissues. The consequences of the presence of HPV, although at low frequency, in
children’s tonsils and adenoids remain to be elucidated. Further research on oral HPV
infection in children will enable as to understand HPV natural history and its possible role in
the development of tonsillar and adenoid hyperplasia in children.
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