Regulation of cell cycles is of key importance in human papillomavirus (HPV)-associated cervical carcinogenesis

Abstract

The rapid progress in molecular biology has allowed the identification of the genes involved in different functions of normal cells and has also improved our understanding of the mechanisms of human carcinogenesis. The human papillomavirus (HPV) is a small double-stranded DNA tumor virus and its genes can manipulate cell cycle control to promote viral persistence and replication. The E6 and E7 proteins of high-risk HPV bind to cell cycle regulatory proteins and interfere with both G1/S and G2/M cell cycle checkpoints much more effectively than the low-risk HPV. The difference between the ability of low and high-risk HPV types to induce immortalization and transformation may well lie in their abilities to interact with the various cell cycle components, resulting in the loss of multiple cell cycle checkpoints, which are important in host genome fidelity, thus potentially resulting in accumulation of genetic abnormalities. Cervical cancer is one of the leading malignancies in women worldwide, with substantial morbidity and mortality. According to current concepts, HPV is recognized as the single most important causal agent in the pathogenesis of this cancer. HPV infection clearly precedes the development of malignancy, while being regularly associated with cervical cancer precursor lesions (all grades of squamous intraepithelial lesions). HPV-infected low-grade squamous intraepithelial lesion (SIL) has three possible outcomes: a) it may regress; b) it can persist; or c) it can make a clinical progression to in situ or invasive carcinoma. It has been well established by prospective cohort studies that the spontaneous regression rate increases in parallel with follow-up duration. In contrast, the clinical progression of lesions usually takes place quite rapidly, i.e. during the first two years from diagnosis. The mechanisms responsible for this divergent clinical behavior of HPV-associated squamous intraepithelial lesions are largely unknown, but currently under intense study in different laboratories worldwide.

The DNA load of six high-risk human papillomavirus types and its association with cervical lesions

“…It has been found recently that low viral load was characteristic of intermittently detected persistent infection [44]. Reduced viral load has been described in women having CIN; this has been explained by HPV genome integration associated with down-regulation of viral DNA synthesis, thereby affecting immune system activation and thus reducing the probability of infection being eliminated [43,45-47]. Accordingly, a long period of latency accompanied by low viral load would probably be observed, representing a greater risk for infection persistence and lesion progression [48].…”

“…This agreed with the finding that clearance of HPV-16 infection has been preceded by a transient viral load peak or a plateau phase [33]; such high load was probably necessary for the immunological system to become induced, thereby favouring HPV elimination. According to the above, HPV-31 infections are probably transitory and such association is mediated by an immune system response to high viral load which can eliminate the infection and thus CC precursor lesions do not progress or such lesions regress spontaneously [47]. …”

Associations of high-risk HPV types and viral load with cervical cancer in China

“…There was no significant association of viral load with invasive CC in this group. The integration and associated down-regulation of viral DNA synthesis is part of the reason that HPV viral load usually decreases in invasive CC (Brenna and Syrjanen, 2003). Hence, among women who do not already exhibit morphologic changes by cytology, measurement of viral load, as a surrogate for HPV persistence, may identify those at increased risk of developing CIN.…”

Biologia molecular do câncer cervical

“…As células-filhas imediatamente entram em fase G1 e podem reiniciar o ciclo celular. Alternativa, também, é parar o ciclo temporária ou definitivamente 3,5 …”

“…Mutações em um gene podem perturbar a célula, alterando a quantidade de proteína ou a atividade desta. [3][4][5] Duas classes de genes, pequenas em relação ao total de genes, têm papel chave no desenvolvimento do câncer. Em suas configurações normais, elas dirigem o ciclo celular em uma intrincada seqüência de eventos, pelos quais as células crescem e se dividem.…”