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Biomedical Reviews

Human papillomavirus infection and cervical cancer

Toshiyuki Sasagawa


More than 50% of young women who have had sex early in life acquire cervical human papillomavirus (HPV) infection. Most of the infections are with the high-risk HPV types, which are potential ethiologic factor for cervical cancer. Although ten or more HPV types are thought to be of high-risk, perhaps less than 30% of such infections persist and less than 1.5% develop cancer. Many previous studies clarify the oncogenic potentials of HPV16 or 18 genes by the experimental transformation of cells, introduced with target genes. Some molecular events induced with E6 and E7 genes of high-risk HPV types could explain the mechanisms of HPV for promoting cancer development. One important step for the malignant progression by HPV is the stable expression of HPV E6 and E7 oncoproteins in the host cells, and this may be caused by the integration of the HPV genome into the host genome. The E6 and E7 proteins induce uncontrollable cell growth and accumulate mutations in the host genome after many cell divisions by inhibiting the functions of Rb and p53, which tightly regulate cell division cycle. However, it is postulated that such molecular events may occur only in cells able to escape from the immune-surveillance system, since all viral proteins are potentially immunogenic and targeted by the immune cells. Thus, immune responses to HPV and immune-evasion mechanisms of HPV play the most important role for persistent HPV infection and the progression of cervical diseases. It is reported that increased helper T type 2 (Th2) responses (suppression of cell-mediated immunity) and reduction of Th1 responses (no stimulation of cell-mediated immunity) are more frequently observed in cervical intraepithelial neoplasia (CIN) lesions than in normal cervices, suggesting that immune suppression is involved in CIN development. Correlations between certain major histocompatibility complex (MHC) class I and class II alleles and susceptibility to cervical carcinoma or protection against HPV infection are reported, suggesting that the genetic background related to immune responses may contribute to different outcome in the women who are infected with HPV. HPV appears to evade the host immune responses by several mechanisms: (i) avoidance of viral antigen recognition, (ii) induction of HPV 16 E7 tolerance, (iii) modulation of the signal transduction pathways of interferons and other cytokines such as interkeukin-18, and MHC antigens, (iv) inhibition of surrounding immune cell activity by secreted E6 and E7 proteins. Both immune-suppressive and oncogenic actions induced with HPV infection may allow HPV-infected cells to transform into cancer cells in vivo by conferring survival abilities against the growth inhibitory or apoptotic stimulation of cytokines and the attack of killer cells.

Biomedical Reviews 2003; 14: 75-93.

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Toshiyuki Sasagawa
Kanazawa University

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