Proteomics Strategies to Analyze HPV-Transformed Cells: Relevance to Cervical Cancer

Fabio Di Domenico; Federico De Marco; Marzia Perluigi

Disclosures

Expert Rev Proteomics. 2013;10(5):461-472. 

In This Article

Brief Overview of HR-HPV Carcinogenic Mechanisms

Human papillomavirus type 16 (HPV16), is the most prevalent HR-HPV type accounting for above than 50% of premalignant and malignant cervical lesions[9] and by far and large the is the most intensively studied one. The oncogenic potential of HR-HPVs will be then briefly outlined mostly based on the HPV-16 biological profile. The major transforming activities of HR-HPVs are provided by the products of the E6 and E7 genes. The E7 protein binds to the cellular products of the retinoblastoma (Rb) family namely the proteins p105 (pRB), p107 and the p130, which are the major cellular factors coupling differentiation with proliferation cell suppression.[10,11] The E7 binding targets Rb protein for proteasome degradation. This results in the release and activation of the E2F factors that enable the expression of the 'S' phase genes. Such an activation being out of context in a differentiation-committed cell can lead to inhibition of cell proliferation and apoptosis through a p53 dependent pathway.

To inactivate this cellular control, HR-HPVs have evolved the E6 protein to target the cellular p53 and to promote its degradation resulting in suppression of apoptosis and other p53 related functions. Thus the combined action of E6 and E7 oncoproteins prevent the inhibition of cell growth, apoptosis and DNA damage sensing and repair in continuously proliferating differentiated and undifferentiated cells together with the abrogation of a number of cell cycle checkpoints (Figure 1). These conditions provide the cellular environment for the generation and accumulation of genetic mutation eventually leading to the neoplastic phenotype.[12]

Figure 1.

Cellular proteins and pathways affected by the human papillomavirus E7 and E6 oncoproteins.

HPV transforming activity is further sustained by the viral E5 oncogene. This is a small, comparatively under-explored, viral protein of approximately 83 amino acids. It has minor transforming activity per se, however it is able to potentiate the activity of the major oncogenes E6 and E7 through a number of mechanisms mainly acting during the early steps of viral infection/transformation. These mechanisms include the activation of the EGF-R mediate signal transduction and the downstream Ras-Raf-MAP kinase pathway or PI3K-Akt pathway, resulting in enhanced response to cell proliferative stimuli, increased activation of pro-angiogenic pathways and suppression of apoptosis induction in response to oxidative stress.[13]

These three fundamental actions of the E5, E6 and E7 viral genes depict a cellular landscape conducive to genetic damage accumulation and cancer development and are those generally used to summarize the oncogenic potentials of HR-HPVs. However it has to be remarked that they represent just a minor part of it. Indeed HPV proteins are highly sophisticated multifunctional devices. They are able to interact with, and thus contribute to cell transformation through, a huge number of cellular functions and factors, a multiple. A detailed description of the wide range of actions of HPV oncogenes has been extensively described in recent publications.[12–17]

To better understand the sharp oncogenic power of the HR-HPVs infection under natural conditions, it is useful to compare it with those associated with risk factors for cancers at other anatomical sites. The increased risk of breast cancer for women receiving post-menopausal hormone replacement therapy (HRT) was only 1.3 in the Women's Health Initiative study (2002). The relative risk of lung cancer in an adult white male smoker (with a 8 year lasting habit to smoke 20 cigarettes per day) compared to a non-smoker is only 8.3 while women who were HPV16 positive had an odds ratio (OR) of having invasive cervical cancer of 434 compared to women who were HPV16 negative.[9,18]

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