Key Molecular Events in Cervical Cancer Development

Abstract

Cervical cancer is the fourth most common cancer among women. Infection by high-risk human papillomavirus (HPV) is the main aetiology for the development of cervical cancer. Infection by high-risk human papillomavirus (HPV) and the integration of the HPV genome into the host chromosome of cervical epithelial cells are key early events in the neoplastic progression of cervical lesions. The viral oncoproteins, mainly E6 and E7, are responsible for the initial changes in epithelial cells. The viral proteins inactivate two main tumour suppressor proteins, p53, and retinoblastoma (pRb). Inactivation of these host proteins disrupts both the DNA repair mechanisms and apoptosis, leading to rapid cell proliferation. Multiple genes involved in DNA repair, cell proliferation, growth factor activity, angiogenesis, as well as mitogenesis genes become highly expressed in cervical intraepithelial neoplasia (CIN) and cancer. This genomic instability encourages HPV-infected cells to progress towards invasive carcinoma. The key molecular events involved in cervical carcinogenesis will be discussed in this review.

Keywords: carcinogenesis; cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; tumour suppressor gene; viral oncoprotein.

Figure 1

Distribution of normal and human papillomavirus (HPV)-infected squamous epithelial cells in normal, precancerous lesions (mild, moderate and severe dysplasia; CIN 1, CIN 2, and CIN 3, respectively) and cancer of the cervix. The initial stage of carcinogenesis is controlled by viral HPV integration and host factors. HPV enters the basal epithelial cells through a micro-wound. Subsequently, the virus integrates its genome into the host genome in the nucleus through nuclear envelope breaks. Once it enters the nucleus, HPV takes over control of the host genome, self-replicates, and spreads throughout the epithelium. Further replication of the viral genome causes the host cells to grow irregularly and in a disorganized manner compared to normal cells. Subsequently, the virions are sloughed off with the dead squamous cells of the host epithelium, facilitating further transmission.

Figure 2

Mechanisms involved upon HPV infection. Upon HPV infection, the host immune system triggers the toll-like receptors (TLR) to activate the nuclear factor-kappa B (NF-κB) and interferon regulatory factor 3 (IRF3) to activate pro-inflammatory factors and antiviral cytokines. The TLR also activate the major histocompatibility complex (MHC) class I and II. However, the HPV can express its viral oncoprotein E5 to inhibit the MHC class I mechanisms. The oncoprotein E6 has the ability to inhibit the production of IRF3. The oncoprotein E6 also binds to Yes-associated protein (YAP1), preventing degradation of YAP1, and inhibiting the TLR.

Figure 3

Mechanisms involving MHC class II upon HPV infection. When HPV enters the epithelium, the host immune system identifies the HPV antigen and phagocytosis is initiated. The phagolysosome sends the antigen to bind on MHC class II molecule. The antigen presenting cell (APC) will then activate CD4+ and T cells to exert cytotoxic effect. Activation of APC will activate pro-inflammatory and antiviral cytokines such as interferon gamma (IFN-γ), tumour necrosis factor alpha (TNF-α), and interleukin 2 (IL-2). The interleukins are also stimulated. Activation of antigen presenting cells (APC) also triggers the production of regulatory T cells (Tregs). Tregs will activate interleukin 10 (IL-10) and transforming growth factor beta (TGF-β), which will inhibit the function of APC.

Figure 4

Schematic diagram illustrating the role of HPV oncoproteins in cervical carcinogenesis. Upon infection, the viral oncoprotein E6 binds to p53, a tumour suppressor protein and disables its normal function. The host cell’s ability to undergo DNA repair, apoptosis, or growth arrest and angiogenesis is disrupted. Activation of p53 will activate cyclin-dependent kinase inhibitor (p21) to force cells to remain at G₁ arrest. However, upon HPV infection, the E6 degrades p53 which causes cells to enter S phase of cell cycle. Simultaneously, the E7 oncoprotein binds to retinoblastoma (pRb). The binding of E7 to pRb causes it to release E2F, a transcription factor that activates the cyclin dependent kinase (CDKs). This causes the cell cycle to lose control, allowing the cells to re-enter into S phase of the cell cycle. When infected cells differentiate and proliferate at a high level, the development of abnormal dysplastic cells will be promoted.