The role of HPV-induced epigenetic changes in cervical carcinogenesis (Review)

Abstract

Cervical cancer is associated with infection by certain types of human papillomaviruses (HPVs), and this affects women worldwide. Despite the improvements in prevention and cure of HPV-induced cervical cancer, it remains the second most common type of cancer in women in the least developed regions of the world. Epigenetic modifications are stable long-term changes that occur in the DNA, and are part of a natural evolutionary process of necessary adaptations to the environment. They do not result in changes in the DNA sequence, but do affect gene expression and genomic stability. Epigenetic changes are important in several biological processes. The effects of the environment on gene expression can contribute to the development of numerous diseases. Epigenetic modifications may serve a critical role in cancer cells, by silencing tumor suppressor genes, activating oncogenes, and exacerbating defects in DNA repair mechanisms. Although cervical cancer is directly related to a persistent high-risk HPV infection, several epigenetic changes have been identified in both the viral DNA and the genome of the infected cells: DNA methylation, histone modification and gene silencing by non-coding RNAs, which initiate and sustain epigenetic changes. In the present review, recent advances in the role of epigenetic changes in cervical cancer are summarized.

Keywords: DNA methylation; HPV-induced carcinogenesis; cervical cancer; epigenetic changes; non-coding RNA.

Figure 1

The role of epigenetic changes in the development of UCC. The process begins with infection of the epithelium that lines the cervix with high-risk HPVs. During productive HPV infection, methylation of the L1 and L2 late viral genes may occur, increasing the risk of viral persistence. Viral persistence favors the methylation of both viral and cellular DNA, also increasing the risk of malignant transformation of the infected cell. Hypermethylation of the LCR of the viral genome blocks the binding site of the viral E2 protein to this region, preventing its regulatory function on the expression of the viral oncogenes E6 and E7, whose products are directly associated with carcinogenesis. Another crucial event in this process is the integration of the viral DNA into the cell genome, which results in the rupture of the viral E2 gene, interrupting the production of the E2 protein and abolishing its regulatory function on the expression of the viral genes E6 and E7, leading to overproduction of viral oncoproteins. E6 protein can act directly by activating the expression of oncogenes or inducing the degradation of the tumor suppressor protein p53, resulting in progression of the cell cycle, preventing DNA repair, increasing cell proliferation, and inhibiting apoptosis. In addition, E6 activates telomerase, prevents cell senescence and activates DNA methyltransferase, which favors the methylation of cellular and viral genes, and promotes the silencing of tumor suppressor genes. Conversely, E7 can act directly by inhibiting the host's immune response, interfering with the presentation of antigens, interferon signaling pathways and maturation of T lymphocytes, as well as increasing the tolerance to these T-cells. In addition, E7 induces degradation or inhibition of the function of the cell's tumor suppressor pRB protein, which results in cell cycle progression, inhibition of DNA repair mechanisms and uncontrolled cell proliferation. Thus, the joint action of viral proteins E6 and E7 leads to the immortalization of cells infected by HPV, followed by the malignant transformation of these cells. UCC, uterine cervix cancer; HPV, human papillomavirus; LCR, long control region; DNMT1, DNA methyltransferase 1.

Figure 2

Role of HPV oncoproteins in regulation of miRNAs. Viral oncoproteins E6 and E7 may also serve a role in cervical carcinogenesis by regulating the expression of miRNAs that function as tumor suppressors, by inhibiting the functions of tumor suppressor cell proteins, such as p53 and pRB. By abolishing the functions of the cellular proteins p53 and pRB, viral proteins E6 and E7 prevent these two cellular proteins from activating the expression of protective miRNAs against UCC, thus preventing inhibition of the transcription of cellular oncogenes associated with tumor initiation and progression. In addition, E6 and E7, acting either alone or together, can also directly activate the expression of tumor-inducing miRNAs which increases expression of oncogenes or inhibits the expression of tumor suppressor genes. This results in increased proliferation, immortalization, progression and invasion of tumor cells. UCC, uterine cervix cancer; HPV, human papillomavirus; miRNA/miR, microRNA.

Figure 3

Role of miRNAs in induction of cervical carcinogenesis. Certain miRNAs possess tumor-promoting functions in UCC by increasing the expression of both HPV and host cell oncogenes, or inhibiting the expression of tumor suppressor genes. In cells derived from UCC, expression of these miRNAs is upregulated, together with the viral and cellular oncogenes controlled by these transcripts, whereas the target tumor suppressor genes of these miRNAs is downregulated in these cells. This positive regulation of viral or cellular oncogenes, and the inhibition of the expression of tumor suppressor genes, results in increased proliferation, immortalization, progression and invasion of tumor cells. UCC, uterine cervix cancer; HPV, human papillomavirus; miRNA/miR, microRNA.

Figure 4

Protective roles of miRNAs against cervical carcinogenesis. Tumor suppressor miRNAs, under physiological conditions, exhibit protective functions against the development to UCC, acting as activators of the expression of tumor suppressor genes, whose products act by suppressing the expression of oncogenes. However, in UCC-derived cells, the expression tumor suppressing miRNAs is downregulated, via different mechanisms, and this effectively abrogates their suppressive functions on the expression of oncogenes involved in proliferation, immortalization and progression of UCC. UCC, uterine cervix cancer; miRNA/miR, microRNA.

Figure 5

Role of lncRNAs and circRNAs in cervical carcinogenesis. Certain lncRNAs functions as tumor promoters in UCC, serving as a sponge of tumor suppressing miRNAs, abrogating their functions as inhibitors of the expression oncogenes of both HPV and host cells. They may also act by directly inhibiting the function of the p53 protein. Others lncRNAs act by increasing the expression of cell oncogenes. CircRNAs function as tumor promoters through different mechanisms. The circRNA CIRCe7 encodes a functional E protein of HPV, which possesses carcinogenic activity. Other circRNAs activate the expression of cellular oncogenes. Still other circRNAs function as tumor promoters, serving as a sponge of tumor suppressor miRNAs, abrogating their functions. This increases cell proliferation leading to immortalization, progression to UCC and invasion of tumor cells. lncRNA, long non-coding RNA; circRNA, circular non-coding; UCC, uterine cervix cancer.