2.2 Viral Oncogene

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Viruses and Oncogenes


Viruses and the oncogenes they carry have been central to the early development of the oncogene field and remain an active area of research today. While the majority of oncoviruses, viruses that can cause cancer, do not affect humans, it is estimated that at least 15-20% of all human cancer cases are linked to viral infection (1). Carcinogenic viruses are categorized based on the type of nucleic acid the virus genome is made from. This include the RNA tumor viruses (including retroviruses) and DNA tumor viruses (2).


Figure 2.2.1. Characteristics and clinical correlates of viruses involved in cancer. Released under the Creative Commons Attribution-ShareAlike 4.0 International license (CC BY-SA 4.0).


(1) Carcinogenic retroviruses


During the retrovirus lifecycle, the RNA genome is reverse transcribed into a DNA intermediate, the provirus, which then integrates into the host genome (2). This integration is random, meaning the location where the provirus enters the genome is usually not predetermined (2). This can effectively result in an insertional mutation whereby the genes adjacent to the provirus can be modified. For example, the provirus may have strong promoter and enhancer regions which upregulate the expression of these nearby genes beyond normal levels. This can result in cancer if the affected gene is implicated in growth regulation or control of the cell cycle. This scenario is much more common in animal cancers and has not yet been demonstrated by human cancer viruses (2). Some retroviruses can also accidentally capture the nearby proto-oncogene and become acutely-transforming viruses carrying cellular-derived oncogenes (2).


Human T-Lymphotropic Virus-I (HTLV-I)


HTVL was the first human retrovirus identified after isolation from an individual suffering from cutaneous T-cell lymphoma.  This viral infection has been found to be rampant in some geographical locations, causing adult T-cell leukaemia/lymphoma (ATLL) (11).  The transformation of T-cells seems to require long-term infection by HTLV-I, potentially childhood infection, but at ATLL onset all malignant cells carry the viral DNA (11).  This can be associated to a clonal development of the disease, as all malignant cells have integration of viral DNA at the same site in the host genome (11).  One key protein encoded by the virus is Tax, the transcriptional activator of region x in the viral genome.  Tax seems to interact with multiple pathways associated with cellular transformation and malignant growth including: inhibition of transcription factor NF(kappa)-B, where an aberrant NF(kappa)-B has been associated with tumor growth in Mdr2 knockout mouse (10); progression of the cell cycle through upregulation of cyclin 2D; and destabilizing the host genome through downregulation of polymerase-(beta), a protein responsible for effective base-excision repair (11). Together, these viral proteins and site of insertion seems to be causing the uncontrolled cellular growth associated with ATLL.


(2) Carcinogenic DNA and RNA viruses


DNA and RNA viruses can cause cancer by directly encoding for oncoproteins which stimulate resting cells to enter the S phase (2). This is advantageous for the viruses as it can then utilize host cell DNA synthesis machinery to replicate its own genome, which is only available during cell growth. These viruses may also express proteins which promote proto-oncogene expression or suppress tumor suppressor gene expression (2). In either case, carcinogenic viruses hijack cellular pathways involved in growth and survival to promote their own replication. Cancer is not the “goal” of a virus per se, but rather a side consequence of dysregulated growth invoked by the virus to continue its lifecycle within the host. Several examples of human carcinogenic viruses are considered below:


Human Papilloma Virus (HPV)


The relationship between Human Papilloma Virus (HPV) and cervical cancer has been well established.  HPV is a DNA virus that infects immature keratinocytes in the basal layer of the epithelium. Its viral replicative cycle closely follows the differentiation of these epithelial cells, until the keratinocytes mature fully and the viral particles are shed along with the dead keratinocytes (5).  The HPV genome contains two viral oncogenes, E6 and E7, which act to dysregulate the cell cycle and promote cellular proliferation. E6 binds to the tumor suppressor gene p53 and targets it for degradation, while E7 binds and inactivates another tumor suppressor gene Rb.  The inactivation of these two critical tumor suppressors within the cell causes dysregulation of the G1/S cellular checkpoint, and leads to uncontrolled cell proliferation (5,6). In 15 % of HPV cases, the infection cannot be cleared properly, resulting in a chronic infection (5). In these persistent infections, there is an increased chance of viral DNA being incorporated into the host genome.  Incorporation of the viral oncogenes E6 and E7 into the host genome, and their subsequent constitutive expression, is one of the events required for malignant transformation of these infected cells into cancerous cells (6).


Kaposi's Sarcoma-associated Herpes Virus


Kaposi's Sarcoma-associated Herpes Virus (KSHV) is a tumor causing DNA virus originally determined to be exogenous from the human host genome based on differential cellular expression of KS330Bam and KS631Bam between KS-lesions and other wild type control tissues, and furthermore, through sequence homology to gammaherpesviral protein genes (7). The gammaherpesvirus subfamily is notable for causing tumor formation with particular emphasis on lymphoproliferative disorders (8), where KSHV is the primary and necessary factor in the progression of Kaposi sarcomoa cutaneous lesions. The KSHV genome contains several oncogenes homologous to human counterparts, such as a retinoblastoma inhibiting cyclin, and an apoptosis-preventing Bcl-2 like protein (8).  In addition to encoding a Bcl-2 like apoptotic inhibitor, KSHV also encodes three structural proteins that inhibit the p53-pathway; all of which are expressed in either the latent or early lytic viral phases (9).  However, these inhibitors are not particularly potent at blocking p53 activated apoptosis as KSHV(+) latent cells receiving p53-activating agents were selectively killed with comparison to uninfected or Epstein-Barr (another gammaherpesvirus subfamily virus) cells (9).  Despite the therapeutic use of p53-stabilizing molecules that cause regression of Kaposi sarcomas, patients are unable to fully complete remission as viral cells that enter the lytic phase could cause relapse (9).




Both hepatitis B virus (HBV), a hepadna virus (containing DNA) , and hepatitis C virus (HCV), a flavivrus (containing RNA), have been identified as two of the leading cause of hepatocellular carcinoma (HCC) worldwide, being the number one and number two causes of HCC, respectively (10).  As HCC is the third leading cause of cancer-related deaths, and many cases are linked to chronic infection by HBV or HCV, this is a very prevalent form of cancer, especially in geographical areas plagued by these viruses (10). Viral suppression of HBV and treatment for HCV have been shown to decrease the development of HCC in at-risk populations (10), highlighting the importance of expanding treatment of these viruses in the attempt to reduce HCC incidence. 


At risk populations for chronic hepatitis B infections include children and newborns. On the other hand, infections in 95% of adults tend to resolve spontaneously as the disease acts in an acute manner with T-cell recognition and clearance of the viral load. The viral load of chronic hepatitis causes an increase in the inflammatory cascade, which has been associated with liver cancer in Mdr2 mouse knockout, potentially linking the aberrant inflammation of hepatitis infection with cancer development (10).  This is supported by the observation that HBV infected individuals show a 100 fold elevated risk of developing HCC as compared to non-infected individuals (10).  Based on studies done with woodchuck hepatitis virus (WHV), which causes an HBV-like disease in woodchucks, the increased rate of cancer development could be associated with the location of viral DNA insertion into the host genome, such as in the common insertion of the WHV genome in close proximity to the N-Myc proto-oncogene.  Whole genome sequencing of 81 HBV-positive HCC samples showed that 80% of samples had viral insertion into the host genome, with frequent integration close to: telomerase reverse transcriptase (TERT), MLL4, and CCNE1; where these genes undergo upregulation in copy number variation after viral insertion, potentially indicating another mechanistic link between HBV and carcinogenesis (10).  Furthermore, the expression of HBx by the hepatitis viruses has been linked to suppression of p53, through cytoplasmic relocalization in an oncogenic fashion, resulting in the transformation of liver cells (10).  This might also lead to the accumulation of DNA damage and could be a cause of the heterogeneous mutations in HCC.  Although the path to transformation and cancerous growth to hepatocellular carcinoma after chronic infection with hepatitis B has been noted, the direct mechanism by which this happens is yet to be elucidated.


Hepatitis C virus infection, unlike HBV infection, becomes chronic in 50-80% of infected individuals, generally remaining subclinical for upwards of 30 years (10). It was initially believed that the link between chronic HCV and HCC was largely due to the chronic inflammation of the liver that leads to fibrosis and, eventually, cirrhosis, but more recent studies have shown that HCV may participate more directly in the development of HCC, with many HCV proteins having been found to interact with important cell growth regulation pathways (10). For example, the HCV viral protein, NS5A, has been demonstrated to act synergistically with oncogenic Ras in tumour initiation and to promote epithelial to mesnchymal transition, a process that has been implicated in tumour initiation, progression, and metastasis (14). Furthermore, NS5A, along with HCV core protein, acts to stabilise β-catenin, part of the Wnt/β-catenin signaling pathway that regulates many genes involved in cell growth, including c-Myc, cyclin D1, and WISP2, potentially leading to the overexpression of these proto-oncogenes (10, 15). Other HCV proteins potentially involved in HCC development include NS3-4A and NS5B (10). Yet another link from chronic HCV infection to HCC development may be the sequestration by virus proteins of miR-122, an important liver-specific microRNA, which is important for stabilisation of the HCV genome. Loss of miR-122 leads to increased HCC rates in mouse models, implying that HCV's reduction in the levels of functional miR-122 may play a role in HCC development (10). Thus, HCV's tumourigenic potential is due to both the inflammation resulting from viral replication as well as the viral proteins themselves, though the degree of importance of the two in HCC development is a subject of contention.


Merkel Cell Polyomavirus


Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor linked to an infection of Merkel Cell Polyomavirus (MCV), where MCV dependent and independent cellular events are influencing the mechanism of cancer development (12).  The MCV independent events are required for the transformation of normal cells as the presence of the virus is not sufficient to case MCC (12). MCV encodes a large T tumor antigen, as well as a small antigen tumor proteins that act to target several tumor suppressor genes (12). These appear to act in conjunction with other aberrant pathways in neuroendocrine cells as upwards of 80% of MCC patients show MCV infection (12).


Oncogenic Viruses - Prevention and Therapeutics


Vaccinations against some of these viruses are available as a prophylactic measure, both against infection and to protect against cancer. The HBV vaccine has been available for decades and the HPV vaccine has recently been developed specifically with cancer prevention in mind (1). Research is currently underway to develop vaccines for EBV, HCV, and KSHV (1).


Beyond advancing our understanding of oncogenes and the ways in which they cause cancer, carcinogenic viruses have proven to be useful molecular tools in cancer research and provide promising avenues for developing anti-cancer therapies. For example, Friedmann-Morvinski et al. have recently developed a method using lentiviruses as an oncogenic vector to create gliomas in mice (4).  This murine model can then be used to investigate potential treatments for brain cancers (4). Viruses can also be used as vectors for cancer treatment, especially in the delivery of gene therapies. Viral vectors can deliver genes which confer chemotherapeutic drug resistance to normal cells or replace dysregulated genes such as p53 to combat cancer (2). However, these potential treatments currently have several caveats, including their specificity and potential side effects (2). Ongoing research to improve these deficiencies will hopefully result in viral vectors becoming a viable and effective anti-cancer treatment.



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3) Moore, P. S., & Chang, Y. (2010). Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nature Reviews Cancer, 10(12), 878-889.

4) Friedmann-Morvinski, D., E.A. Bushong, E. Ke, Y. Soda, T. Marumoto, O. Singer, M.H. Ellisman, and I.M. Verma.  2012. Dedifferentiation of Neurons and Astrocytes by Oncogenes Can Induce Gliomas in Mice.  Science.  338:1080-1084.

5) Stanley, M.A., Pett, M.R., Coleman, N. (2007). HPV: from infection to cancer.  Biochemical Society Transactions. 35 (6): 1456-1460.

6) Boccardo, E. (2010). HPV-mediated genome instability: At the roots of cervical carcinogenesis. Cytogenetic and Genome Research. 128:57-65.

7) Moore, P. et al (1996). Primary characterization of a herpesvirus agent associated with Kaposi's sarcomae. Journal of Virology. 70(1): 549-558.

8) Antman K, Chang Y. 2000. Kaposi's sarcoma. N Engl J Med. Apr 6;342(14):1027-38.

9) Chudasama, P. et al (2014). Structural proteins of Kaposi's sarcoma-associated herpesvirus antagonize p53-mediated apoptosis. Oncogene. 1-11.

10) Shlomai, A. Jong, YP. and Rice, C (2014). Virus associated malignancies: The role of viral hepatitis in hepatocellular carcinoma.  Elsevier. 1-11.

11) Taylor, G (2007). Molecular aspects of HTLV-I infection and adult leukaemia/lymphoma. Journal of Clinical Pathology. 60: 1392-1396.

12) Hughes, M. et al (2014). Merkel Cell Carcinoma: Epidemiology, Target, and Therapy. Current Derm Rep. 3: 46-53.

13) Debbie Barragan. (2010). Is cervical cancer hereditary? Ask a Geneticist. Retrieved from http://genetics.thetech.org/ask/ask359

14) Akkari, L., Grégoire, D., Floc'h, N., Moreau, M., Hernandez, C., Simonin, Y., Rosenberg, AR., Lassus, P., and Hibner, U.(2012). Hepatitis C viral protein NS5A induces EMT and participates in oncogenic transformation of primary hepatocyte precursors. Journal of Hepatology, 57(5): 1021-1028.

15) Liu, J., Ding, X., Tang, J., Cao, Y., Hu, P., Zhou, F., Shan, X., Cai, X., Chen, Q., Ling, N., Zhang, B., Bi, Y., Chen, K., Ren, H., Huang, A., He, T., and Tang, N. (2011). Enhancement of canonical Wnt/β-catenin signaling activity by HCV core protein promotes cell growth of hepatocellular carcinoma cells. PLoS One. 6(11): e27496