Archives of Virology

, Volume 158, Issue 7, pp 1433–1443 | Cite as

An update on viral association of human cancers

Brief Review


Up to now, seven viruses that infect humans have been identified as oncogenic and are closely associated with different human cancers. Most of them encode oncogenes whose products play important roles in the development of cancers in the context of environmental and genetic factors; others may act via indirect mechanisms. The transforming activities of the human oncogenic viruses have much in common with the well-studied tumorigenic processes elicited by the acutely transforming murine retroviruses. Many of these mechanisms have been elucidated for or are represented in the successive steps leading to the efficient in vitro immortalization by the lymphotropic herpesvirus Epstein-Barr virus, although the establishment of malignancy in vivo takes longer. The development of cancer is a complicated process involving multiple factors, from the host and the environment. Although any one of these etiologic factors may exert an effect on the carcinogenic process, vaccination against the viral pathogen in several cases has shown efficacy in preventing the spread of the virus and, in turn, the development of the associated cancers. Modern laboratory techniques can be expected to facilitate the identification of new emerging viruses whose association with malignancies is suggested by epidemiologic and clinical data.


To date, seven human viruses have been identified as tumorigenic and are closely associated with the occurrence of human cancers. Nearly 20 % of cancer cases arising worldwide can be linked to infectious agents, including viruses. These viruses include two lymphotropic herpesviruses, Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV8). EBV is the etiologic agent of post-transplant lymphoproliferative disorder (PTLD), Burkitt lymphoma (BL), and nasopharyngeal carcinoma (NPC) and is considered a cofactor in a subset of gastric carcinomas. KSHV/HHV8 is the causative agent of Kaposi sarcoma (KS), alone or in combination with HIV infection [1, 2]; pleural effusion lymphomas (PELs), formerly called body-cavity-based lymphomas (BCL) [3]; and multicentric Castleman’s disease. Two hepatitis viruses, hepatitis B virus and hepatitis C virus (HBV and HCV), are associated with hepatocellular carcinoma (HCC). Both high- and low-risk human papillomaviruses (HPVs) are the agents responsible for cervical cancer. Human T cell lymphoma virus (HTLV) is the pathogen of the T cell lymphoma endemic in southwestern Japan and other regions in the world. A new polyomavirus, Merkel cell polyomavirus (MCV), was added to the list after its identification in 2008 [4]. MCV is the pathogen of a rare but aggressive human skin cancer, Merkel cell carcinoma (MCC) normally affects elderly and immunosuppressed individuals, a feature suggestive of an infectious origin.

Studies in the field of infection-associated cancer may greatly facilitate the design of prevention strategies, particularly where vaccination proves effective in suppressing the occurrence of such cancers. In 2008, the Nobel Prize in Medicine or Physiology was awarded to Harald zur Hausen for his pioneering work on the role of HPV in the genesis of cervical cancer. The discovery that HPV is the major cause of cervical carcinoma has allowed global vaccination efforts to prevent this particular cancer, and follow-up studies have shown a greatly reduced incidence of this gynecologic neoplasia since the introduction of the anti-HPV vaccine. This followed the earlier introduction of HBV vaccines in areas with high endemic primary liver cancer, which successfully has reduced this cancer.

The co-discoverers of two human tumorigenic viruses (KSHV and MCV), Yuan Chang and Patrick Moore from University of Pittsburgh, were elected members of The National Academy of Science of the United States of America for their discovery of the viral etiology of two human cancers, KS and MCC, as well as for their development of techniques for the identification of tumorigenic viruses. The current expansion of our knowledge concerning viral tumorigenic agents owes greatly to their investigations.

Currently available laboratory data suggest that more viruses could play a role in the causation of human cancers. Additions to the list of tumorigenic viruses are to be expected as solid confirmation of current hypotheses materializes. The present paper aims at reviewing the latest advances in the field of oncogenic viruses, with some emphasis on the newly discovered MCV and the two established oncogenic herpesviruses, KSHV and EBV.

An overview of viral carcinogenesis

The seminal discovery by Peyton Rous in 1911, that a filterable agent isolated from chicken sarcoma tissue caused the same disease in the same experimental animal [5], laid the foundation of modern tumor virology. It took quite a long time for the scientific community to accept the model of carcinogenesis mediated by retroviruses. Rous was finally awarded the Nobel Prize for his discovery in 1966. These retroviruses behave as acute transforming agents in different animal models, and following the cloning of the v-src gene from Rous sarcoma virus in chickens, a group of genes, known as viral oncogenes, that are responsible for retroviral tumorigenesis were eventually identified. This, together with the discovery of the eukaryotic homologs of these genes (cellular proto-oncogenes) and transforming mutants of the latter, elucidates how malignancy arises by cellular gene mutations. The subsequent study of tumor transformation by DNA viruses added a new dimension by demonstrating the existence of a new group of cellular genes, tumor suppressor genes (TSGs), whose loss of function, either by interference of viral genes from DNA tumor viruses or by inactivating mutations, could predispose cells to a malignant development.

It is known that each of the known human tumorigenic viruses encodes at least one oncogene: for example, the Tax gene of HTLV, the X antigen of HBV (HBx), and the latent membrane protein (LMP1) of EBV [6]. An exception is HCV. The proteins encoded by these viral genes play essential roles in the biogenesis of the respective virus-associated malignancies (Table 1).
Table 1

Characteristics of seven human tumorigenic viruses

Name of virus

Associated cancers

Host cell origin


Anogenital cancers, including cervical cancer, and skin cancer

Mucosa epithelium


Hepatocellular carcinoma



Same as above

Same as above


Kaposi sarcoma; pleural effusion lymphoma

B and endothelial cells


Human T cell lymphoma

T cell


Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin’ s disease

B cell, epithelial cell and T cell


Merkel cell carcinoma

Endocrine epithelial cells

MCV, a new emerging human tumorigenic virus

Since 1971, five polyomaviruses have been found that can infect humans. Human polyomaviruses JC and BK (JCPyV and BKPyV) are two members of the family that persistently infect humans and cause disease in immunocompromised individuals. They are ubiquitous worldwide, and in adult populations the seroprevalence rate of JC and BK virus approaches 75 % and 100 %, respectively [7]. Murine polyomaviruses are one of the standard experimental models for viral carcinogenesis. The fact that they encode proteins (the T-antigens) with potential transforming activity has long suggested that viruses belonging to the family Polyomaviridae might contribute to the development of malignancy, also when infecting human hosts [8, 9].

In 2007 and 2008, three new polyomaviruses, KI, WU and Merkel cell polyomavirus (KIPyV, WUPyV and MCV), were reported in humans [4, 10, 11].

A previously unknown polyomavirus (KI) was identified from viral screening of respiratory tract samples for unrecognized pathogens [10]. The virus is phylogenetically related to other primate polyomaviruses in the early region of the genome but has very little homology (<30 % amino acid identity) to known polyomaviruses in the late region. This finding further illustrates how unbiased screening of respiratory tract and other clinical samples can be used for the discovery of diverse virus types [10]. WUPyV is a novel polyomavirus present in respiratory secretions from human patients with symptoms of acute respiratory tract infection [11]. Phylogenetic analysis clearly revealed that the WU virus was divergent from all known polyomaviruses. The presence of multiple strains of the virus in Oceania and North America suggests that this virus is geographically widespread in the human population and raises the possibility that the WU virus may be a human pathogen.

MCV was initially detected in Merkel cell carcinoma (MCC) by digital transcriptome subtraction. MCV was found in 92 % of MCC specimens [13]. Identification of a fusion transcript between a previously undescribed viral T antigen and a human receptor, tyrosine phosphatase, led to its discovery [4].

Merkel cell carcinoma (MCC) is a skin tumour with neuroendocrine features. In MCC, MCV is integrated in the gene for the receptor tyrosine phosphatase type G (PTPRG). Viral infections are often associated with epigenetic silencing of tumor suppressor genes (TSG). In MCC tumors, frequent promoter hypermethylation of RASSF1A, PTPRG, and CDKN2A was detected, while that on promoter of TP73, PTPRG, and FHIT was infrequent [12].

The MCV large T (LT) gene sequences obtained from tumor-derived viruses have truncating mutations that are not present in wild-type virus. These mutations eliminate a helicase domain present at the C-terminus of the LT protein but preserve the N-terminal interaction site with the retinoblastoma tumor suppressor protein (Rb) [4]. Loss of viral helicase activity prevents MCV from actively replicating its own genome, and thus the virus cannot be a passenger virus in tumors.

Clonal integration of MCV into the host genome was seen in all MCC cases and was detected by fluorescent in situ hybridization (FISH) in one case. A recurrent pattern was observed in which viral sequences encompassing the replication origin, the small tumor (ST), and the 5’ part of the large tumor (LT) antigen DNA sequences were conserved. Both ST and LT viral sequences were found to be significantly expressed in all MCCs. Neither a recurrent site of integration nor alterations of cellular genes located near the viral sequences was observed. The tight association of MCV with MCC, the clonal pattern of MCV integration, and the expression of the viral oncoproteins strongly support a causative role for MCV in the tumorigenic process. This information will help the development of novel approaches for the assessment and therapy of MCC and biologically related tumors [4].

HPV, an etiologic agent of anogenital cancer, is a target for vaccination in the population

Multiple types of HPV have been described, and evidence has suggested that more remain to be identified [14]. High-risk types of HPV are associated with non-melanoma skin cancer and cancers arising from the mucosal epithelium of the genitourinary and lower intestinal tracts. The etiologic role of HPV in the occurrence of cervical cancer has prompted a global program of preventive vaccination. Where implemented, HPV vaccination has effectively reduced the incidence of the associated cancers [15]. The efficacy has been similar with the vaccination program against HBV, which was initiated in different countries more than 20 years, where numbers of acute cases of hepatitis B and of carriers of HBsAg were decreased and the incidence of cirrhosis and HCC was lowered [16].

Recent efforts have attempted to establish an association between certain histologic types of NPC with HPV infection. It has been reported that oncogenic HPV has been detected in well-differentiated NPC, e.g. WHO I type or even EBV-associated NPC in certain parts of the world, but not in EBV-associated, undifferentiated WHO III cases in the endemic region [17, 18, 19].

The ability of high-risk HPVs to transform epithelial cells in which they establish infection is attributed to the ability of oncoproteins E6 and E7 to associate with and inactivate host tumor suppressors. P53 is among many binding partners of E6, one of the early antigens coded by HPV. E6 binding to p53 also leads to the downregulation of p21 and hMDM2, both of which are normally transcriptionally activated by p53 and which are the effectors of the tumor suppressive function of p53 [20]. But E6, which is associated with hMDM2 binding to p53, is degraded by hMDM2, forming a complicated feedback loop.

The interactions with cellular tumor suppressor genes of the oncogenic HPV proteins have been intensively studied in recent years. Structurally, another HPV oncoprotein, E7, is composed of three functional domains. Conserved region 1 (CR1) and CR2 share homology with the corresponding domains of adenovirus proteins [21]. A third domain, CR3, contains the binding motif of the human tumor suppressor retinoblastoma susceptibility protein (pRb) [22]. While pRB is normally phosphorylated at the late stage of the G1 phase of the cell cycle to release transcription factor E2F, which enables entry into the S phase, its interaction with E7 prevents binding of E2F to pRb and thus promotes the unscheduled progression of the host cells to the S phase [23]. This effect promotes cell proliferation and leads to malignancy.

Role of HBx, an oncogenic protein encoded by hepatitis B virus, in the genesis of HCC

Hepatocellular carcinoma (HCC) remains a major health problem worldwide due to its high incidence and its importance as a cause of cancer-related deaths. In men, liver cancer is the fifth most frequently diagnosed cancer and the second most frequent cause of cancer death; in women, its frequency of diagnosis ranks seventh, and as a cause of death it ranks sixth among cancers. In 2008, half of the new liver cancer cases and deaths were estimated to occur in China [24]. HCC represents the major histological subtype, accounting for 70 % to 85 % of the total liver cancer burden worldwide [25].

HBx, encoded by HBV, acts as a major oncogene. It is a multifunctional protein that activates many viral and cellular genes, modulates cellular signal transduction pathways, and regulates cell proliferation, apoptosis and invasion [26]. HBx stimulates cell proliferation and upregulates vascular endothelial growth factor (VEGF) production. These HBx-upregulated phenotypes are abolished when IKKβ or mTOR are blocked. The association of HBx-modulated IKKβ/mTOR/S6K1 signaling with liver tumorigenesis was verified in an HBx transgenic mouse model in which pIKKβ, pS6K1, and VEGF expression was found to be higher in cancerous than in non-cancerous liver tissues [27].

HBx does not bind DNA directly but regulates gene expression by transactivating multiple transcription factors, including AP-1, NF-kB, HIF-1, and CREB [28]. These interactions provide molecular mechanisms by which HBx facilitates the development of HBV-associated HCC. HBx has been strongly implicated in tumor invasion and metastasis during hepatocarcinogenesis.

The transactivating activity of HBx is mediated through binding to different cellular factors. A HBx-associated cellular protein, XAP2, was identified recently. The interaction between HBx and XAP2 requires a small region on HBx containing amino acids 13-26. Its overexpression abolishes transactivation by the HBx protein. Data have suggested that XAP2 is an important cellular negative regulator of the HBx protein and may play a role in HBV pathology [29]. Using a yeast two-hybrid assay, Kashuba and collaborators have shown that XAP2 is also associated with the transforming protein EBNA3 encoded by EBV [30].

Targets of HBx-protein-mediated regulation of transcription include the methyltransferases DNMT1 and DNMT3, which catalyze the addition of a methyl group at CpG dinucleotide positions in DNA. This catalytic activity contributes to regional hypermethylation of DNA, which results in silencing of tumor suppressor genes, for example, E-cadherin [31], or global hypomethylation, resulting in chromosomal instability. These activities play a role in hepatocarcinogenesis. The HBx protein increases the expression of TERT and telomerase activity, prolonging the lifespan of hepatocytes and contributing to malignant transformation [32, 33]. Carboxyl-terminally truncated HBx protein loses its inhibitory effects on cell proliferation and pro-apoptotic properties, and it may enhance the protein’s transforming potential [34]. Truncated HBx with a deletion of the C-terminus was found in nearly half of the HCC tumors that were tested, but not in normal liver tissues.

The truncation is thought to be generated by random integration of the hepatitis B virus (HBV) DNA into the host genome during development of HCC. The presence of naturally COOH-truncated HBx in tumors significantly correlates with the presence of venous invasion, a hallmark of metastasis. In line with this, in vitro expression of the COOH-truncated HBx protein (with 24 amino acids deleted at the C-terminal end) in HepG2 cells enhanced their invasive ability when compared to full-length HBx. It also resulted in increased C-Jun transcriptional activity and enhanced transcription of matrix metalloproteinase 10 (MMP10), whereas activation of the MMP10 promoter by COOH-truncated HBx was abolished when the AP-1 binding sites in the MMP10 promoter were mutated. Furthermore, silencing of MMP10 by siRNA in HepG2 cells expressing COOH-truncated HBx resulted in significant reduction of cell invasiveness. The data suggest that COOH-truncation of HBx plays a role in enhancing cell invasiveness and metastasis in HCC by activating MMP10 through C-Jun [35].

Higher titers of circulating interleukin-6 (IL-6) and increased signaling activities of the IL-6/STAT3 and Wnt/β-catenin pathways have been found in HBx transgenic mice, suggesting that HBx may induce intrinsic changes that provide hepatocytes with tumorigenic potential. Thus, the fact that HBx activates several mechanisms associated with tumor transformation in transgenic mice points to a likely role of HBx in the development of liver cancer induced by chronic hepatitis infection [36].

HCV, a tumorigenic virus that lacks known oncogenes

Hepatitis C virus (HCV) is the major etiologic agent of non-A, non-B hepatitis. Persistent HCV infection frequently causes chronic hepatitis, which may progress to liver cirrhosis and HCC. HCV belongs to the family Flaviviridae. Its plus-strand RNA genome carries a long open reading frame (ORF) encoding a polyprotein precursor of 3010 amino acids, which can be cleaved into ten different proteins (three structural and seven nonstructural). Although HCV oncogenesis is not well understood, persistent HCV infection is a prerequisite for the development of HCV-associated liver cancer [37]. There are no oncogenes in the viral genome, but liver-specific miR-122 is required for HCV replication [38]. The HCV proteins not only function in viral replication but also affect a variety of cellular functions. In vitro studies of HCV coevolution with hepatoma host cells have revealed the emergence of more-virulent virus variants as well as the development of cellular resistance at the level of viral entry and RNA replication, perhaps reflecting mechanisms that also operate in favor of hepatocellular tumor development [39]. The carcinogenesis mediated by the virus may be the result from the evolutionary competition between HCV and its host in addition to inflammation of the liver caused by the persistence of the virus infection.

Role of microRNA (miRNA) in KSHV tumorigenesis

Originally identified in Caenorhabditis elegans as important regulators of development, it is now known that all metazoan organisms encode miRNAs [40, 41]. Recently, miRNAs have been identified in several DNA viruses including polyomaviruses and herpesviruses [42, 43]. Both EBV and KSHV have been shown to encode and express miRNAs. The role of these viral miRNAs in viral biology is currently the subject of intense study, and several of their cellular and viral targets genes have been identified. EBV encodes at least 27 miRNAs [43, 44, 45], while 12 miRNA genes have been reported for KSHV [46, 47, 48]. Compared to metazoan miRNAs, viral miRNAs are much less conserved between related viruses.

The miRNAs belong to a large class of small noncoding regulatory RNAs that originate in the nucleus as 5′-capped, polyadenylated transcripts but undergo a series of maturation and transport steps, generating the final 17- to 25-nucleotide-long mature miRNAs found in cytoplasmic miRNPs [49, 50, 51, 52, 53, 54, 55, 56, 57, 58].

Several studies have established that viral microRNAs are involved in modulation of the immune response as well as in oncogenesis. Laboratory findings indicate that the KSHV-encoded miR-K12-11 is an ortholog of miR-155. Based on in silico predictions, reporter assays, and data from expression profiling in miRNA-expressing stable cell lines, miR-K12-11 and miR-155 down-regulate a common set of cellular targets. For example, both of them target the transcriptional repressor BACH, and reduce the BACH protein level. Thus, miR-K12-11 appears to be a unique adaption of KSHV to its target cells, since PELs do not express miR-155 but do express high levels of miR-K12-11. It is speculated that miR-K12-11 may contribute to the distinct developmental phenotype of PEL cells, which are arrested at a late stage of B-cell development [59].

In diffuse large-B-cell-lymphoma (DLBCL) cells, miR-155 has been reported to directly target the bone morphogenic protein (BMP)-responsive transcriptional factor SMAD5, contributing to the development of lymphoid and myeloid malignancies [60, 61]. In addition, miR-155 inhibits BMP signaling by targeting SMAD1/5 [62, 63], and is implicated in the survival of tumors associated with the latency of Epstein-Barr virus (EBV) type III, through the inhibition of BMP-mediated viral reactivation and cell death.

Also, miR-155 regulates transforming growth factor TGF-β signaling in myeloid cells by targeting SMAD2, with a significant effect on fibrosis, angiogenesis, and immunity [64]. Ectopic expression of miR-K12-11 in Ramos, a TGF-β-sensitive cell line, downregulated TGF-β signaling and facilitated cell proliferation upon TGF-β treatment by directly activating SMAD5, a downstream signaling protein in the TGF- β activation pathway. In addition, the downregulation of SMAD5 by miR-K12-11 was further confirmed in a de novo KSHV infection system and in latently infected KSHV-positive B-lymphoma cell lines. More importantly, repression of miR-K12-11 restored the expression of SMAD5 in both de novo-infected and latently infected cells.

The restoration of SMAD5, in addition to the TGF-α type II receptor, which was epigenetically silenced by the KSHV latency-associated nuclear antigen (LANA), a viral episome maintenance factor, again sensitizes target cells to the cytostatic effect of TGF-α signaling [65]. The finding of this novel mechanism through which miR-K12-11 downregulates TGF-α signaling suggests that viral miRNAs and proteins may provide dual regulation in virus-induced oncogenesis by targeting the same signaling pathway.

Cancer association of EBV and its utilization in anti-cancer biotherapy

The occurrence of opportunistic lymphomas in immunocompromised individuals provides an in vivo correlate to the in vitro immortalization of B lymphocytes meditated by EBV. In both instances, EBV expresses the full spectrum of genomic products, some are which are transforming. The viral proteins activate the cellular proliferation programs by a number of mechanisms, for example, induction of NF-κB. This transcription factor has been proposed as a therapeutic target for lymphoproliferative disorders, including various lymphomas [66].

It is noteworthy that common EBV-associated human neoplasias such as BL and NPC arise in immunocompetent hosts and that the development of malignancies is the result of complicated interactions between genetic and environmental factors, including EBV infection, as discussed above. The limited number of EBV antigens expressed during the particular latent state imposed by the tumor cell phenotype may trigger the genetic and epigenetic alterations leading to tumor formation. The EBV genome is present in all cases of the endemic form of BL, and the non-immunogenic nuclear antigen EBNA1 is consistently expressed. The characteristic BL karyotype, with chromosomal translocations involving the short arm of chromosome 8 (8p), e.g., t (8:22), generating a juxtaposition of the myc protooncogene and one of the immunoglobulin (Ig) genes, is seen in all BL cases. These cytogenetic aberrations are considered diagnostic of BL of both endemic and sporadic types. The possibility that EBV protein(s) orchestrate the cytogenetic changes mentioned above has been studied by different laboratories [67]. Although EBV is not generally regarded as a driving force of BL cell proliferation, it plays an important role in the pathogenesis of endemic (e) BL. Latency-associated EBV gene products can inhibit a variety of pathways that lead to apoptosis and senescence; therefore EBV probably counteracts the proliferation-restricting activities of deregulated Myc oncoprotein expression and so facilitates the development of BL.

Undifferentiated NPC has a distinctive ethnic and geographic distribution. In southern China, this type of NPC, i.e., with tumor cells of WHO type III, comprises approximately 97 % of all nasopharynx tumors, and the annual incidence is more than 30 cases per 100,000 population. A high frequency of NPC is also seen in some regions in Southeast Asia, and a moderate rate in North Africa, Greenland and Alaska.

Its occurrence involves multiple genetic and epigenetic lesions, for example, aberrations in certain regions of the short arms of chromosomes 3 and 9 [68, 69]. Epigenetic inactivation of tumor suppressor genes is a prominent anomaly in these particular tumors; hypermethylation of promoter regions of multiple TSGs has been observed in NPC biopsies from endemic regions [70, 71, 72, 73]. A functional study suggested that the lost expression of TSGs plays an essential role in the growth and proliferation of NPC cells [74]. Accumulating data indicate that the development of NPC involves interactions between host genetic factors and environmental factors. NPC is unique among head and neck tumors of epithelial origin in that 100 % of the cases are positive for EBV; the viral genome is identifiable in virtually every tumor cell. In NPC cells, EBV invariably adopts the Latency II phenotype, in which EBNA1 and latent membrane protein 1 (LMP1), and/or LMP2A/2B are expressed [75]. However, EBV infection may not be an initiating factor for NPC development but may drive its progression to malignancy.

Although they are very rarely diagnosed, low-grade precancerous lesions in the nasopharyngeal epithelium including severe dysplasia or carcinoma in situ (CIS) have been reported [76, 77, 78]. In studies of chromosomal losses of heterozygosity (LOH), higher frequencies of allelic deletion of chromosomes 3p and 9p were identified in normal nasopharynx (NP) tissue from Southern Chinese as compared with those from low-risk groups [79, 80]. In addition, frequent aberrant methylation of TSGs in 3p21 was also identified in NPC cells and tissues [79, 80, 81, 82].

The fact that EBV infection was not detected in these low-grade NP lesions suggests that that the LOH on 3p and 9p may be the earliest events in NPC development, followed by EBV infection. The clonality of EBV genomes in the high-grade dysplastic nasopharyngeal epithelium that subsequently develops also argues for an active role of EBV in the progression to malignancy. Transformation of the high-grade dysplastic nasopharyngeal epithelium into invasive cancer likely involves expression of the viral oncogenes, such as LMP1 [75, 83], as outlined below.

The transforming transmembrane protein LMP1 is expressed in a considerable fraction of NPC tumors. LMP1 is a viral homolog of the eukaryotic T cell activator CD40 and functions to transduce signals of growth, proliferation and apoptosis. Antigenic epitopes recognized by T cells have been mapped on EBV proteins of the prototype strain B95-8 and other strains, but it has been reported that the immunogenicity of LMP1 is attenuated in strains prevalent in endemic regions due to sequence mutations, contributing to an immune escape mechanism of the tumorigenic viruses associated with NPC [83, 84].

As noted above, LMP1 is believed to play a role in promoting the proliferation of premalignant nasopharyngeal epithelial cells that carry genetic lesions on the chromosomal 3p and 9p fragments [76, 85, 90]; its presence can be demonstrated in situ in preinvasive carcinoma of the nasopharynx [76]. In recent years, experimental data have suggested that the transforming integral membrane protein LMP1 of EBV contributes to the development of NPC and BL through the following mechanisms:

Stimulation of proliferation, through different mechanisms

LMP1 is a prime candidate for driving tumorigenesis given its ability to activate multiple signaling pathways and to alter the expression and activity of variety of downstream targets. Induction of the NF-κB-dependent transcription factor Id1 by LMP1 negatively regulates the negative regulator of proliferation p16 and inhibits TGF beta signaling, thus contributing to the clonal expansion of premalignant nasopharyngeal cells [86, 87]. Resistance to TGF-β-mediated cytostasis is one of the growth transforming effects of LMP1 [89].

Modulation of cell cycle entry

It has been observed that EBV modulates the cell cycle so as to support its replication in the host. Experimentally induced LMP1 expression almost completely inhibited cell growth for 4 to 5 days, after which the cells recovered a limited proliferative capacity. This cytostatic effect of LMP1 was observed in all B cell lines studied. Further analysis showed that induction of LMP1 coincided with a reduction in the levels of c-myc, and that the cytostatic effect was due to an accumulation of cells at the G2/M phase of the cell cycle. These data suggest a novel function for the LMP1 oncogene in controlling the proliferation of EBV-infected cells by regulating progress through the G2/M phase [88]. LMP1 also impacts on the G2 checkpoint in nasopharyngeal epithelial cells. It was found that LMP1 impaired the G2 checkpoint in nasopharyngeal epithelial cells [89], leading to the formation of unrepaired chromatid-type aberrations in metaphase cells. Defective Chk1 activation was responsible for induction of this defect at the G2 checkpoint in LMP1-expressing nasopharyngeal epithelial cells [89] (Fig. 1).
Fig. 1

The scheme of cancer related activities of EBV encoded LMP1. The two oval symbols represent transforming effector domains CTAR1 and CTAR2

Induction of genomic instability

EBV latency is associated with increased genomic instability in Burkitt’s lymphoma, suggesting that viral products may induce this tumor phenotype. Using a panel of transfected sublines of the B-lymphoma line BJAB expressing the viral genes associated with latent infection, we have shown that the EBV nuclear antigens EBNA-1 and EBNA-3C and the latent membrane protein 1 (LMP-1) independently promote genomic instability, as detected by nonclonal chromosomal aberrations [90].

EBNA-1 promotes the generation of DNA damage by inducing reactive oxygen species (ROS) [91]. Whereas DNA repair is inhibited in LMP-1-expressing cells through downregulation of the DNA-damage-sensing kinase ataxia telangiectasia mutated (ATM), a reduction of phosphorylation of its downstream target Chk2 leads to inactivation of the G2 checkpoint [92].

The tight association of EBV with undifferentiated forms of NPC also suggests that the virus and its replication machinery might be effective targets for anti-NPC biotherapy.

EBV is expressed in a latent form exclusively in cancer cells, and not in the surrounding tissues. EBNA1, the viral protein expressed in all EBV-positive cells, is regulated by a promoter element, OriP (origin of replication of plasmid), which forms a positive feedback loop with EBNA1. A novel replication-deficient adenovirus vector (ad5.oriP) in which transgene expression is under the transcriptional regulation of EBV OriP was constructed. When EBNA1 binds to the “family of repeats” sequence (from the EBV genome), this activates transcription of a copy of the p53 tumor suppressor gene placed downstream in the expression plasmid. These results suggest that under the control of OriP, extensive expression of p53 occurred only in EBV-positive NPC cells, and specifically in response to the presence of EBNA1 [93]. In a cytokine expression system currently in clinical trial as an anti-cancer biotherapy, interferon gamma (IFN-γ) is adapted to the same construct by mounting its coding part downstream of EBV OriP sequence. This construct has started to pave the way for novel therapeutic agents against NPC, a head-and-neck cancer closely associated with EBV infection [94].


Development of vaccines directed against oncogenic viruses

The induction of tumor formation by transforming retroviruses and the in vitro immortalization of B lymphocytes by EBV are known to be highly efficient events. The development of tumors in vivo in human subjects, however, requires much more time and involves complicated interactions between genetic factors and environmental carcinogens, including oncogenic viruses. It is known that viruses, when acting as carcinogens, are necessary but not sufficient factors for the development of tumors.

Thus, it is encouraging that vaccination against HBV and HPV has proven to be an effective strategy for the prevention of cervical cancer [15]. The primary public-health goal of an immunization programme is to stop the spread of infection and ultimately the disease. HPV vaccination targeting individuals prior to their entry into the sexually active population has proven to be effective by limiting the spread of the virus and in turn reducing cervical cancer incidence.

Prophylactic vaccines against other pathogenic viruses have an excellent record as public-health interventions. These considerations should prompt efforts to develop and implement vaccines against oncoviruses. Safe and effective HBV and HPV vaccines, as mentioned above, based on virus-like particles are commercially available, and the major focus is now on vaccine availability, delivery and acceptance by the population at risk, especially in low-resource settings.

Epidemiologic data suggest that more oncogenic viruses remain to be identified and characterized

The etiologic role of tumor viruses has now been confirmed for seven viruses that infect humans. Recent decades have witnessed a rapid development of highly efficient new laboratory techniques, which have facilitated the rapid discovery of new emerging pathogens [95]. Results from experimental carcinogenesis suggest that polyomaviruses, as a group of efficient oncogenic viruses, may contain more pathogens causing human cancers. Epidemiologic as well as clinical data imply that more microbial carcinogens remain to be identified. For example, an increased risk for colorectal cancer has been reported to be correlated with consumption of cooked and processed red meat in certain parts of the world. While in the past, this was frequently attributed to chemical carcinogens arising during the process cooking of meat, the available epidemiologic data are compatible with the interpretation that a specific beef factor, suspected to be one or more thermoresistant, potentially oncogenic bovine viruses (e.g., polyoma-, papilloma- or possibly single-stranded DNA viruses) that may contaminate beef preparations and lead to latent infections in the colorectal tract [96].

Expanding the list of viruses associated with human tumors would improve our understanding of the role of infections in relation to human tumors. Elucidation of the molecular mechanisms by which viruses contribute to human cancers may also provide us with tools for prevention or therapy against these forms of cancer.



The work on anti-NPC biotherapy was supported by a research grant from Scientific and Technology Project of Dongguan City, China. IE is supported by the Swedish Cancer Society (Cancerfonden) and the Swedish Childhood Cancer Society. The present MS was composed based on a presentation delivered to the annual meeting of Provincial Society of Preventive Medicine of Guangdong, China.


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Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Department of Pathophysiology, and Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Sino-American Cancer Research InstituteGuangdong Medical CollegeDongguanChina
  2. 2.Ludwig Institute for Cancer Research and Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
  3. 3.Department of OtolaryngologyGuangxi Medical UniversityNanningChina
  4. 4.Department of MicrobiologyGuangdong Medical CollegeDongguanChina
  5. 5.Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden

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