Environmental and Molecular Mutagenesis 45:304^325 (2005) Review Article Impact of Transforming Viruses on Cellular Mutagenesis, Genome Stability, and Cellular Transformation Michael L.Gatza,1,2 Chandtip Chandhasin,2 Razvan I. Ducu,2 and Susan J. Marriott1,2* 1Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas 2Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas It is estimated that 15% of all cancers are etiologi- been explicitly linked to the expression of onco- cally linked to viral infection. Specific cancers proteins encoded by these viruses. This review including adult T-cell leukemia, hepatocellular car- discusses mechanisms utilized by these viral onco- cinoma, and uterine cervical cancer are associated proteins, Tax, HBx, and E6/E7, to mediate geno- with infection by human T-cell leukemia virus type I, mic instability and cellular transformation. Environ. hepatitis B virus, and high-risk human papilloma Mol. Mutagen. 45:304–325, 2005. c virus, respectively. In these cancers, genomic 2005 Wiley-Liss, Inc. instability, a hallmark of multistep cancers, has Key words: viral transformation; genomic instability; viral-associated cancer; human T-cell leukemia virus type I; hepatitis B virus; human papilloma virus INTRODUCTION hepatitis B virus (HBV), and human papilloma virus (HPV). These viruses, respectively, are the etiologic The World Health Organization estimates that each agents of adult T-cell leukemia (ATL), hepatocellular car- year approximately 10 million new cancer cases will be cinoma (HCC), and uterine cervical cancer (UCC). reported worldwide and an estimated 6 million people (12% of worldwide deaths) will succumb to some form of this disease (www.who.int/cancer/en). In the United States OVERVIEW OF VIRUSES alone, 2.3 million new cancer cases will be diagnosed and Adult T-Cell Leukemia and HTLV-1 an estimated 556,000 Americans (> 1,500 per day) will die each year from cancer [American Cancer Society, HTLV-1 was the first human oncogenic retrovirus dis- 2003]. Worldwide, it has been estimated that 15% of can- covered [Poiesz et al., 1980] and is now recognized as the cer cases are etiologically linked to viral infection, etiological agent of both ATL and a neurodegenerative accounting for nearly 1.5 million new cases and 900,000 disease, tropical spastic paraparesis/HTLV-1-associated deaths annually [Butel, 2000]. myelopathy (TSP/HAM). HTLV-1 is endemic in parts of Viruses have been etiologically linked to specific forms Japan, South America, Africa, and the Caribbean and is of cancer (Table I), and many other viruses not formally currently estimated to infect nearly 20 million people implicated in human tumorigenesis encode proteins cap- worldwide [Franchini, 1995]. Transmission of this virus able of immortalizing cells in culture and causing tumors in transgenic animals. As in most cancers, cancers asso- *Correspondence to: Susan J. Marriott, Department of Molecular Virol- ciated with these viruses demonstrate gross chromosomal ogy and Microbiology, Baylor College of Medicine, One Baylor Plaza, abnormalities, which have been argued to cause, or at Houston, TX 77030. E-mail: [email protected] least contribute to, cellular transformation and tumor pro- Invited article: 25th anniversary of Environmental and Molecular gression. This review focuses on mechanisms of genomic Mutagenesis instability and cellular transformation mediated by the DOI 10.1002/em.20088 oncoproteins encoded by three well-studied oncogenic Published online 11 January 2005 in Wiley InterScience (www.interscience. viruses: human T-cell leukemia virus type 1 (HTLV-1), wiley.com). c 2005 Wiley-Liss, Inc. Impact of Transforming Viruses 305 ic occurs horizontally through the transfer of body fluids ma rs ease g ithial (i.e., intravenous drug use, blood transfusion, and sexual spast dis n othe ep l thelio T-A bone, ’s known contact) and vertically through the ingestion of milk- SV40 cells, meso borne lymphocytes during breastfeeding [Hino et al., tropica None 5.2 6 Kidney dsDNA Lg/Sm Unknow Brain, ); 1985; Sugiyama et al., 1986; Wiktor et al., 1993; Ferreira Hodgkin et al., 1997]. Due in part to the long latency period (SV40 (BL); (2–4 decades), only 4–5% of the infected population are 40 expected to develop ATL, mostly those who were oma horosis infected as children [Johnson et al., 2001]. Despite the virus cirr an relatively low incidence of ATL, it is a rapidly progres- lymph HCV cytes sing fatal disease that does not respond to any known simi NA C mmon ); rkitt’s treatments and has a mean survival time of 6 months epatitis, epato S3? C u H 9.4 ssR Co 9 H N H B [Jaffe et al., 1984; Shimoyama et al., 1988]. ; (HCV The HTLV-1 genome encodes several proteins that CC) (H virus appear to contribute to infection and oncogenesis. How- C ever, numerous studies have established the viral tran- itis oplakia scriptional transactivator, Tax, as the major viral onco- ithial omas ep leuk carcinoma protein [Grassmann et al., 1992]. Tanaka et al. [1990] hepat V lls ar EB demonstrated that Tax can transform NIH 3T3 and Rat1 lymph hairy B-ce yngeal , l cells and confirmed these observations using mutational D (EBV); ocellul H ora 0 analysis. Later Tax alone, and in combination with Ras, 90 cells, virus IM, 172. dsDNA Common LMP-1 * Orophar BL, hepat was shown to be capable of transforming primary rodent r embryo fibroblasts [Pozzati et al., 1990; Smith and Greene, 1991]. Tax transgenic mice developed neurofibro- (ATL); ein-Bar ital mas and mesenchymal tumors when Tax was ubiquitously Epst emia cells ; expressed in all tissues, but developed primary peripheral eous) l skin, warts leuk anogen lymphomas comprised of CD8þ T- and NK cells when cutan (HPV) nx, the Tax transgene was targeted to lymphocytes using epithia HPV genital T-cell sal, cervical, the lymphocyte-specific human granzyme B-promoter t ous virus and a ophary E7 [Hinrichs et al., 1987; Nerenberg et al., 1987; Grossman adul (muco or et al., 1995]. Although these studies provide strong Skin 8–10 8.0 Uterine dsDNA E6, Squam Common pillom (IM); evidence for the involvement of Tax in tumorigenesis, the pa sis exact mechanisms of Tax function have yet to be fully elucidated. Generally, it is believed that Tax promotes human ucleo and a a ); tumorigenesis by increasing genomic instability through incidence Asia Afric cells the disruption of normal host-cell processes, including monon (HBV V od B ran cellular transcription, DNA repair mechanisms, and cell Viruses high cirrhosis H , theast blo s, cycle progression. virus cytes, Sou B infectious in sub-Saha white ); itis Hepatiti 4 3.2 dsDNA HCC Common HBx Hepato Hepatocellular Carcinoma and HBV hepat /HAM Transforming HBV is a double-stranded DNA virus with a ubiquitous (TSP (ds). n, worldwide distribution. It is estimated that over 75% of LV-1); Asia thy the world’s population lives in regions of high infection ded merica, (HT Human A 1 M [Hollinger and Liang, 2001]. Similar to HTLV-1, HBV is elopa Caribbea e th theast HTLV-1 transmitted both horizontally through transfer of body le-stran my NA typ L P/HA Sou Sou cells pan, , T fluids and vertically from mother to child, and 70–90% of ted TS 6 ssR 9.0 Ja A Tax T- doub Common mothers chronically infected with HBV will pass the virus virus of (ss); on to their child, many of whom will become lifelong car- emia riers. Although the exact mechanism of vertical transmis- nt anded leuk age genes sion is not clear, virus-associated antigen has been found ll in cers of acid eases in amniotic fluid, cord blood, breast milk, and vaginal ing Properties gle-str T-ce dis can . (kB) nce tion esis/HTLV-1-associa I secretions, suggesting perinatal rather than transplacental sin E an tropism ze ucleic umber L transmission [Chen et al., 2004]. It has been estimated B infec N Si N A hum Prevale T Characteristic Genome Cell a Human Human Transform parapar (HD); that over 350 million people are chronic carriers of HBV 306 Gatza et al. and it is believed that over time the infection, potentially Uterine Cervical Cancer and HPV in combination with other environmental factors including aflatoxin B ingestion, cigarette smoking, and alcohol con- HPV is one of the most common sexually transmitted sumption, may result in the development of cirrhosis and diseases (STDs) worldwide and is believed to be the most HCC. In fact, it is currently believed that over 80% of all prevalent STD in the United States. Despite the fact that HCC cases are the result of infection by either HBV or genital HPV infection is not a reported disease, it is esti- hepatitis C virus (HCV) [Chen et al., 1997]. mated that between 1 and 5.5 million new cases occur each HCC is the fifth most frequently diagnosed cancer and year, and the overall prevalence of infection is greater than the fourth leading cause of cancer-related deaths 20 million people in the United States alone [Cates, 1999]. (> 500,000 annually) worldwide. Although the incidence HPV is most often transmitted by direct contact between rate in industrialized nations is rather low, due in part to two epithelial surfaces and is facilitated in part by the pre- immunization programs, HCC is the leading cause of can- sence of abrasions or lesions [Oriel, 1971; Moy et al., cer-related deaths among adults in Southeast Asia and 1989; Euvrard et al., 1993]. The incidence of HPV infec- sub-Saharan Africa. Worldwide, the mortality-to-incidence tion correlates directly with the number of sexual partners rate is close to or greater than 1, indicating that most an individual has encountered and infections are rare in patients will not survive longer than 1 year [Hollinger sexually inexperienced and/or young women [Rosenfeld and Liang, 2001].