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Cellular Transformation by a Unique Isolate of Human Papillomavirus Type 111 Ronald C

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Cellular Transformation by a Unique Isolate of Human Papillomavirus Type 111 Ronald C (CANCERRESEARCH52, 5872-5878, November1, 19921 Cellular Transformation by a Unique Isolate of Human Papillomavirus Type 111 Ronald C. McGlennen, Jyotsna Ghai, Ronald S. Ostrow,2 Kurt LaBresh, John F. Schneider, and AnthonyJ. Faras Departments ofLaboratory Medicine and Pathology fR. C. M.J, and Microbiology (I. G., R. S. 0., A. J. F.J, and the institute ofHuman Genetics (R. C. M., I. G., R. S. 0., K. L, I. F. S., A. I. F.], University ofMinnesota Medical School, Minneapolis, Minnesota 55455 ABSTRACT questions regarding the role of “lowoncogenic potential― vi ruses like HPV 11 to be involved in malignant transformation. Infection with human papillomvirus type 11 (HPV 11) is associated There are two aspects to the problem ofevaluating the role of with benign epithelial proliferations and rarely with malignant and HPVs in tumorigenesis in vivo. One consideration is the extent metastasizing tumors. Because of the biological diversity displayed in tissues InfectedwithHPV 11, wehaveexaminedthe capacityof various to which the infected cell or, in the larger context, the host and isolates of HPV 11 to transform cultured cells and compared their its environment play in promoting the progression of benign molecular differences by DNA sequence analysis. Five isolates of HPV HPV lesions on to malignant transformation. Included here are 11 were examinedfor their ability to transformprimaryneonatalrat factors such as environmental carcinogens in cigarette smoke, kidney epithellal cells and NIH 3T3 mouse flbroblasts in DNA trans and other chemicals which are tumor promotors (9, 10). fection experiments using calcium phosphate precipitation. Induded in Chronic immunosuppression, whether associated with preg these studies are the prototype isolate from a laryngeal papillonsa(HPV nancy or occurring with organ transplantation, has been shown liP); HPV 11VCfroma verrucouscarcinomaofthe penis HPV ilEpi to be an important predisposing factor to the development of from the viral episomes of a primary squamous cell carcinoma and two integrated genomes (HPV hInt 1 and HPV hInt 2) ofthe metastases. malignant cutaneous and mucosal HPV-associated tumors (11— Only HPV I1VC cotrausfectedwith the oncogeneHa-nsa transformed 13). Our laboratory has recently characterized a squamous cell neonatal rat kidney eplthelial cells with an efficiencycomparable to that carcinoma in a renal allograft recipient arising from the peria of HPV 16 DNA. HPV 1IVC DNA alone transformed NIH 3T3 cells. nal skin and containing HPV 11 (14). Analysis of the DNA sequence of HPV lip and 11VC revealed 16 A second aspect important in the evaluation of HPV-associ single nucleotide changes In the upstream regulatory region and open ated malignancy is to consider the oncogenic potential of the reading frames El, E2, E4, and ES, five resulting in amino acid substi virus itself. At the molecular level, human papillomaviruses tutions. This is the first demonstration of cellular transformation by a share a high degree of similarity in their genomic organization, natural Isolate HPV 11 DNA in ritro and illustrates that minimal changes In the DNA sequence of certain viruses confer oncogenicityto yet only a specific subset of HPV types are typically oncogenic what are normally nontransforming viruses. in vivo(1). Oneexplanationof the differencesin the oncogenic potential between these two groups of HPVs is thought to be due to simple base pair mutations in critical areas of the viral INTRODUCTION genome such as in the URR, which contains viral early promot HPVs3 are a group of small DNA viruses, of which there are ers and enhancers, or in the region of the early genes of the over 60 distinct types that cause a variety of epithelial lesions, virus, which encode for several putative oncoproteins (15). but are most notable because of their etiological association Transfection ofcloned viral DNAs into cultured mammalian with cervical cancer (1). Infection with HPV causes a wide cells has been used to measure the transforming potential of spectrum of mucosal and cutaneous lesions which include be certain viruses (15). Stable integration of the transfected viral nign epithelial proliferations and highly invasive and metasta DNA into cultured cells can induce morphological changes, sizing malignant tumors of the skin, respiratory tract, and gen with concomitant alterations in several growth parameters. ital mucosa (2, 3). Epidemiological data have demonstrated Among the human papillomaviruses, HPV 16 DNA has been that certain HPV types such as HPV 16, 18, 31, and 33 are shown to efficiently transform neonatal rat kidney epithelial more commonly associated with premalignant and malignant cells when cotransfected with the activated form of the onco lesions and thus have been designated as the oncogenic HPV gene Ha-ras and when in the presence of glucocorticoid hor types (4). By contrast, virus types with low oncogenic potential, mone (16, 17). Under identical conditions, however, the proto such as the closely related HPVs 6 and 11, frequently are as type HPV 11 DNA, molecularly cloned from a laryngeal sociated with condyloma acuminatum and orolaryngeal papil papilloma, failed to transform NRK cells (18). With the diver lomas, which except in cases where patients are immunocom sity of in vivo biological activities displayed in tumors contain promised or have received radiation therapy, have rarely been ing HPV 11 DNA from several patients, we have speculated shown to undergo malignant transformation (5, 6). In recent that different isolates of HPV 11 obtained from malignant tu years, several published reports have described patients with mors may have been altered in significant ways, rendering them primary and metastatic tumors of the lung, vulvar skin, and capable of cellular transformation in vitro, similar to HPV 16 anal mucosa found to harbor episomal and integrated forms of DNA. To examine this hypothesis, we have characterized five HPV 6 or 11 DNA (7, 8). These clinical examples have raised molecularly cloned, naturally occurring isolates of HPV 11 de rived from a spectrum of lesions and have performed in vitro Received9/23/91; accepted8/26/92. transfections to evaluate their respective potentials for trans The costs of publication of this article were defrayed in part by the payment of pagecharges.Thisarticle mustthereforebeherebymarkedadvertisementinaccord forming NRK and NIH 3T3 cells. The capacity of these viral ance with 18 U.S.C. Section 1734 solely to indicate this fact. isolates to transform cultured cells and several functional pa I Supported by NIH Grant CA25462 and the Leukemia Research Fund. rameters of the effects of these cloned viral DNAs on cellular 2 To whom requests for reprints should be addressed, at University of Minnesota Medical SChOOl,BOX206, Harvard Street at East River Road, Minneapolis, MN growth and differentiation were determined. Finally, by com 55455. paring the molecular structure of these viral isolates by DNA 3 The abbreviations usedare: HPV, human papillomavirus; NRK cells, neonatal rat kidneyepithelialcells URR, upstreamregulatoryregion;CM, completemedia, sequence analysis, we have attempted to explain their respective ORF,openreadingframe. biological differences. 5872 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1992 American Association for Cancer Research. UNIQUE HPV 11 ISOLATETRANSFORMSCELLS MATERIALS AND METHODS 20x standard saline citrate phosphate (lx is 0.12 M NaCl, 0.015 M sodium citrate, 0.013 Mpotassium phosphate, 0.001 MEDTA, pH 7.2) Molecular Cloning of Various HPV 11 Species. The prototype spe (24). Filters wereprobed with 5 nglml ofrandom-primed HPV 11DNA cies ofHPV (HPV 11P) was a generous gift from Dr. L. Gissmann and (specific activity, 4—8x 10@cpin/@ig)(25). Filters were washed under was derived from a benign laryngeal papilloma. The sample we received high stringency conditions (temperature midpoint —25C)and then had been molecularlycloned into a bacterialplasmid vector at the autoradiographed using Kodak XAR-5 X-ray film (Eastman Kodak, unique BamHI restriction endonuclease site that occurs in the struc Rochester, NY). tural gene Li (19). The full-length (8-kilobase) HPV 11P was excised Assay of Anchorage-independent Growth and Tumorigenesis in and recloned into the unique BamHI site of the vector pUC 19. HPV Athymic Nude Mice. The ability of transformed cells to display an 11VC is a full-length (8-kilobase) episomal viral genome originally chorage-independent growth was assayed by incubating various cell cloned in the BamHI site from the ACharon 27 genomic library derived lines in semisolid media. Tissue culture plates contained a support layer from a penile (Buschke-Lowenstein)verrucouscarcinomapreviously of 0.5%agarosein CM and a feederlayercomprising0.3%agarosein described (20). Three additional isolates of HPV 11 were cloned di CM seededwith 1.0, 2.0, or 4.0 x [email protected] were incubatedat rectly into pUC 19 from the cellular DNA extracts from tissues de 3TC in 7% CO2 and observed periodically for the appearance of cell scribed previously including a primary squamous cell carcinoma of the clusters. Tumorigenesis studies were performed by injecting 1.0 X l0@ perianalskinanda metastaticlivertumorofa renaltransplantrecipient cells s.c. from the various transformed cell lines and controls into the (14). Two-dimensional agarose gel electrophoresis ofuncleaved cellular hindquarter of 2—3-week-old BALB/c athymic nude mice. Animals DNA was used to separatecircularepisomalviralDNA fromlinearor were examined
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