Tumorigenesis and Aberrant Signaling in Transgenic Mice Expressing the Human Herpesvirus-8 K1 Gene

• Published in: JNCI : Journal of the National Cancer Institute Vol. 94; no. 12; pp. 926 - 935
• Main Authors: Prakash, Om, Tang, Zhen-Ya, Peng, Xiaochang, Coleman, Roy, Gill, Javed, Farr, Gist, Samaniego, Felipe
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 19.06.2002; Oxford Publishing Limited (England)
• Subjects: Animal tumors. Experimental tumors; Animals; B-Lymphocytes - immunology; Biological and medical sciences; Cytokines - genetics; DNA Primers; Enzyme Activation; Experimental digestive system and abdominal tumors; Experimental malignant blood diseases; Glycoproteins - genetics; Glycoproteins - metabolism; Herpesviridae Infections - virology; Herpesvirus 8, Human - genetics; Humans; Interleukin-12 - genetics; Lymphoma - genetics; Lymphoma - pathology; Lymphoma - virology; Medical sciences; Mice; Mice, Transgenic; Protein-Tyrosine Kinases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; T-Lymphocytes - immunology; Tumors; Viral Proteins - genetics; Viral Proteins - metabolism; Transgenic animal; Omentum; Plasmocyte; Carcinogenesis; Signal transduction; Gene; Lymphoproliferative syndrome; Genetics; Gammaherpesvirinae; Herpesviridae; Rodentia; Fusiform cell; Precursor cell; Malignant hemopathy; Tumorigenicity; Malignant tumor; Lymphoma; Herpesvirus hominis 8; Infection; Virus; Vertebrata; Mammalia; Mouse; Abdominal disease; Viral disease
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/94.12.926

Background: The K1 gene of human herpesvirus-8 (HHV-8; also known as Kaposi's sarcoma-associated herpesvirus) encodes a transmembrane signaling protein that elicits cellular activation events. To evaluate the potential role of K1 in HHV-8-associated pathogenesis, we produced transgenic mice expressing the HHV-8 K1 gene under the transcriptional control of the simian virus 40 promoter. Methods: Three independent heterozygous transgenic K1 mouse lines were generated from founder mice. Mouse splenic and thymic lymphocytes and tumor tissues were analyzed for the expression of cytokines involved in inflammatory and immune responses, including tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF), and interleukin 12 (IL-12); for the activation of the transcription factors nuclear factor-κB (NF-κB) and the B cell-specific transcription factor Oct-2; and for the activation of the Src and Syk family kinases, components of B-cell receptor-induced signal-transduction pathways. Results: Expression of bFGF was increased in K1-transgenic mice as compared with nontransgenic mice, whereas expression of TNF-α and IL-6 did not differ using reverse transcriptase–polymerase chain reaction. K1-transgenic mice showed substantially less serum IL-12 induction than did nontransgenic mice when challenged with a lipopolysaccharide. B lymphocytes from K1-transgenic mice but not from nontransgenic mice showed constitutive activation of NF-κB and Oct-2. K1 expression in human B lymphocytes stimulated NF-κB-dependent promoter activity. B lymphocytes from K1-transgenic mice also showed increased phosphorylation of Lyn, a Src family tyrosine kinase, and enhanced Lyn activity. Tumors in K1-transgenic mice showed features indicative of a spindle-cell sarcomatoid tumor and a malignant plasmablastic lymphoma. The pattern of cytokine, transcription factor, and Lyn kinase activity in the lymphoma was similar to that in B lymphocytes from K1-transgenic mice. Conclusion: K1 may be involved in the activation of NF-κB signaling. The enhanced NF-κB activity in nonmalignant lymphocytes of K1 mice and its persistence in lymphoma tumors of these mice suggest that the K1 mouse may be a model of premalignancy.