The Role of CADM1 in Viral-Mediated Oncogenesis

Approximately 15% of human cancers worldwide, including leukemias and lymphomas, are caused by infection from oncogenic viruses, such as human T-cell lymphotropic virus 1 (HTLV-1) and Kaposi\u27s sarcoma herpesvirus (KSHV). Oncogenes of these viruses, such as Tax of HTLV-1, and viral G-protein coupled receptor (vGPCR) and viral FLICE inhibitory protein (vFLIP) of KSHV, maintain persistent inflammation via activation of NF-kB, a family of transcription factors. NF-kB is normally transiently activated in response to TNF, IL-1, and bacteria or viral infections. However, under certain pathologic conditions, such as inflammation or tumorigenesis, it is chronically activated. Here we show host factor Cell Adhesion Molecule 1 (CADM1) expression is significantly upregulated in primary human PBMCs infected with HTLV-1 or KSHV viruses. Viral oncogenes Tax, vGPCR, and vFLIP usurp host factor CADM1 to maintain chronic activation of NF-kB. Tax, vGPCR, and vFLIP interact with the cytoplasmic tail of CADM1 to maintain chronic activation of NF-kB in infected cells. Furthermore, NF-kB activation by Tax and vFLIP is initiated in the plasma membrane lipid rafts of HTLV-1 and KSHV-infected cells, respectively. In addition, CADM1 is critical for the proliferation and survival of KSHV-associated Primary Effusion Lymphoma (PEL) cells. These results strongly suggest that CADM1 plays key roles in HTLV-1 and KSHV-mediated tumorigenesis and may lead to the development of novel therapies