Abstract 1987: Tumor suppressor ADAM23 mediates the HPV-associated carcinogenesis.

Abstract

Abstract “High risk” human papillomaviruses (HPV) are known to cause or are closely associated with the development of human cervical, anal and some types of head and neck cancers. Integration of HPV DNA into host genome and subsequent expression of viral oncogenes, such as E6 and E7, are critical initial events for the HPV-associated cancer development; however, HPV infection alone is not sufficient to convert normal cells to malignant phenotypes, suggesting that other additional genetic and/or epigenetic events in the HPV-infected cells are required. The aim of the current study is to identify molecular determinants that are functionally linked to the pathogenesis of the HPV-associated cancers. We used HPV-16 harboring immortalized but non-transformed oral epithelial cells (HOK-16B), infected with high-throughput Decode RNAi lentiviral screening pools containing about 70,000 shRNAmir constructs capable of knocking down the target genes individually (3-4 constructs per gene), and selected them in DMEM-based high calcium/serum media in which HOK-16B cells are not permissive to survive. From the surviving colonies, we have identified several putative tumor suppressors including A Disintegrin and etalloproteinase domain-containing protein 23 (ADAM23). The function of ADAM23 was further validated such that singly knocking down in HOK-16B cells (HOK16B/ADAM23i) acquired proliferative potential in DMEM-based medium. HOK16B/ADAM23i cells also gained resistance to ionizing radiation (IR), cisplatin treatment, and differentiation as demonstrated by colonogenic assay, MTT assay, and the 3-dimensional raft culture systems, respectively. More importantly, the expression is largely diminished in squamous cell carcinoma (SCC) cell lines but more so in HPV-harboring SCC. We further found that ADAM23 expression is high in normal human oral epithelial tissues but low or none in HPV-positive OSCC tissue specimens as determined by immunohistochemical staining. Our data suggest that ADAM23 may play a role in development of HPV-associated cancers. Citation Format: Paul Yang, Drake W. Williams, Terresa Kim, Ki-Hyuk Shin, Mo Kang, No-Hee Park, Reuben H. Kim. Tumor suppressor ADAM23 mediates the HPV-associated carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1987. doi:10.1158/1538-7445.AM2013-1987