Roles of long non-coding RNAs in human normal and neoplastic epidermis

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This proposal seeks insight into the functional relevance of long non-coding RNAs (lncRNAs) in human normal and neoplastic skin. The human genome encodes several thousand long non-protein coding transcripts >200 base pairs in length. Although recent studies have shown that lncRNAs play important roles in a variety of biological processes, their impact on controlling the transition of mature human tissue into a neoplastic state during cancer development remains largely unknown. With the projects proposed here, I plan to characterize the impacts of 6 skin cancer-associated lncRNAs on neoplastic progression using human organotypic epidermis as a model system. All 6 lncRNAs were selected for this study based on previous deep RNA sequencing analyses, and were repressed in human skin cancer specimens (squamous cell carcinoma; SCC) as well as enriched during differentiation. Thus, these lnRNAs have high propensity for a dual-role in control of epidermal tissue differentiation as well as SCC- development and will be functionally analyzed through 2 broad aims:Aim I is designed to characterize the functional impact of SCC-associated lncRNAs on epidermal differentiation. We will generate human epidermis deficient for all of the 6 SCC-associated lncRNAs using RNA interference. These tissues will then be used to examine functional roles of these lncRNAs on epidermal differentiation. In Aim II, we will characterize the impacts of functional SCC-associated lncRNAs on human tissue neoplasia. For this, we will generate organotypic, neoplastic tissue with sustained expression of SCC-associated lncRNAs that prove to be functionally important for human epidermal differentiation (as tested in Aim I). We will then use these neoplastic tissues to analyze the impacts of sustained lncRNA expression on tumor cell growth and invasion rate. Characterization of long non-coding RNAs that are mis-regulated in cancer will gain further insight into functions and mechanisms of lncRNAs in differentiation as well as neoplasia of mature human tissue, and may provide novel targets for prevention and treatment of disorders of epidermal homeostasis as well as skin cancer.