title: LncRNA profiling reveals new mechanism for VDR protection against skin cancer formation.
abstract: Accumulating evidence strongly suggests a protective role of vitamin D signaling against chemical and UVR-induced skin cancer formation. However, the mechanism remains largely unknown. Recently, the emerging role of long, non-coding RNA (lncRNA) as a hallmark of cancer has become better appreciated. LncRNAs are mRNA-like transcripts ranging in length from 200 bases to 100kb lacking significant open reading frames, which are involved in a broad spectrum of tumorigenic/metastatic processes. In this study we profiled 90 well-annotated mouse lncRNAs from cultured mouse keratinocytes after deleting the vitamin D receptor (VDR) (∼90%) vs. control cells using an lncRNA array analysis. We found that several well-known oncogenes, including H19, HOTTIP and Nespas, are significantly increased (6.3-1.8-fold), whereas tumor suppressors (Kcnq1ot1, lincRNA-p21) are decreased (up to 50-70%) in VDR deleted keratinocytes. A similar pattern of lncRNA profiling is observed in the epidermis of K14 driven, tamoxifen-regulated epidermal-specific VDR null vs. wild-type control mice. Additionally there is an increase in the expression levels of other oncogenes (mHOTAIR, Malat1 and SRA) and a decrease of other tumor suppressors (Foxn2-as, Gtl2-as, H19-as). The increased expression levels of HOTTIP and H19 were further confirmed by real-time PCR analysis with individually designed primer sets. The major finding of this study is a novel mechanism for protection by VDR against skin cancer formation by maintaining the balance of oncogenic to tumor suppressing lncRNAs. In keratinocytes lacking VDR this balance is disturbed with increased expression of oncogenes and decreased expression of tumor suppressors, a mechanism that predisposes the VDR deficient mice to skin cancer formation. This article is part of a Special Issue entitled "Vitamin D Workshop".
authors.affiliation: Endocrine Research Unit (111N), Department of Medicine, VAMC/UCSF, NCIRE, United States. Electronic address: yan.jiang@med.va.gov.
authors.forename: Yan J
authors.initials: YJ
authors.lastname: Jiang
authors.affiliation: Endocrine Research Unit (111N), Department of Medicine, VAMC/UCSF, NCIRE, United States.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D062085:RNA, Long Noncoding / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000502:physiology*; D012878:Skin Neoplasms / Q000209:etiology / Q000517:prevention & control*; D014807:Vitamin D / Q000494:pharmacology*; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D062085:RNA, Long Noncoding; D018167:Receptors, Calcitriol; D014815:Vitamins; D014807:Vitamin D
keywords: Keratinocytes; Mice; Profiling; VDR; lncRNAs