511 lncRNA PVT1 is overexpressed in cutaneous squamous cell carcinoma and regulates apoptosis

Abstract

Cutaneous SCC (cSCC) represents the most frequently occurring cancer with metastatic potential accounting for 20% of all skin cancer-related deaths. The incidence of cSCC has been increasing alarmingly especially in Nordic countries. Long noncoding RNAs (lncRNAs) are operationally defined subclass of ncRNAs, representing transcripts that are larger than 200 nt that do not appear to have protein-coding potential and play important role in gene regulation. To identify candidate clinically relevant lncRNAs in cSCC, we performed RNA sequencing in human cSCCs. One of the most upregulated lncRNA in cSCC was plasmacytoma variant translocation 1 gene (PVT1). Results from RNAseq was validated in an independent set of samples by q-RT-PCR demonstrating the overexpression of PVT in cSCC. RNAScope single-molecule in situ hybridization and analysis of the subcellular distribution of PVT1 lncRNA demonstrated that PVT1 is localized to the cell nucleus. GapmeR-mediated knockdown of PVT1 resulted in increased apoptosis. Bioinformatic analysis of the PVT1 promoter identified binding sites for STAT1 and STAT3, confirmed by ENCODE chromatin-immunoprecipitation data. Results obtained with chemical inhibitors demonstrated that PVT1 is regulated by the components of JAK/STAT pathway. Our study suggests an oncogenic role for PVT1 in cSCC and that it is regulated by the JAK/STAT-pathway.