Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs

Ivan Vannini,Francesca Fanini,Samanta Salvi,Linda Fabris,Erika Bandini,Han Liang,Ramana V Davuluri,Massimo Negrini,George A Calin,Manuela Ferracin,Cecilia Fernandez-Cymering,Hui Ling,Kishore B Challagundla,Xinna Zhang,Amelia Cimmino,Barbara J Gitlitz,Cristina Ivan,Lu Chen,Silvia Carloni,Ite A Laird-Offringa,Mariam Murtadha,Patrick Nana‐Sinkam ,María Angélica Cortez ,Zhengguang Guo ,Petra Wise ,Shuxing Zhang,Dino Amadori,Melissa Crawford,Paolo Neviani,Giorgia Paliaga,Leng Han,Meropi Plousiou,Mirco Raffini,Muller Fabbri

doi:10.1038/s41467-017-01562-9

Abstract

The transcribed ultraconserved regions (T-UCRs) encode long non-coding RNAs implicated in human carcinogenesis. Their mechanisms of action and the factors regulating their expression in cancers are poorly understood. Here we show that high expression of uc.339 correlates with lower survival in 210 non-small cell lung cancer (NSCLC) patients. We provide evidence from cell lines and primary samples that TP53 directly regulates uc.339. We find that transcribed uc.339 is upregulated in archival NSCLC samples, functioning as a decoy RNA for miR-339-3p, -663b-3p, and -95-5p. As a result, Cyclin E2, a direct target of all these microRNAs is upregulated, promoting cancer growth and migration. Finally, we find that modulation of uc.339 affects microRNA expression. However, overexpression or downregulation of these microRNAs causes no significant variations in uc.339 levels, suggesting a type of interaction for uc.339 that we call “entrapping”. Our results support a key role for uc.339 in lung cancer.

Highlights

The transcribed ultraconserved regions (T-UCRs) encode long non-coding RNAs implicated in human carcinogenesis
We previously described the upregulation of uc.[339] in colorectal cancer (CRC) primary samples[2], and another report confirmed an oncogenic role for uc.[339] in HCC9, limited to in vitro experiments
The mechanism of action and regulation of uc.[339] and T-UCRs in general are currently unknown. It is unclear how T-UCR dysregulation occurs in cancerous tissues, and how they contribute to cancer cell increased growth and invasiveness

Summary

Introduction

The transcribed ultraconserved regions (T-UCRs) encode long non-coding RNAs implicated in human carcinogenesis. Their mechanisms of action and the factors regulating their expression in cancers are poorly understood. Cancer is a complex genetic disease driven by dysregulation of protein-coding genes, and of non-coding RNAs (ncRNAs) Among the latter group, microRNAs (miRNAs) are the most widely studied, but other families of ncRNAs are emerging as involved in human carcinogenesis. The ultraconserved regions (UCRs) are a family of genomic sequences longer than 200 base pairs (bp) with 100% identity between orthologous regions of the human, murine, and rat genomes[1] We previously identified their transcriptional activity and named these as transcribed UCRs (T-UCR) genes[2]. Our results support a key role for uc.[339] in lung cancer

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Results

Conclusion