Researchers Identify RNAs Involved in Tumor Growth

Cancer researchers have linked a specific long non-coding RNA (lncRNA) to the growth and metastasis of certain types of cancer.

Long non-coding RNAs (lncRNAs) are considered to be non-protein coding transcripts longer than 200 nucleotides. This somewhat arbitrary limit distinguishes lncRNAs from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. LncRNAs have been found to be involved in numerous biological roles including imprinting, epigenetic gene regulation, cell cycle and apoptosis, and metastasis and prognosis in solid tumors. Most lncRNAs are expressed only in a few cells rather than whole tissues, or they are expressed at very low levels, making them difficult to study.

Investigators at the Medical University of South Carolina (Charleston, SC, USA) were studying the contribution of lncRNAs to tumor progression and the regulatory mechanisms driving their expression.

They reported in the August 21, 2017, online edition of the journal Nature Cell Biology that they had characterized the binding of the heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) to a nucleic acid structural element located in exon 12 of PNUTS (also known as PPP1R10) pre-RNA, which regulated its alternative splicing. HnRNP E1 release from this structural element, following its silencing, nucleocytoplasmic translocation, or in response to transforming growth factor beta (TGFbeta), allowed alternative splicing and generated a non-coding isoform of PNUTS.

Functionally the lncRNA called PNUTS was shown to serve as a competitive sponge for the microRNA miR-205 during epithelial–mesenchymal transition (EMT). In mesenchymal breast tumor cells and in breast tumor samples, the expression of lncRNA-PNUTS was elevated and correlated with levels of ZEB1 (Zinc finger E-box-binding homeobox 1) mRNAs. Simply put, breast and lung tumors grew faster and larger when their cells contained more PNUTS lncRNA.

Thus, PNUTS was determined to be a bifunctional RNA encoding both PNUTS mRNA and lncRNA-PNUTS, each eliciting distinct biological functions. While PNUTS mRNA was ubiquitously expressed, lncRNA-PNUTS appeared to be tightly regulated dependent on the status of hnRNP E1 and tumor context.

"My prediction is that this mechanism did not evolve to make just one long non-coding RNA," said senior author Dr. Philip H. Howe, professor of biochemistry and molecular biology at the Medical University of South Carolina. "There are probably others that are generated in this same fashion."

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