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TsRNA signatures in cancer.

ABSTRACT: Small, noncoding RNAs are short untranslated RNA molecules, some of which have been associated with cancer development. Recently we showed that a class of small RNAs generated during the maturation process of tRNAs (tRNA-derived small RNAs, hereafter "tsRNAs") is dysregulated in cancer. Specifically, we uncovered tsRNA signatures in chronic lymphocytic leukemia and lung cancer and demonstrated that the ts-4521/3676 cluster (now called "ts-101" and "ts-53," respectively), ts-46, and ts-47 are down-regulated in these malignancies. Furthermore, we showed that tsRNAs are similar to Piwi-interacting RNAs (piRNAs) and demonstrated that ts-101 and ts-53 can associate with PiwiL2, a protein involved in the silencing of transposons. In this study, we extended our investigation on tsRNA signatures to samples collected from patients with colon, breast, or ovarian cancer and cell lines harboring specific oncogenic mutations and representing different stages of cancer progression. We detected tsRNA signatures in all patient samples and determined that tsRNA expression is altered upon oncogene activation and during cancer staging. In addition, we generated a knocked-out cell model for ts-101 and ts-46 in HEK-293 cells and found significant differences in gene-expression patterns, with activation of genes involved in cell survival and down-regulation of genes involved in apoptosis and chromatin structure. Finally, we overexpressed ts-46 and ts-47 in two lung cancer cell lines and performed a clonogenic assay to examine their role in cell proliferation. We observed a strong inhibition of colony formation in cells overexpressing these tsRNAs compared with untreated cells, confirming that tsRNAs affect cell growth and survival.

SUBMITTER: Balatti V

PROVIDER: S-EPMC5544330 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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tsRNA signatures in cancer.

Balatti Veronica V Nigita Giovanni G Veneziano Dario D Drusco Alessandra A Stein Gary S GS Messier Terri L TL Farina Nicholas H NH Lian Jane B JB Tomasello Luisa L Liu Chang-Gong CG Palamarchuk Alexey A Hart Jonathan R JR Bell Catherine C Carosi Mariantonia M Pescarmona Edoardo E Perracchio Letizia L Diodoro Maria M Russo Andrea A Antenucci Anna A Visca Paolo P Ciardi Antonio A Harris Curtis C CC Vogt Peter K PK Pekarsky Yuri Y Croce Carlo M CM

Proceedings of the National Academy of Sciences of the United States of America 20170710 30

Small, noncoding RNAs are short untranslated RNA molecules, some of which have been associated with cancer development. Recently we showed that a class of small RNAs generated during the maturation process of tRNAs (tRNA-derived small RNAs, hereafter "tsRNAs") is dysregulated in cancer. Specifically, we uncovered tsRNA signatures in chronic lymphocytic leukemia and lung cancer and demonstrated that the ts-4521/3676 cluster (now called "ts-101" and "ts-53," respectively), ...[more]

PMID: 28696308

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Project description:BACKGROUND:Transfer RNA-derived small RNAs (tsRNAs) are a recently discovered form of non-coding RNA capable of regulating myriad physiological processes. The role of tsRNAs in hMSC adipogenic differentiation, however, remains incompletely understood. The purpose of this study was to identify the novel tsRNA-16902 as a regulator of hMSC adipogenic differentiation. METHODS:In this study, we conducted transcriptomic sequencing of hMSCs after inducing their adipogenic differentiation, and we were thereby able to clarify the molecular mechanism underlying the role of tsRNA-16902 in this context via a series of molecular biology methods. RESULTS:When we knocked down tsRNA-16902 expression, this impaired hMSC adipogenic differentiation and associated marker gene expression. Bioinformatics analyses further revealed tsRNA-16902 to target retinoic acid receptor ? (RAR?). Luciferase reporter assays also confirmed the ability of tsRNA-16902 to bind to the RAR? 3'-untranslated region. Consistent with this, RAR? overexpression led to impaired hMSC adipogenesis. Further analyses revealed that Smad2/3 phosphorylation was increased in cells that either overexpressed RAR? or in which tsRNA-16902 had been knocked down. We also assessed the adipogenic differentiation of hMSCs in which tsRNA-16902 was knocked down and at the same time a Smad2/3 inhibitor was added to disrupt Smad2/3 phosphorylation. The adipogenic differentiation of hMSCs in which tsRNA-16902 was knocked down was further enhanced upon the addition of a Smad2/3 signaling inhibitor relative to tsRNA-16902 knockdown alone. CONCLUSIONS:Through a comprehensive profiling analysis of tsRNAs that were differentially expressed in the context of hMSC adipogenic differentiation, we were able to identify tsRNA-16902 as a previously uncharacterized regulator of adipogenesis. tsRNA-16902 is able to regulate hMSC adipogenic differentiation by targeting RAR? via the Smad2/3 signaling pathway. Together, our results may thus highlight novel strategies of value for treating obesity.

Dataset Information

TsRNA signatures in cancer.

Publications

tsRNA signatures in cancer.

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