An SLCO2B1 mRNA Isoform Acts as a Noncoding RNA to Drive Cancer Progression by Triggering Protein Biosynthesis.

UNLABELLED: The eukaryotic 5' untranslated region (5' UTR) canonically influences mRNA translation efficiency. Accumulating evidence has demonstrated that alternative promoters generate distinct transcription start sites (TSS), producing many mRNA isoforms with divergent 5' UTR sequences. Herein, we comprehensively analyzed the 5' UTR sequence structure and protein abundance of RNA transcripts with altered TSSs in hepatocellular carcinoma (HCC). The analysis uncovered an mRNA isoform of solute carrier organic anion transporter family member 2B1 (SLCO2B1), named SLCO2B1-isoformNovel (SLCO2B1-isoN), that was highly expressed in HCC and correlated with poor patient prognosis but did not encode a detectable protein product. The 5' end stem-loop of SLCO2B1-isoN abrogated its translational capacity and turned it into a noncoding RNA. The SLCO2B1-isoN noncoding isoform stabilized fragile X messenger ribonucleoprotein 1 (FMR1) to trigger HCC progression by facilitating de novo protein biosynthesis. Targeting SLCO2B1-isoN effectively inhibited orthotopic tumor xenograft growth and metastasis in vivo. In conclusion, this study revealed a noncoding isoform of SLCO2B1 mRNA and highlighted the dual characteristics of mRNAs harboring protein-coding and noncoding isoforms.

SIGNIFICANCE: A tumor-promoting SLCO2B1 isoform features an altered 5' end stem-loop that abrogates translation, establishing that the 5' UTR structure impacts noncoding RNA generation and revealing a promising category of cancer therapeutic targets.