hnRNPC induces isoform shifts in miR-21-5p leading to cancer development

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https://www.nature.com/articles/s12276-022-00792-2

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https://doi.org/10.1038/s12276-022-00792-2
 http://hdl.handle.net/11603/25167

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2022-06-21

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journal articles
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Park, S., Yang, H.D., Seo, JW. et al. hnRNPC induces isoform shifts in miR-21-5p leading to cancer development. Exp Mol Med (2022). https://doi.org/10.1038/s12276-022-00792-2

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Abstract

MicroRNA (miRNA) processing is a critical step in mature miRNA production. Its dysregulation leads to an increase in miRNA isoforms with heterogenous 5′-ends (isomiRs), which can recognize distinct target sites because of their shifted seed sequence. Although some miRNA genes display productive expression of their 5′-isomiRs in cancers, how their production is controlled and how 5′-isomiRs affect tumor progression have yet to be explored. In this study, based on integrative analyses of high-throughput sequencing data produced by our group and publicly available data, we demonstrate that primary miR-21 (pri-miR-21) is processed into the cancer-specific isomiR isomiR-21-5p | ±1, which suppresses growth hormone receptor (GHR) in liver cancer. Treatment with antagomirs against isomiR-21-5p | ±1 inhibited the in vitro tumorigenesis of liver cancer cells and allowed the recovery of GHR, whereas the introduction of isomiR-21-5p | ±1 mimics attenuated these effects. These effects were validated in a mouse model of spontaneous liver cancer. Heterogeneous nuclear ribonucleoprotein C and U2 small nuclear RNA auxiliary factor 2 were predicted to bind upstream of pre-miR-21 via a poly-(U) motif and influence Drosha processing to induce the production of isomiR-21-5p | ±1. Our findings suggest an oncogenic function for the non-canonical isomiR-21-5p | ±1 in liver cancer, and its production was shown to be regulated by hnRNPC.