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Splicing regulator SLU7 preserves survival of hepatocellular carcinoma cells and other solid tumors via oncogenic miR-17-92 cluster expression

Oncogene volume 35, pages 4719–4729 (2016)Cite this article

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Abstract

Resisting death is a central hallmark of cancer cells. Tumors rely on a number of genetic mechanisms to avoid apoptosis, and alterations in mRNA alternative splicing are increasingly recognized to have a role in tumorigenesis. In this study, we identify the splicing regulator SLU7 as an essential factor for the preservation of hepatocellular carcinoma (HCC) cells viability. Compared with hepatocytes, SLU7 expression is reduced in HCC cells; however, further SLU7 depletion triggered autophagy-related cellular apoptosis in association with the overproduction of reactive oxygen species. Remarkably, these responses were not observed in primary human hepatocytes or in the well-differentiated HepaRG cell line. Mechanistically, we demonstrate that SLU7 binds the C13orf25 primary transcript in which the polycistronic oncomir miR-17-92 cluster is encompassed, and is necessary for its processing and expression. SLU7 knockdown altered the splicing of the C13orf25 primary transcript, and markedly reduced the expression of its miR-17, miR-20 and miR-92a constituents. This led to the upregulation of CDKN1A (P21) and BCL2L11 (BIM) expression, two bona fide targets of the miR-17-92 cluster and recognized mediators of its pro-survival and tumorigenic activity. Interestingly, altered splicing of miR-17-92 and downregulation of miR-17 and miR-20 were not observed upon SLU7 knockdown in non-transformed hepatocytes, but was found in other (HeLa, H358) but not in all (Caco2) non-hepatic tumor cells. The functional relevance of miR-17-92 dysregulation upon SLU7 knockdown was established when oxidative stress, autophagy and apoptosis were reversed by co-transfection of HCC cells with a miR-17 mimic. Together, these findings indicate that SLU7 is co-opted by HCC cells and other tumor cell types to maintain survival, and identify this splicing regulator as a new determinant for the expression of the oncogenic miR-17-92 cluster. This novel mechanism may be exploited for the development of antitumoral strategies in cancers displaying such SLU7-miR-17-92 crosstalk.

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Acknowledgements

FIMA and the ‘UTE project CIMA’; RTICC-RD06 00200061; CIBERehd; Grant numbers: FIS PI10/02642, PI13/00359, PI10/00038, PI13/00385 from Instituto de Salud Carlos III (ISCIII) co-financed by ‘Fondo Europeo de Desarrollo Regional’ (FEDER) ‘Una manera de hacer Europa’; Gobierno de Navarra; ‘Torres Quevedo’ and ‘Ramón y Cajal’ contracts from Ministerio de Educación; PFIS fellowship from ISCIII; FPU fellowship from Ministerio de Educación, Cultura y Deporte; Fundaciónes Mario Losantos, MTorres, Eugenio Rodríguez Pascual; Agustina Damboriena Support.

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Author notes

  1. R Urtasun and M Elizalde: These authors contributed equally to this work.

  2. M A Ávila and C Berasain: These authors share senior authorship.

Authors and Affiliations

  1. Division of Hepatology, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona,, Spain

    R Urtasun, M Elizalde, M Azkona, M U Latasa, O García-Irigoyen, M G Fernández-Barrena, J Prieto, M A Ávila & C Berasain

  2. IDISNA, Navarra Institute for Health Research,, Pamplona,, Spain

    R Urtasun, M U Latasa, M G Fernández-Barrena, S Vicent, M M Alonso, M A Ávila & C Berasain

  3. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain

    I Uriarte, J Muntané, J Prieto, M A Ávila & C Berasain

  4. Division of Oncology, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain

    S Vicent & M M Alonso

  5. Oncology Division, Clínica Universidad de Navarra, Pamplona, Spain

    M M Alonso

  6. Department of General Surgery, ‘Virgen del Rocío’-‘Virgen Macarena’, University Hospital/IBiS/CSIC/Universidad de Sevilla, Sevilla, Spain

    J Muntané

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  1. R Urtasun
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Urtasun, R., Elizalde, M., Azkona, M. et al. Splicing regulator SLU7 preserves survival of hepatocellular carcinoma cells and other solid tumors via oncogenic miR-17-92 cluster expression. Oncogene 35, 4719–4729 (2016). https://doi.org/10.1038/onc.2015.517

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