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MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways

Oncogene volume 38, pages 6035–6050 (2019)Cite this article

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Abstract

Ovarian cancer is the most lethal gynecological malignancy due to the silent nature on its early onset and the rapid acquisition of drug resistance. Histologically heterogeneous, it includes several subtypes with different mutational landscapes, hampering the development of effective targeted therapies. Non-coding RNAs are emerging as potential new therapeutic targets in cancer. To search for a microRNA signature related to ovarian carcinomas and study its potential as effective targeted therapy, we examined the expression of 768 miRNA in a large collection of tumor samples and found miR-654-5p to be infraexpressed in ovarian serous carcinomas, the most common and aggressive type. Restoration of miR-654-5p levels reduced tumor cell viability in vitro and in vivo and impaired sphere formation capacity and viability of ovarian cancer patient-derived ascitic cells ex vivo. CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AKT pathways. Together, we unveiled the tumor suppressor function of miR-654-5p, suggesting that its restoration or co-targeting of CDCP1 and PLAGL2 may be an effective therapeutic approach for ovarian cancer.

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Acknowledgements

We are thankful to Drs. Diego Arango and Agueda Martinez, Dr. Sung Goo Park and Dr. Rosanna Paciucci for 9E10 c-Myc, anti-HAX1 and anti-RB and anti-p-RB antibodies, respectively. We thank Dr. Francesc Viñals, Dr. Barbara Vanderhyden, Dr. Antonio Rosato, Dr. Erich A. Nigg and the Ovarian Cancer Research Team for cell lines. We are grateful to Drs. Aroa Soriano and Luz Jubierre for experimental help. We acknowledge technical support from the Flow Cytometry Facility at Center of Genomic Regulation (CRG) and the Unitat d’Estadística i Bioinformàtica (UEB) and the Unitat d’Alta Tecnologia (UAT) at VHIR. We thank all our lab members for support and helpful discussions. This work was supported in part by grants from Instituto de la Mujer Dexeus (DEXEUS-B29/012), CIBER (CB16/12/00328), SGR (2017 SGR 1661), the Ministerio de Economia y Competitividad and Fondos FEDER (RTC-2015-3821-1), Instituto Carlos III (PI15/00238 to A.S. and PI17/00564 to M.F.S) and the Miguel Servet Program (CP13/00158 and CPII18/00027 to AS. and CPII16/00006 to MFS). AP and LS were supported by predoctoral VHIR fellowships and CJ by an AGAUR predoctoral fellowship (VHIR: PRED-VHIR-2014-11 and PRED-VHIR-2017; AGAUR: 2017FI_B_00095, respectively).

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Author notes

  1. Blanca Majem

    Present address: Cell Death Regulation Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08908, Spain

Authors and Affiliations

  1. Cell Cycle and Cancer Laboratory, Group of Biomedical Research in Urology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Spain

    Blanca Majem, Alfonso Parrilla, Leticia Suárez-Cabrera, Marta Barber, Andrea Marín, Gabriel Tamayo & Anna Santamaría

  2. Group of Translational Research in Child and Adolescent Cancer, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Spain

    Carlos Jiménez & Miguel F. Segura

  3. Department of Pathology, Vall Hebron University Hospital, 08035, Barcelona, Spain

    Josep Castellví

  4. Department of Biochemistry, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), CIBERONC, IdiPaz, 28029, Madrid, Spain

    Gema Moreno-Bueno

  5. Fundación MD Anderson Internacional, 28033, Madrid, Spain

    Gema Moreno-Bueno

  6. Departement of Gynaecology, University Hospital of Bellvitge (IDIBELL), University of Barcelona, Barcelona, 08908, Spain

    Jordi Ponce

  7. Department of Pathology Hospital Universitari Arnau de Vilanova, University of Lleida, IRB-Lleida, Lleida, 25198, Spain

    Xavier Matias-Guiu

  8. Department of Pathology Hospital Universitari de Bellvitge, IDIBELL, CIBERONC, 08908, Barcelona, Spain

    Xavier Matias-Guiu & Jaume Reventós

  9. Pathology Department, Hospital del Mar, 08003, Barcelona, Spain

    Francesc Alameda

  10. Department of Medical Oncology, Instituto Valenciano de Oncología (IVO), 46009, Valencia, Spain

    Ignacio Romero

  11. Department of Gynecological Oncology, Vall Hebron University Hospital, Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Spain

    José Luis Sánchez, Asunción Pérez-Benavente & Antonio Gil-Moreno

  12. Group of Biomedical Research in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), CIBERONC, 08035, Barcelona, Spain

    José Luis Sánchez, Asunción Pérez-Benavente & Antonio Gil-Moreno

  13. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), CIBERONC, 08908, Barcelona, Spain

    Sebastián Moran & Manel Esteller

  14. Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), 08036, Barcelona, Spain

    Manel Esteller

  15. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain

    Manel Esteller

  16. Department of Basic Sciences, Universitat Internacional de Catalunya, 08017, Barcelona, Spain

    Jaume Reventós

  17. Bellvitge Biomedical Research Institute (IDIBELL), 08908, Barcelona, Spain

    Marina Rigau

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  1. Blanca Majem
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  2. Alfonso Parrilla
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Contributions

BM and AS conceived and designed the study with help of AP and MFS. BM performed the miRNA and mRNA microarray analyses, and CJ carried out the mRNA microarray statistics and bioinformatics. BM and AP carried out all experiments and data analyses with the help of LS and MB. AM and GT provided technical support. ME and SM performed the DNA methylation analyses. JC analyzed and interpreted the IHC. JLS, APB, and AGM coordinated samples collection at HUVH and XMG, GM, FA, JP, and JAL provided with OC samples for the multicenter study. JR and MR initiated the miRNA screening. BM and AS wrote the manuscript with input from all other authors. AS supervised the project.

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Correspondence to Anna Santamaría.

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Majem, B., Parrilla, A., Jiménez, C. et al. MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways. Oncogene 38, 6035–6050 (2019). https://doi.org/10.1038/s41388-019-0860-0

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