Original Article

Citation: Cell Death and Disease (2017) 8, e2802; doi:10.1038/cddis.2017.209
Published online 18 May 2017

Survivin, a key player in cancer progression, increases in obesity and protects adipose tissue stem cells from apoptosis
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Miriam Ejarque1,2,8, Victòria Ceperuelo-Mallafré1,2,8, Carolina Serena1,2, Gisela Pachón2,3,4, Yaiza Núñez-Álvarez5, Margarida Terrón-Puig1, Enrique Calvo1,2, Catalina Núñez-Roa1,2, Wilfredo Oliva-Olivera6,7, Francisco J Tinahones6,7, Miguel Angel Peinado5, Joan Vendrell1,2 and Sonia Fernández-Veledo1,2

  1. 1Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgili, Tarragona, Spain
  2. 2CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
  3. 3Department of Dermatology, Program of Excellence in Glycosciences, Brigham & Women’s Hospital/Harvard Medical School, Boston, MA, USA
  4. 4Department of Medicine, Program of Excellence in Glycosciences, Brigham & Women’s Hospital/Harvard Medical School, Boston, MA, USA
  5. 5Health Sciences Research Institute Germans Trias i Pujol, Institute of Predictive and Personalized Medicine of Cancer, Badalona, Spain
  6. 6CIBER de la Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain
  7. 7Laboratory of Biomedical Research, Virgen de la Victoria Clinical University Hospital, Málaga, Spain

Correspondence: J Vendrell or S Fernández-Veledo, Endocrinology, Pere Virgili, Research Unit,University Hospital of Tarragona Joan XXIII, c/o Dr Mallafré Guasch, 4, Tarragona 43007, Spain. Tel: +34 977 29 58 00 Ext 3401; Fax: +34 977 29 58 23; E-mail: jvo@comt.es or sonia.fernandezveledo@gmail.com

8Co-first authors.

Received 11 January 2017; Revised 3 April 2017; Accepted 10 April 2017

Edited by G Raschellà

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Abstract

Adipose tissue (AT) has a central role in obesity-related metabolic imbalance through the dysregulated production of cytokines and adipokines. In addition to its known risk for cardiovascular disease and diabetes, obesity is also a major risk for cancer. We investigated the impact of obesity for the expression of survivin, an antiapoptotic protein upregulated by adipokines and a diagnostic biomarker of tumor onset and recurrence. In a cross-sectional study of 111 subjects classified by body mass index, circulating levels of survivin and gene expression in subcutaneous AT were significantly higher in obese patients and positively correlated with leptin. Within AT, survivin was primarily detected in human adipocyte-derived stem cells (hASCs), the adipocyte precursors that determine AT expansion. Remarkably, survivin expression was significantly higher in hASCs isolated from obese patients that from lean controls and was increased by proinflammatory M1 macrophage soluble factors including IL-1β. Analysis of survivin expression in hASCs revealed a complex regulation including epigenetic modifications and protein stability. Surprisingly, obese hASCs showed survivin promoter hypermethylation that correlated with a significant decrease in its mRNA levels. Nonetheless, a lower level of mir-203, which inhibits survivin protein translation, and higher protein stability, was found in obese hASCs compared with their lean counterparts. We discovered that survivin levels determine the susceptibility of hASCs to apoptotic stimuli (including leptin and hypoxia). Accordingly, hASCs from an obese setting were protected from apoptosis. Collectively, these data shed new light on the molecular mechanisms governing AT expansion in obesity through promotion of hASCs that are resistant to apoptosis, and point to survivin as a potential new molecular player in the communication between AT and tumor cells. Thus, inhibition of apoptosis targeting survivin might represent an effective strategy for both obesity and cancer therapy.