Author, as appears in the article.: Ejarque M; Ceperuelo-Mallafre V; Serena C; Pachon G; Nuñez-Alvarez Y; Terron-Puig M; Calvo E; Núñez-Roa C; Oliva-Olivera W; Tinahones F; Peinada MA; Vendrell J; Fernandez-Veledo S.

Department: Medicina i Cirurgia Ciències Mèdiques Bàsiques

URV's Author/s: Fernandez Veledo, Sonia / Vendrell Ortega, Juan José

Keywords: Proliferation Pathway Leptin Insulin-resistance Inflammation Dna methylation Cycloheximide Breast-cancer Body-weight Adipocytes

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-1?. 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.

Thematic Areas: Química Psicología Odontología Medicine (miscellaneous) Medicina iii Medicina ii Medicina i Interdisciplinar Immunology Farmacia Engenharias ii Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Cellular and molecular neuroscience Cell biology Cancer research Biotecnología

licence for use: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 20414889

Author's mail: sonia.fernandez@urv.cat juanjose.vendrell@urv.cat

Author identifier: 0000-0003-2906-3788 0000-0002-6994-6115

Record's date: 2023-02-18

Papper version: info:eu-repo/semantics/publishedVersion

Link to the original source: https://www.nature.com/articles/cddis2017209

Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/

Papper original source: Cell Death & Disease. 8 (5): e2802-

APA: Ejarque M; Ceperuelo-Mallafre V; Serena C; Pachon G; Nuñez-Alvarez Y; Terron-Puig M; Calvo E; Núñez-Roa C; Oliva-Olivera W; Tinahones F; Peinada MA; V (2017). Survivin, a key player in cancer progression, increases in obesity and protects adipose tissue stem cells from apoptosis. Cell Death & Disease, 8(5), e2802-. DOI: 10.1038/cddis.2017.209

Article's DOI: 10.1038/cddis.2017.209

Entity: Universitat Rovira i Virgili

Journal publication year: 2017

Publication Type: Journal Publications