Survivin, a key player in cancer progression, increases in obesity and protects adipose tissue stem cells from apoptosis

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.

Crohn's Disease Disturbs the Immune Properties of Human Adipose-Derived Stem Cells Related to Inflammasome Activation

“…Moreover, it has been demonstrated that a pro-inflammatory stimulus such as tumor necrosis factor α (TNF-α) can stimulate the proliferation of adipocyte precursors ( Zubkova et al., 2016 ). Accordingly, precursors may be conditioned by the systemic inflammatory environment characteristic of CD, as previously described in other inflammatory-based diseases, including obesity, whereby an activation of the ASC niche occurs through an increase in ASC proliferative capacities ( Pachon-Pena et al., 2016 , Serena et al., 2016 ) and a decrease in their sensitivity to apoptosis ( Ejarque et al., 2017 ).…”

Mammary Adipose Tissue Control of Breast Cancer Progression: Impact of Obesity and Diabetes

“…Survivin is an antiapoptotic protein strongly linked to cancer cell growth. Consistently, its increase in obesity protects MSCs from apoptosis and controls adipocyte lipolysis and lipid storage and may contribute to cancer progression (77,78). Increased lipid content and external lipid stimuli largely modify adipocyte-BC cell communication.…”

Emerging Importance of Survivin in Stem Cells and Cancer: the Development of New Cancer Therapeutics

“…CD44 + /CD105 + human amniotic fluid MSCs, that proliferate rapidly and are ideal for stem cell transplantation, also express high levels of survivin [ 39 ]. The involvement of hematopoietic adipocyte-derived stem cells (ASCs) in apoptotic resistance displayed by adipocyte tissue in obese subjects was correlated to upregulated survivin expression [ 40 ]. Keratinocyte Stem Cells (KSCs) show high expression of survivin, that plays a prominent role in preventing abnormal mitosis in these cells [ 41 , 42 ].…”