The activation of leptin-mediated survivin is limited by the inducible suppressor SOCS-3 in MCF-7 cells

Abstract

Although leptin has been found to be implicated in obesity-related breast carcinogenesis in postmenopausal women, the molecular mechanisms involved are yet to be defined. Recently, the antiapoptotic gene survivin has been recognized as a target gene for leptin in breast cancer. The aim of this study was to investigate the effect of leptin on the expression of survivin and on the transcriptional activity of its promoter in MCF-7 breast cancer cells. We also studied the potential involvement of SOCS-3 (a negative regulator of leptin's main signaling pathway JAK2/STAT3) in the expression of leptin-mediated survivin. Our results showed a significant increase in the mRNA (dose-dependent increase of 40-70%) and protein expression levels of survivin 24 h post-leptin treatment, which was followed by a significant decrease at 48 and 72 h (of 60-70%). In accordance, a chromatin immunoprecipitation assay revealed an initial strong binding of STAT3 to the survivin promoter, which was no longer detected after 24 h. Myc/mad/max network proteins and histone H3 acetylation status were not found to contribute to the expression of leptin-mediated survivin. Furthermore, a protein immunoprecipitation assay detected an enhanced SOCS-3 binding to the long isoform of leptin's receptor (Ob-Rb) 48 and 72 h after leptin administration, thus conferring inhibition to leptin signaling. In conclusion, our findings suggest, for the first time to our knowledge, that the effect of leptin on the antiapoptotic gene survivin is limited by the inhibitory role of SOCS-3 in the leptin-activated JAK2/STAT3 signaling pathway in MCF-7 breast cancer cells.

Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p

“…The suppressor of cytokine signaling 3 (SOCS3), a primary member of the SOCS family of proteins, is a negative feedback regulator of the JAK/STAT signaling pathway [9]. Recent studies have revealed SOCS3 overexpression can inhibit cell proliferation and anchorage-independent growth in breast cancer cells [10], whereas down-regulation of SOCS3 reflects a poor prognosis in gastric cancer and hepatocellular carcinoma [11, 12]. However, whether SOCS3 acts as the target of miR-222-3p, thereby contributing to gemcitabine resistance in NSCLC, remains unclear.…”

Constitutive activation of STAT3 in breast cancer cells: A review

“…68 SOCS-3 was found to be inhibiting the expression of antiapoptotic gene Survivin in Leptin-mediated activation of the JAK2/STAT3 signaling pathway in MCF-7 BC cells. 69 Correlation between Survivin and SOCS-3 expression in Leptin expressing BC patient samples are needed to confirm this finding in a clinical context.…”

“…High levels of STAT3 expression were associated with the early stages of BC development and patients in the control group with obesity showed higher expression of SOCS‐3, thus suggesting that SOCS‐3 expression can be used as biomarker for risk assessment in obese overweight subjects . SOCS‐3 was found to be inhibiting the expression of antiapoptotic gene Survivin in Leptin‐mediated activation of the JAK2/STAT3 signaling pathway in MCF‐7 BC cells . Correlation between Survivin and SOCS‐3 expression in Leptin expressing BC patient samples are needed to confirm this finding in a clinical context.…”

Multifaceted Leptin Network: The Molecular Connection Between Obesity and Breast Cancer

“…Leptin also regulates cyclin D1 expression in several other breast cancer cells [87,109,110] and luminal epithelial cells of mouse MMTV-Wnt1 mammary tumors [111]. Leptin-mediated increased expression of survivin, a member of inhibitor-of-apoptosis proteins (IAP) family, has been reported in breast cancer cells [52,112,113]. Our recent work showing leptin-mediated increased survivin expression implicates a complex upstream network involving activation of EGFR-Notch1 axis.…”