Novel oncogenic and chemoresistance-inducing functions of resistin in ovarian cancer cells require miRNAs-mediated induction of epithelial-to-mesenchymal transition

Abstract

Resistin plays a role in the growth, proliferation, angiogenesis, metastasis and therapeutic resistance in different cancers. However, such effects of resistin have never been evaluated in ovarian cancer, a deadly gynecological malignancy. We observed a significant induction of ovarian cancer cells’ growth, invasion and cisplatin resistance, and established a mechanism of resistin action that included induction of EMT and stemness, as evidenced by down-regulated epithelial marker e-cadherin and up-regulated mesenchymal markers vimentin/ ZEB1 and stemness markers sox2, oct4 and nanog. The mechanism also included suppression of tumor suppressor miRNAs, let-7a, miR-200c and miR-186. Over-expression of these miRNAs significantly reversed the resistin-mediated effects on invasion and chemoresistance. We further validated our results in vivo where resistin administration significantly enhanced tumor growth in mice. Our results provide first evidence for such oncogenic effects of resistin in ovarian cancer models and a rationale for future studies to further understand the mechanistic role of resistin in ovarian cancer invasiveness, metastasis and therapy resistance.

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

“…This cytokine induced platinum resistance, EMT, and stemness in vitro and in vivo by binding Toll-like receptor-4 (TLR4), and by stimulating the NF-κB-STAT3 pathway [119]. Moreover, STAT3 expression was associated with platinum resistance in EOC cells [120].…”

Resistin increases cisplatin-induced cytotoxicity in lung adenocarcinoma A549 cells via a mitochondria-mediated pathway

“…Liu's study found resistin could signi cantly increase ovarian cancer cell growth, colony formation, and invasion in 72 h. The IC50 of 25 ng/ml resistin + 2.5µM cisplatin group was about three times that of 2.5µM cisplatin group. While the growth of ovarian cancer cell was increased over three times by 25 ng/ml resistin in 72h [23]. So resistin could signi cantly increase ovarian cancer cells proliferation might partly due to that resistin decreased cisplatin-induced cytotoxicity.…”

Epigenetic control of autophagy in women’s tumors: role of non-coding RNAs

“…Besides targeting BECLIN 1, miR20a also targets ATG16 in breast cancer [107] , while miR376b also targets ATG4 in breast cancer [105] . Let-7a is a tumor suppressor miRNA known to down-regulate the RAS oncogenic pathway in a variety of cancers, and its high expression correlates with chemo-responsiveness, low invasiveness, and better survival in ovarian cancer patients [110,111] . In ovarian cancer, this miRNA was shown to prevent the formation of autophagosomes by targeting ATG4 (the LC3 processing enzyme), ATG9A, and ATG16L [94] .…”