STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance

Abstract

Leptin (LEP) binds to the long form of the leptin receptor (LEPRb), leading to activation of multiple signaling pathways that are potential targets for disrupting the obesity-breast cancer link. In triple-negative breast cancer (TNBC), LEP is hypothesized to predominantly mediate its tumorigenic effects via a subpopulation of LEPRb-positive tumor cells termed cancer stem cells (CSCs) that can initiate tumors and induce tumor progression. Previously, we showed that LEP promotes CSC survival in vivo. Moreover, silencing LEPRb in TNBC cells compromised the CSC state. The mechanisms by which LEPRb regulates TNBC CSC intracellular signaling are not clear. We hypothesized that activation of LEPRb signaling is sufficient to drive CSC maintenance in TNBC. Here, we show that activation of LEPRb in non-CSCs isolated using our CSC reporter system resulted in a transition to the stem cell state. In CSCs, LEP induced STAT3 phosphorylation, whereas LEP did not induce STAT3 phosphorylation in non-CSCs. Introduction of constitutively active STAT3 into LEPRb-transfected non-CSCs significantly induced NANOG, SOX2, and OCT4 expression compared with control non-CSCs. To determine the intracellular phospho-tyrosine residue of LEPRb that is necessary for the induction of the stem cell state in non-CSCs, we transfected the tyrosine residue point mutants L985, F1077, and S1138 into non-CSCs. Non-CSCs transfected with the L985 mutant exhibited increased STAT3 phosphorylation, increased SOCS3 expression, and an induction of GFP expression compared with non-CSCs expressing the F1077 and S1138 mutants. Our data demonstrate that LEPRb-induced STAT3 activation is essential for the induction and maintenance of TNBC CSCs.

Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway

“…The suppression of phosphorylated STAT3 (p-STAT3) can induce apoptosis and inhibit metastasis in cancer [32,33]. In TNBC, poor prognosis and chemotherapy resistance are related to the activation of STAT3 [34]. It has been reported that activated STAT3 was mainly found in TNBC cells [13].…”

Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells

“…It has been reported that pluripotent transcription factors (SOX2, Oct4, Nanog, and c-Myc,) are involved in self-renewal of CSCs [13,14]. To explore the molecular mechanisms involved in PRR11 mediated self-renewal and tumorigenic potential of gastric CSCs, we first examined the expression of these genes in gastric CSCs upon PRR11 silencing.…”

Blocking of STAT3 activation by miR-491, acting via EGFR, is involved in metastasis of hepatocellular carcinoma cells through inhibiting cancer stem cell-like properties

“…Moreover, IL-6 and EZH2 activate STAT3 signaling to maintain the self-renewal and tumorigenic potential of GSCs [42,43]. STAT3 activation is essential for maintenance of TNBC stem cells [44]. Its activation also orients carcinoma cells towards a CSC phenotype [45], confirming the involvement of STAT3 signaling in acquisition of stem cell-like characteristics.…”