Leukemia inhibitory factor promotes EMT through STAT3-dependent miR-21 induction

Abstract

// Xuetian Yue 1 , Yuhan Zhao 1 , Cen Zhang 1 , Jun Li 1 , Zhen Liu 1 , Juan Liu 1 , Wenwei Hu 1, 2 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ, USA 2 Department of Pharmacology, Rutgers State University of New Jersey, New Brunswick, NJ, USA Correspondence to: Wenwei Hu, e-mail: wh221@cinj.rutgers.edu Keywords: LIF, miR-21, epithelial-mesenchymal transition, STAT3 Received: September 07, 2015      Accepted: November 26, 2015      Published: December 24, 2015 ABSTRACT Leukemia inhibitory factor (LIF) is a multi-function cytokine. Its role in cancer is not well-understood. Recent studies including ours show that LIF is frequently overexpressed in many types of human tumors and promotes the progression and metastasis of tumors. However, the underlying mechanism of LIF’s promoting effects on tumor progression and metastasis is poorly defined. Epithelial-mesenchymal transition (EMT) plays an important role in tumor metastasis. This study reports that LIF promotes EMT in human tumor cells. Overexpression of LIF promotes tumor cells to acquire mesenchymal features, including morphological changes of cells from epithelial-like to mesenchymal-like, increased expression levels of mesenchymal markers and decreased expression of epithelial markers. Knockdown of endogenous LIF reverses EMT in cancer cells. We further identified that LIF induces the expression of microRNA-21 (miR-21), which in turn mediates the promoting effect of LIF on EMT. LIF induces miR-21 expression through the activation of STAT3. Importantly, blocking miR-21 function greatly abolished the promoting effect of LIF on EMT and the migration ability of cancer cells. Taken together, results from this study identified an important function and a novel underlying mechanism of LIF in EMT and tumor metastasis.