Osteopontin production by TM4SF4 signaling drives a positive feedback autocrine loop with the STAT3 pathway to maintain cancer stem cell-like properties in lung cancer cells

Soo Im Choi; Seo Yoen Kim; Jei Ha Lee; Jung Yul Kim; Eun Wie Cho; In-Gyu Kim

doi:10.18632/oncotarget.21021

Osteopontin production by TM4SF4 signaling drives a positive feedback autocrine loop with the STAT3 pathway to maintain cancer stem cell-like properties in lung cancer cells

Oncotarget. 2017 Sep 18;8(60):101284-101297. doi: 10.18632/oncotarget.21021. eCollection 2017 Nov 24.

Authors

Soo Im Choi¹, Seo Yoen Kim¹, Jei Ha Lee^{1

2}, Jung Yul Kim^{1

2}, Eun Wie Cho³, In-Gyu Kim^{1

2}

Affiliations

¹ Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Yuseong-Gu, Daejeon 34057, Korea.
² Department of Radiation Biotechnology and Applied Radioisotope, Korea University of Science and Technology (UST), Yuseong-Gu, Daejeon 34057, Korea.
³ Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-Gu, Daejeon 34141, Korea.

Abstract

Transmembrane 4 L6 family proteins have been known to promote cancer. In this study, we demonstrated that transmembrane 4 L6 family member 4 (TM4SF4), which is induced by γ-radiation in non-small cell lung cancer (NSCLC) cells, is involved in epithelial-to-mesenchymal transition (EMT) and cancer stem cell (CSC) properties of NSCLC through the regulation of osteopontin (OPN). Forced TM4SF4 overexpression in A549 cells increased the secretion of OPN, which activates CD44 or integrin signaling and thus maintains EMT-associated CSC-like properties. OPN, known as a downstream target of β-catenin/T-cell factor 4 (TCF-4), was induced by up-regulated β-catenin via TM4SF4-driven phosphorylation of glycogen synthase kinase 3b (GSK3β). TCF4 complexed to promoter regions of OPN in TM4SF4-overexpressing A549 cells was also confirmed by chromatin immunoprecipitation. Knockout of either β-catenin or TCF4-suppressed OPN expression, demonstrating that both factors are essential for OPN expression in NSCLC cells. OPN secreted by TM4SF4/GSK3β/β-catenin signaling activated the JAK2/STAT3 or FAK/STAT3 pathway, which also up-regulates OPN expression in an autocrine manner and consequently maintains the self-renewal and metastatic capacity of cancer cells. Neutralizing antibody to OPN blocked the autocrine activation of OPN expression, consequently weakened the metastatic and self-renewal capacity of cancer cells. Collectively, our findings indicate that TM4SF4-triggered OPN expression is involved in the persistent reinforcement of EMT or cancer stemness by creating a positive feedback autocrine loop with JAK2/STAT3 or FAK/STAT3 pathways.

Keywords: TM4SF4; cancer stem cells; epithelial-to-mesenchymal transition; lung cancer; osteopontin.