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

被引:31
作者
Choi, Soo Im [1 ]
Kim, Seo Yoen [1 ]
Lee, Jei Ha [1 ,2 ]
Kim, Jung Yul [1 ,2 ]
Cho, Eun Wie [3 ]
Kim, In-Gyu [1 ,2 ]
机构
[1] Korea Atom Energy Res Inst, Dept Radiat Biol, Environm Radiat Res Grp, Daejeon 34057, South Korea
[2] Korea Univ Sci & Technol UST, Dept Radiat Biotechnol & Appl Radioisotope, Daejeon 34057, South Korea
[3] Korea Res Inst Biosci & Biotechnol, Rare Dis Res Ctr, Daejeon 34141, South Korea
关键词
cancer stem cells; epithelial-to-mesenchymal transition; lung cancer; osteopontin; TM4SF4; EPITHELIAL-MESENCHYMAL TRANSITION; HEPATOCELLULAR-CARCINOMA CELLS; TUMOR-INITIATING CELLS; BREAST-CANCER; JAK/STAT PATHWAY; SOLID TUMORS; IN-VITRO; GROWTH; LIVER; ACTIVATION;
D O I
10.18632/oncotarget.21021
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.-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 beta-catenin/T-cell factor 4 (TCF-4), was induced by up-regulated beta-catenin via TM4SF4-driven phosphorylation of glycogen synthase kinase 3b (GSK3 beta). TCF4 complexed to promoter regions of OPN in TM4SF4-overexpressing A549 cells was also confirmed by chromatin immunoprecipitation. Knockout of either beta-catenin or TCF4-suppressed OPN expression, demonstrating that both factors are essential for OPN expression in NSCLC cells. OPN secreted by TM4SF4/GSK3 beta/beta-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.
引用
收藏
页码:101284 / 101297
页数:14
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