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.
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.
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DOI：
10.18632/oncotarget.21021
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发表时间：
2017-11-24
期刊：
影响因子：
--
通讯作者：
Kim IG
中科院分区：
文献类型：
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作者：
Choi SI;Kim SY;Lee JH;Kim JY;Cho EW;Kim IG
已知跨膜4 L6家族蛋白可促进癌症。在本研究中，我们证实了γ辐射诱导的非小细胞肺癌细胞跨膜4L6家族成员4(TM4SF4)参与了非小细胞肺癌上皮向间充质转化和肿瘤干细胞特性的调节。在A549细胞中强制过表达TM4SF4会增加OPN的分泌，从而激活CD44或整合素信号，从而维持EMT相关的CSC样特性。OPN是β-连环蛋白/T细胞因子4(β-catenin/T-cell factor4，TCF4)的下游靶点，由TM4SF4介导的糖原合成酶激酶3b(GSK3GSK3β)的磷酸化诱导。染色质免疫沉淀法也证实了TCF4与OPN启动子区域的络合。剔除β-连环蛋白或TCF4-抑制骨桥蛋白的表达，表明这两个因素对骨桥蛋白在非小细胞肺癌细胞中的表达是必不可少的。TM4SF4/GSK3FAK/STAT3信号通路分泌的OPN激活了β/β/STAT3或FAK/STAT3通路，并以自分泌的方式上调OPN的表达，从而维持癌细胞的自我更新和转移能力。OPN中和抗体阻断了OPN表达的自分泌激活，从而削弱了癌细胞的转移和自我更新能力。综上所述，我们的发现表明，TM4SF4触发的OPN表达通过与JAK2/STAT3或FAK/STAT3通路建立正反馈自分泌循环，参与持续增强EMT或癌症的干性。
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.