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.
Highlights
Epithelial-to-mesenchymal transition (EMT) is a cellular process by which epithelial cells lose cell polarity and cell-cell adhesion properties by cytoskeleton reorganization, trans-differentiating into mesenchymal cells
To determine whether TM4SF4 is associated with epithelial-to-mesenchymal transition (EMT) or cancer stem cell (CSC) characteristics, changes in metastatic activity or representative EMT markers were investigated according to TM4SF4 knockout or overexpression (Figure 1B)
We suggest that TM4SF4 up-regulates OPN expression by triggering the GSK3β/β-catenin signaling pathway and that secreted OPN persistently activates the Janus kinase 2 (JAK2)/STAT3 pathway or www.impactjournals.com/oncotarget via SRC/focal adhesion kinase (FAK)/STAT3 pathway autocrine signaling for EMT-associated CSC-like properties in non-small cell lung cancer (NSCLC) cells (Figure 6)
Summary
Epithelial-to-mesenchymal transition (EMT) is a cellular process by which epithelial cells lose cell polarity and cell-cell adhesion properties by cytoskeleton reorganization, trans-differentiating into mesenchymal cells. EMT is involved in the acquisition of cancer stem cell (CSC) properties, which lead to chemo- and radio-therapeutic resistance and self-renewal of cancer cells, thereby facilitating tumor recurrence. Tumor cells take advantage of EMT as an intermediary phenotype to achieve self-renewal capacity of CSC [5]. The Tumor microenvironment is known as a critical regulator of EMT or CSC-like properties that facilitate metastatic dissemination [6]. OPN is involved in a variety of physiological events, including regulation of bone formation, tissue repair, and immune reaction [7–9]. It has been recognized as a key component of the EMT-associated pathogenic events in a variety of tumor types. OPN has been reported to reinforce stem cell-like properties and to promote γ-radiation resistance in glioblastoma and hepatocellular carcinoma [14, 15]
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