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.