<i>CHL1</i> suppresses tumor growth and metastasis in nasopharyngeal carcinoma by repressing PI3K/AKT signaling pathway via interaction with Integrin β1 and Merlin

Abstract

Deletion of Chromosome 3p is one of the most frequently detected genetic alterations in nasopharyngeal carcinoma (NPC). We reported the role of a novel 3p26.3 tumor suppressor gene (TSG) <i>CHL1</i> in NPC. Down-regulation of <i>CHL1</i> was detected in 4/6 of NPC cell lines and 71/95 (74.7%) in clinical tissues. Ectopic expressions of CHL1 in NPC cells significantly inhibit colony formation and cell motility in functional study. By up-regulating epithelial markers and down-regulating mesenchymal markers <i>CHL1</i> could induce mesenchymal-epithelial transition (MET), a key step in preventing tumor invasion and metastasis. <i>CHL1</i> could also cause the inactivation of RhoA/Rac1/Cdc42 signaling pathway and inhibit the formation of stress fiber, lamellipodia, and filopodia. <i>CHL1</i> could co-localize with adhesion molecule Integrin-β1, the expression of <i>CHL1</i> was positively correlated with Integrin-β1 and another known tumor suppressor gene (TSG) Merlin. Down-regulation of Integrin-β1 or Merlin was significantly correlated with the poor survival rate of NPC patients. Further mechanistic studies showed that <i>CHL1</i> could directly interact with integrin-β1 and link to Merlin, leading to the inactivation of integrin β1-AKT pathway. In conclusion, <i>CHL1</i> is a vital tumor suppressor in the carcinogenesis of NPC.