Int J Biol Sci 2019; 15(9):1802-1815. doi:10.7150/ijbs.34785
CHL1 suppresses tumor growth and metastasis in nasopharyngeal carcinoma by repressing PI3K/AKT signaling pathway via interaction with Integrin β1 and Merlin
1. Departments of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
2. Department of Clinical Oncology, The Seventh Affiliated Hospital, Sun Yat-sen University.
3. Departments of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
4. Departments of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
5. State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China;
6. Department of Nasopharyngeal, Sun Yat-Sen Cancer Center, Guangzhou, China.
7. Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Shenzhen University International Cancer Research Centre, Shenzhen University school of Medicine, Shenzhen, China.
8. Department of Orthopedics, Union Hospital, Tongji Medical College, Science and Technology of Huazhong University, Wuhan, China.
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) CHL1 in NPC. Down-regulation of CHL1 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 CHL1 could induce mesenchymal-epithelial transition (MET), a key step in preventing tumor invasion and metastasis. CHL1 could also cause the inactivation of RhoA/Rac1/Cdc42 signaling pathway and inhibit the formation of stress fiber, lamellipodia, and filopodia. CHL1 could co-localize with adhesion molecule Integrin-β1, the expression of CHL1 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 CHL1 could directly interact with integrin-β1 and link to Merlin, leading to the inactivation of integrin β1-AKT pathway. In conclusion, CHL1 is a vital tumor suppressor in the carcinogenesis of NPC.
Keywords: nasopharyngeal carcinoma, tumor suppressor gene, tumor invasion, tumor metastasis
Chen J, Jiang C, Fu L, Zhu CL, Xiang YQ, Jiang LX, Chen Q, Liu WM, Chen JN, Zhang LY, Liu M, Chen C, Tang H, Wang B, Tsao SW, Kwong DLW, Guan XY. CHL1 suppresses tumor growth and metastasis in nasopharyngeal carcinoma by repressing PI3K/AKT signaling pathway via interaction with Integrin β1 and Merlin. Int J Biol Sci 2019; 15(9):1802-1815. doi:10.7150/ijbs.34785. Available from http://www.ijbs.com/v15p1802.htm