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Int J Biol Sci. 2019 Jul 11;15(9):1802-1815. doi: 10.7150/ijbs.34785. eCollection 2019.

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

Author information

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
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.
4
Department of Nasopharyngeal, Sun Yat-Sen Cancer Center, Guangzhou, China.
5
Departments of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
6
Department of Orthopedics, Union Hospital, Tongji Medical College, Science and Technology of Huazhong University, Wuhan, China.
7
Departments of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
8
State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.

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) 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 invasion; tumor metastasis; tumor suppressor gene

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