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Association of Expression Aberrances and Genetic Polymorphisms of Lysyl Oxidase with Areca-Associated Oral Tumorigenesis

Authors' Affiliations: ¹ Institute of Oral Biology, School of Dentistry, National Yang-Ming University; ² Oral and Maxillofacial Surgery, Taipei Mackay Memorial Hospital; ³ Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan

Requests for reprints: Kuo-Wei Chang, School of Dentistry, National Yang-Ming University, No. 155, Li-Nong Street, Section 2, Peitou, Taipei 112, Taiwan. Phone: 886-2-28267000; Fax: 886-2-28264053; E-mail: ckcw{at}ym.edu.tw.

Purpose: Areca nut use is the major cause of oral squamous cell carcinoma (OSCC) in Southern Asians. Areca nut contains a high level of free copper ions. Lysyl oxidase (LOX) is a copper-activated enzyme critical for extracellular matrix organization. Contradictory evidence has been put forward to suggest that LOX may be either an oncogenic or a suppressive element. This study investigated the oncogenic significance of LOX in areca-associated OSCC.

Experimental Design: The expression assays and polymorphism analysis were done to know the clinicopathologic implications of LOX status in OSCC. Knockdown and overexpression experiments were conducted to know the phenotypic effects of LOX on OSCC cells.

Results: Up-regulation of LOX mRNA and LOX protein expression in OSCCs relative to adjacent oral mucosa was found. Precancerous lesions had the highest LOX mRNA expression. Areca nut extract up-regulated LOX expression in oral epithelial cells. Knockdown of LOX induced cellular migration and invasion, but it reduced the anchorage-independent growth and xenographic tumorigenesis of OSCC cells. The reduction of migration and invasion by LOX overexpression was partially rescued by blockage of LOX activity. The Arg158Gln polymorphism was associated with earlier clinical stage of OSCC. Wild-type LOX overexpression induced anchorage-independent growth in OSCC cells, but this was not for LOXArg158Gln overexpression.

Conclusion: LOX exerts oncogenic roles in areca-associated OSCC. This potential could be affected by the existence of LOX propeptide domain or genetic polymorphism.