Association of expression aberrances and genetic polymorphisms of lysyl oxidase with areca-associated oral tumorigenesis.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
LOX exerts oncogenic roles in areca-associated OSCC. This potential could be affected by the existence of LOX propeptide domain or genetic polymorphism.
Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
Tzong-Ming
TM
Shieh
Shu-Chun
SC
Lin
Chung-Ji
CJ
Liu
Shu-Shin
SS
Chang
Ti-Hsuan
TH
Ku
Kuo-Wei
KW
Chang
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001114:Areca / Q000737:chemistry*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects* / Q000378:metabolism; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D009361:Neoplasm Invasiveness / Q000473:pathology; D010936:Plant Extracts / Q000633:toxicity*; D011110:Polymorphism, Genetic; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D046888:Tissue Array Analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D010936:Plant Extracts; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D008249:Protein-Lysine 6-Oxidase