Carcinogenesis Advance Access published online on November 6, 2003
Carcinogenesis, doi:10.1093/carcin/bgh006
© 2003 by Oxford University Press
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CARCINOGENESIS
1 Graduate Institute of Life Sciences, National Defense Medical Center, College of Medicine, National Taiwan University, Taipei, Taiwan
* Corresponding author. E-mail: jou{at}nhri.org.tw.
Received 24 July 2003
; revised 30 September 2003
; accepted 19 October 2003
Betel quid (BQ) chewing, a popular habit in numerous Asian countries including India and Taiwan, has a strong correlation with an increased risk of oral squamous cell carcinoma (OSCC). While substantial efforts have been made to test the cytotoxic, genotoxic and mutagenic effects of BQ extract and its components, the disease mechanisms underlying BQ-induced oral carcinogenesis remain obscure. Here, we show that a neuronal protein, microtubule-associated protein 2 (MAP2), was induced by BQ extract in cultured normal human oral keratinocytes (NHOKs). Subsequent analyses demonstrated that such induction was more eminent and consistent in the high-molecular-weight isoform of MAP2 (hmw-MAP2) than that in its low-molecular-weight counterpart (lmw-MAP2). Furthermore, we analyzed expression of hmw-MAP2 protein in 88 oral specimens consisting of clinicopathologically premalignant (leukoplakia) and malignant (OSCC) lesions, along with their adjacent normal mucosa. Immunohistochemistry revealed that, with the exposure to BQ, the hmw-MAP2 was overexpressed in 41.2% (7/17) of OSCC, 11.2% (1/9) of leukoplakia and none (0/19) of normal mucosa. In contrast, expression of the hmw-MAP2 was barely detected in BQ-free OSCC. These results suggest a significant correlation between expression of the hmw-MAP2 and BQ-associated progression of oral carcinogenesis (P = 0.0046). Interestingly, the hmw-MAP2 was found to preferentially express in histopathologically less differentiated OSCC (P = 0.014); the percentages of positive staining in poorly, moderately, and well differentiated OSCC were 62.5%, 21.4%, and 7.1%, respectively. However, BQ-chewing appeared to have marginal correlation with such propensity. Finally, we show that the majority of hmw-MAP2-positive poorly differentiated lesions were also histopathologically invasive. Taken together, these findings suggest the possibility that the hmw-MAP2 may be a diagnostic marker for BQ-chewing lesions and a potential therapeutic target. To our knowledge, this study has provided the first clinical implication that closely links a cytoskeletal protein to BQ-associated oral cancer.
Specific induction of the high-molecular-weight microtubule-associated protein 2 (hmw-MAP2) by betel quid extract in cultured oral keratinocytes: clinical implications in betel quid-associated oral squamous cell carcinoma (OSCC)
2 Department of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
3 Department of Otolaryngology, College of Medicine, National Taiwan University, Taipei, Taiwan
4 Division of Molecular and Genomic Medicine, National Health Research Institutes, Taipei, Taiwan
5 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
6 Graduate Institute of Life Sciences, National Defense Medical Center, College of Medicine, National Taiwan University, Taipei, Taiwan; Division of Molecular and Genomic Medicine, National Health Research Institutes, Taipei, Taiwan
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