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).
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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 pre-malignant (leukoplakia) and malignant (OSCC) lesions, along with their adjacent normal mucosa. Immunohistochemistry revealed that, with the exposure to BQ, the hmw-MAP2 was over-expressed 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. (+info)
Lack of correlation of betel nut chewing, tobacco smoking, and alcohol consumption with telomerase activity and the severity of oral cancer.
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BACKGROUND: Oral cancer is one of the most frequent cancers. A strong association has been found between oral cancer incidence and the use of betel nut, alcohol, and tobacco. Telomerase activity (TA) has also been shown to play a role in carcinogenesis. We therefore surveyed the consumption habits of betel nut chewing, alcohol drinking, and tobacco smoking in oral cancer patients and evaluated the association of these habits with TA level and clinical stage. METHODS: In total, 154 oral cancer patients were recruited. TA was measured in paired (grossly normal and cancerous) tissues using a polymerase chain reaction-based enzyme immunoassay. Associations of these factors with clinical stage and TA level were analyzed using the Pearson chi-square test. RESULTS: In these patients, 86.4%, 61.0%, and 83.3% used betel nut, alcohol, and tobacco, respectively. For all tissue assayed, 80.5% of cancerous and 3.2% of grossly normal mucosae were positive for TA. However, neither clinical stage nor TA level in cancerous tissues had a statistical association with the use of individual substances (betel nut, alcohol, and tobacco) or their combined use. CONCLUSION: Even though the habitual uses of these substances have been previously reported to be associated with oral cancer incidence, we found a lack of correlation with TA level or with disease severity in our study. These results imply that these consumption habits might only be associated with the early stages of oral cancer development, while the later stages of cancer progression may be more associated with other external factors or dependent on host cellular factors, all of which require confirmation through further investigations. (+info)
High-risk human papillomaviruses may have an important role in non-oral habits-associated oral squamous cell carcinomas in Taiwan.
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To evaluate the etiologic role of human papillomavirus (HPV) in oral carcinogenesis, DNA samples were purified from 103 oral squamous cell carcinoma (OSCC) and 30 normal oral mucosal (NOM) specimens. A nested polymerase chain reaction, DNA sequencing, and gene-chip HPV typing were used to identify multiple HPV types in our samples. We found that the positive rates of all HPV types and of high-risk HPV types were significantly higher in OSCC samples (49.5% and 41.7%, respectively) than in NOM samples (6/30 [20%; P < .01] and 5/30 [17%; P < .05], respectively) and significantly higher in non-oral habits (OH)-associated OSCC samples (31/51 [61%] and 28/51 [55%], respectively) than in OH-associated OSCC samples (20/52 [38%; P < .05] and 15/52 [29%; P < .001], respectively). High-risk HPV types and all HPV types had odds ratios of 3.97 (P = .0097) and 3.92 (P = .006), respectively. Our results suggest that HPVs, particularly high-risk HPVs, might be associated with the development of OSCCs, especially the non-OH-associated OSCCs. (+info)
Oral mucosal lesions associated with use of quid.
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Quid is a mixture of substances that is placed in the mouth or actively chewed over an extended period, thus remaining in contact with the mucosa. It usually contains one or both of 2 basic ingredients, tobacco and areca nut. Betel quid or paan is a mixture of areca nut and slaked lime, to which tobacco can be added, all wrapped in a betel leaf. The specific components of this product vary between communities and individuals. The quid habit has a major social and cultural role in communities throughout the Indian subcontinent, Southeast Asia and locations in the western Pacific. Following migration from these countries to North America, predominantly to inner city areas, the habit has remained prevalent among its practitioners. Many dentists are unaware of the prevalence of the quid or paan habit in the Asian patient population. The recognition of the role of such products in the development of oral precancer and cancer is of great importance to the dental practitioner. A variety of oral mucosal lesions and conditions have been reported in association with quid and tobacco use, and the association of these conditions with the development of oral cancer emphasizes the importance of education to limit the use of quid. In most cases, cessation of the habit produces improvement in mucosal lesions as well as in clinical symptoms. (+info)
Alert for an epidemic of oral cancer due to use of the betel quid substitutes gutkha and pan masala: a review of agents and causative mechanisms.
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In south-east Asia, Taiwan and Papua New Guinea, smoking, alcohol consumption and chewing of betel quid with or without tobacco or areca nut with or without tobacco are the predominant causes of oral cancer. In most areas, betel quid consists of a mixture of areca nut, slaked lime, catechu and several condiments according to taste, wrapped in a betel leaf. Almost all habitual chewers use tobacco with or without the betel quid. In the last few decades, small, attractive and inexpensive sachets of betel quid substitutes have become widely available. Aggressively advertised and marketed, often claimed to be safer products, they are consumed by the very young and old alike, particularly in India, but also among migrant populations from these areas world wide. The product is basically a flavoured and sweetened dry mixture of areca nut, catechu and slaked lime with tobacco (gutkha) or without tobacco (pan masala). These products have been strongly implicated in the recent increase in the incidence of oral submucous fibrosis, especially in the very young, even after a short period of use. This precancerous lesion, which has a high rate of malignant transformation, is extremely debilitating and has no known cure. The use of tobacco with lime, betel quid with tobacco, betel quid without tobacco and areca nut have been classified as carcinogenic to humans. As gutkha and pan masala are mixtures of several of these ingredients, their carcinogenic affect can be surmised. We review evidence that strongly supports causative mechanisms for genotoxicity and carcinogenicity of these substitute products. Although some recent curbs have been put on the manufacture and sale of these products, urgent action is needed to permanently ban gutkha and pan masala, together with the other established oral cancer-causing tobacco products. Further, education to reduce or eliminate home-made preparations needs to be accelerated. (+info)
Polymorphism in heme oxygenase-1 (HO-1) promoter is related to the risk of oral squamous cell carcinoma occurring on male areca chewers.
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Areca (betel) chewing is associated with the high incidence of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF) in Asians. Heme oxygenase-1 (HO-1), encoding an oxidative response protein, plays protective roles in cells. A (GT)n microsatellite repeat in HO-1 promoter shows polymorphisms and modulates the level of gene transcription. We examined allelotypic frequencies of (GT)n repeats in 83 controls, 147 OSCC and 71 OSF. All subjects were male areca chewers. Logistic regression was used to adjust the age confounding for odds ratio (OR). (GT)n repeat polymorphism was classified into short (S), medium (M) and long (L) alleles. The adjusted OR in OSCC subjects carrying L allelotype relative to S allelotype was 1.75. Buccal squamous cell carcinoma (BSCC) is the most common OSCC subset in areca chewers. L allelotype implied the risk of BSCC with adjusted OR of 2.05, whereas M allelotype appeared protective for non-BSCC with adjusted OR of 0.49. Our findings indicated that longer (GT)n repeat allele in HO-1 promoter is associated with the risks of areca-related OSCC, while the shorter (GT)n repeat allele may have protective effects for OSCC. (+info)
The induction of prostaglandin E2 production, interleukin-6 production, cell cycle arrest, and cytotoxicity in primary oral keratinocytes and KB cancer cells by areca nut ingredients is differentially regulated by MEK/ERK activation.
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There are about 200-600 million betel quid (BQ) chewers in the world. BQ chewing is one of the major risk factor of hepatocarcinoma, oropharyngeal, and esophagus cancers in Taiwan, India, and Southeast Asian countries. Thus, the precise molecular mechanisms deserve investigation. We used cultured primary keratinocytes and KB cells, RT-PCR, flow cytometry, Western blotting, and ELISA to evaluate whether alterations in early gene expression is crucial in the carcinogenic processes of BQ. We observed the induction of c-Fos mRNA expression in human gingival keratinocyte (GK) and KB carcinoma cells by areca nut (AN) extract and arecoline. A maximal increment in c-fos gene expression was shown at about 30 min after challenge. AN extract (100-800 microg/ml) and arecoline (0.1-0.8 mM) also stimulated ERK1/ERK2 phosphorylation with a maximal stimulation at 5-10 min of exposure. Pretreatment by U0126 (30 microM), a MEK inhibitor, markedly inhibited the c-Fos, cyclooxygenase-2 (COX-2), and IL-6 mRNA expression of the KB epithelial cells. In addition, U0126 and PD98059 (50 microM) also decreased AN extract- and arecoline-associated PGE2 and IL-6 production in GK and KB cells. However, U0126 by itself arrested the cells in G0/G1 phase, but was not able to prevent AN- and arecoline-induced cell death or apoptosis. In contrast, U0126 enhanced the AN-induced apoptosis of KB cells. AN ingredients thus play a significant role in the pathogenesis of oropharyngeal cancer by activation of MEK1/ERK/c-Fos pathway, which promotes keratinocyte inflammation, cell survival, and affects cell cycle progression. (+info)
Epidemiology of betel quid usage.
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Betel quid chewing is an ancient practice common in many countries of Asia and among migrated communities in Africa, Europe and North America. It enjoys complete social acceptance in many societies and is also popular among women. In its most basic form, betel quid consists of betel leaf (Piper betel), areca nut, the main psychoactive ingredient, and slaked lime (calcium hydroxide). Areca nut is said to be the fourth most commonly used psychoactive substance in the world, after caffeine, nicotine and alcohol. There are a great variety of ingredients and ways of preparing betel quid in different countries. In some, particularly in India, tobacco is added to the quid. In recent years, commercially-manufactured non-perishable forms of betel quid (pan masala or betel quid mixtures and gutka), not containing betel leaf, have been marketed. Within a short period of about 2 decades, this industry has risen in value to several hundred US million dollars. Use of areca nut in any form is not safe for oral health; the use of commercially manufactured forms seems even riskier. (+info)