Chemoprevention of oxidative stress-associated oral carcinogenesis by sulforaphane depends on NRF2 and the isothiocyanate moiety.

Oxidative stress is known to play an important role in oral cancer development. In this study we aimed to examine whether a chemical activator of NRF2, sulforaphane (SFN), may have chemopreventive effects on oxidative stress-associated oral carcinogenesis. We first showed that Nrf2 activation and oxidative damage were commonly seen in human samples of oral leukoplakia. With gene microarray and immunostaining, we found 4-nitroquinoline 1-oxide (4NQO) in drink activated the Nrf2 pathway and produced oxidative damage in mouse tongue. Meanwhile whole exome sequencing of mouse tongue identified mutations consistent with 4NQO's mutagenic profile. Using cultured human oral keratinocytes and 4NQO-treated mouse tongue, we found that SFN pre-treatment activated the NRF2 pathway and inhibited oxidative damage both in vitro and in vivo. On the contrary, a structural analogue of SFN without the isothiocyanate moiety did not have such effects. In a long-term chemoprevention study using wild-type and Nrf2-/- mice, we showed that topical application of SFN activated the NRF2 pathway, inhibited oxidative damage, and prevented 4NQO-induced oral carcinogenesis in an Nrf2-dependent manner. Our data clearly demonstrate that SFN has chemopreventive effects on oxidative stress-associated oral carcinogenesis, and such effects depend on Nrf2 and the isothiocyanate moiety.

[Analysis of risk factors for carcinogenesis of oral leukoplakia].

OBJECTIVE: To investigate the risk factors for malignant transformation of oral leukoplakia. METHODS: A total of 409 cases with oral leukoplakia was retrospectively analyzed. Single factor test was first performed to examine the associations between oral leukoplakia's histopathological classification and each of risk factors including sex, age, systemic diseases, course of disease, clinical classification, site, size, numbers of lesion, alcohol and tobacco consumption, and symptom. Then the association of these selected factors with oral leukoplakia's histopathological classification was evaluated using multiple logistic regression analysis. RESULTS: Fifty-two cases of all 409 patients with oral leukoplakia (including 9 severe dysplasia) developed oral cancer. The ratio of malignant transformation was 12.7%. Sex, age, clinical type, site and symptom were chosen as risk factors incorporated into the multiple logistic regression models. The risk of mild-moderate dysplasia in female was 2.40 times as high as that in male. The risk of mild-moderate dysplasia of speckled leukoplakia was 2.81 times as high as that of homogeneous leukoplakia. The risk of mild-moderate dysplasia of dangerous site was 1. 98 times as high as that non-dangerous site. The risk of mild-moderate dysplasia with symptom was 1.84 times as high as that without symptom. The risk of severe dysplasia and oral cancer in female was 3.11 times as high as that in male. The risk of severe dysplasia and oral cancer of speckled (4.50 times), ulcerative (5.63 times), verrucous leukoplakia (4.09 times) were much higher than that of homogeneous leukoplakia. The risk of severe dysplasia and oral cancer in dangerous site was 2.79 times as high as in non-dangerous site. The risk of severe dysplasia and oral cancer in leukoplakia with symptom was 4.38 times as high as without symptom. CONCLUSIONS: The malignant transformation of oral leukoplakia is correlated to sex, clinical type, site and symptom.