Abstract
Cancers in the upper aerodigestive tract, including cancers of the tongue and the esophagus, are the third leading cause of cancer-related deaths in the world, and oxidative stress is well recognized as one of the major risk factors for carcinogenesis. The Keap1-Nrf2 system plays a critical role in cellular defense against oxidative stress, but little is known about its association with upper aerodigestive tract carcinogenesis. In this study, we examined whether loss of Nrf2-function exacerbates carcinogenesis by using an experimental carcinogenesis model that is induced by 4-nitroquinoline-1-oxide (4NQO). We found that Nrf2-knockout (Nrf2-KO) mice were more susceptible to 4NQO-induced tongue and esophageal carcinogenesis than wild-type mice, which suggests that Nrf2 is important for cancer prevention. We also examined how the suppression of Keap1 function or the induction of Nrf2 activity affected 4NQO carcinogenesis. Keap1-knockdown (Keap1-KD) mice were resistant to 4NQO-induced tongue and esophageal carcinogenesis. Importantly, no growth advantage was observed in tongue tumors in the Keap1-KD mice. These results show that the Keap1-Nrf2 system regulates an important defense mechanism against upper aerodigestive tract carcinogenesis. In addition to several important functions of Nrf2 that lead to cancer chemoprevention, we hypothesize that a mechanical defense of thickened keratin layers may also be a chemopreventive factor because thickened, stratified, squamous epithelium was found on the tongue of Keap1-KD mice.
Highlights
Cancers in the upper aerodigestive tract, including cancers in the oral cavity, oropharynx, hypopharynx, larynx, and esophagus, are the third leading cause of cancer-related deaths in the world [1]
To explore the roles the Keap1–Nrf2 system plays in upper aerodigestive tract carcinogenesis, we used a 4NQO experimental carcinogenesis model
Consistent with the observation that 4NQO did not change NRF2 expression, 4NQO did not increase the mRNA expression of either NAD(P)H quinone oxidoreductase 1 (NQO1) or glutamate–cysteine ligase catalytic subunit (GCLC), while Diethyl maleate (DEM) strongly increased the expression of both genes (Fig. 1B)
Summary
Cancers in the upper aerodigestive tract, including cancers in the oral cavity, oropharynx, hypopharynx, larynx, and esophagus, are the third leading cause of cancer-related deaths in the world [1]. Tongue and esophageal cancers are the most frequent among them. Because both the tongue and the esophagus are covered by stratified squamous epithelium [2], squamous cell carcinoma is the most common cancer type in these regions. Important risk factors for tongue and esophageal cancers include tobacco smoking and alcohol use, and the cancer risk attributable to both factors is estimated to be more than 60% [3]. It has been reported that carcinogenesis induced by tobacco and alcohol is mediated, at least in part, by oxidative stress [4]. While the importance of oxidative stress in oral and esophageal carcinogenesis is well recognized, little is known about the mechanisms mediating how stress pro-
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