The Role Of Aldh1A2 In Head And Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinomas (HNSCC) are one of the most common cancers worldwide. The patient 5-year survival rate has remained approximately 50% for decades, necessitating discovery of novel therapies and targets. To date, all-trans retinoic acid (RA) and its isoforms – retinoids – are some of the most-studied and most-active agents in the treatment and prevention of HNSCC. A key enzyme involved in catalyzing the synthesis of endogenous RA from retinol (vitamin A), aldehyde dehydrogenase 1a2 (ALDH1a2), has previously been shown to act as a tumor suppressor in human prostate cancer. Among HNSCC patients, high ALDH1a2 protein expression correlates with better overall survival. Our primary objective was to delineate the role of ALDH1a2 in HNSCC carcinogenesis; further study into the proteins involved in endogenous retinoid synthesis and signaling, such as ALDH1a2, could reveal new and more effective strategies for retinoid therapy. We found that ALDH1a2 transcript levels are dramatically reduced in RNA data sets from over 300 human HNSCC samples, as well as in SCC tumor tissue from mice subjected to the 4-nitroquinoline 1-oxide (4-NQO)-induced murine model of human oral carcinogenesis developed in our lab. Through retroviral gene transduction, we overexpressed ectopic ALDH1a2 in human HNSCC cell lines SCC-4, SCC-9, and SCC-25. We observed that ALDH1a2 overexpression affects the phenotype of these transformed cells in vitro, decreasing both proliferation and clonogenicity. In addition, we created transgenic mice that inducibly express transgenic ALDH1a2 specifically in select, stratified epithelial tissues including the tongue, skin, and esophagus. These mice underwent 4-NQO treatment, to determine whether ectopic ALDH1a2 expression can suppress oral cavity carcinogenesis in vivo. We found that the expression of ectopic ALDH1a2 during 4-NQO-induced carcinogenesis reduced the tongue protein expression of enhancer of zeste homolog 2 (EZH2) and vimentin, two markers of epithelial-to-mesenchymal transition (EMT) and tumor migration in this disease. This work provides evidence that ALDH1a2 has tumor suppressive functions in HNSCC and has furthered our understanding of retinoid signaling and cancer chemoprevention.