. Cigarette smoke extract induces oral squamous cell carcinoma cell invasion in a receptor for advanced glycation end-products-dependent manner. Eur J Oral Sci 2018; 126: 33-40. © 2017 Eur J Oral SciOral squamous cell carcinoma (OSCC) affects approximately 30,000 people and is associated with tobacco use. Little is known about the mechanistic effects of second-hand smoke in the development of OSSC. The receptor for advanced glycation end-products (RAGE) is a surface receptor that is upregulated by second-hand smoke and inhibited by semi-synthetic glycosaminoglycan ethers (SAGEs). Our objective was to determine the role of RAGE during cigarette smoke extractinduced cellular responses and to use SAGEs as a modulating factor of Ca9-22 OSCC cell invasion. Ca9-22 cells were cultured in the presence or absence of cigarette smoke extract and SAGEs. Cell invasion was determined and cells were lysed for western blot analysis. Ras and nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-jB) activation were determined. Treatment of cells with cigarette smoke extract resulted in: (i) increased invasion of OSCC; (ii) increased RAGE expression; (iii) inhibition of cigarette smoke extract-induced OSCC cell invasion by SAGEs; (iv) increased Ras, increased AKT and NF-jB activation, and downregulation by SAGEs; and (v) increased expression of matrix metalloproteinases (MMPs) 2, 9, and 14, and downregulation by SAGEs. We conclude that cigarette smoke extract increases invasion of OSCC cells in a RAGE-dependent manner. Inhibition of RAGE decreases the levels of its signaling molecules, which results in blocking the cigarette smoke extract-induced invasion.