It has been reported to involve detachment of cells from the tumor tissue, regulation of cell motility and invasion, proliferation and evasion through the lymphatic system or blood vessels. Efforts have been made to elucidate tumor-related proteins that could influence the appearance of metastases in oral squamous cell carcinoma, which occur in about 40% of patients with oral cancer. Therefore, the study of altered molecules in cell lines originated from distinct sites is essential to understand the molecular basis of this process. GAGs polysaccharide chains are the main contributors to the proteoglycan functional properties and essential part of the matured proteoglycan molecules. Besides, it was reported that glycans play a crucial role at various pathophysiological steps of cancer progression, especially by acting as coreceptors to stabilize growth-factor receptor signaling complexes and enhancing integrin-mediated cell adhesion, motility and intracellular signaling. The disruption of GAGs modification by heparanase was shown to facilitate tumor cell invasion angiogenesis and metastasis. In order to further understand the role of chondroitin sulfate modification in oral cancer, SCC-9 LN-1 cell lines were treated with chondroitinase and tested in adhesion and migration processes. Interestingly, when SCC-9 LN-1 cells were treated with chondroitinase, they had reduced ability to adhere to extracellular matrix proteins. It is important to mention that this event may be a result of the disruption of many cell surface chondroitin sulfate proteoglycans, such as syndecans, chondroitin sulfate proteoglycan 4, betaglycan, neuropilin-1, receptor protein tyrosine phosphatase, integrin and VEGFR-2, which were also previously demonstrated to be overexpressed in cancer. It is well established that based upon their direct involvement in cell–cell and cell–ECM interactions, PGs have been strongly implicated in the regulation of cell movement. However, how PGs actually affect this process is only partially understood and in some instances, CP-690550 controversial. In this study, we have demonstrated that agrin and perlecan play a role in the oral cancer cell movement by silencing agrin and perlecan, which promoted a strongly reduced in the ability of SCC-9 and SCC-9 LN-1 cell line to migrate and to adhere to matrigel. Perlecan has been associated with the induction of cellular proliferation, differentiation and angiogenesis by interacting with a number of growth factors including FGFs 1, 2, 7, 9, and 18; hepatocyte growth factor, platelet derived growth factors-AA and -BB, and VEGF. Perlecan also exhibits adhesive or anti-adhesive properties presumably by differentially affecting surface receptors such as a2b1 integrin. Agrin is also able to interact with integrins, however there is still very limited acknowledgement on how agrin signals through the integrin receptors and how these interactions influence cell behavior. Therapeutic PGs- and GAG-targeting modifications have been considered as anti-invasion and tumor-specific drug delivery potential approaches.