Though, no evidence was reported regarding their role in oral cancer. Perlecan is a large proteoglycan harboring five distinct structural domains, to which long chains of heparan sulfate and/or WZ4002 chondroitin sulfate are attached. This molecule is present in all vascularized tissues with a distribution that is primarily confined to basement membranes. Also, other studies have also identified perlecan in the stromal spaces of various pathophysiological conditions. Agrin shares a rather intriguing multimodular organization with perlecan, but more complexity to agrin can be added due to at least four sites of alternative splicing. The amino acid sequence of agrin encodes a protein with a molecular size of 220 kDa, but the observed molecular weight is around 400 kDa due to the long heparan sulfate and chondroitin sulfate glycosaminoglycans attached to the core protein. Although originally discovered in the neuromuscular junctions, agrin has been observed in numerous other tissues, and it is described as highly expressed in hepatocellular carcinomas and cholangiocellular carcinomas. Nevertheless, little is known about its role at locations other than the neuromuscular junctions, and even less information is known about its role in tumor tissues. In the present study, we focused on understanding the role of the proteoglycans agrin and perlecan in oral cancer. First, we sought to validated the overexpression of agrin and perlecan in oral cancer tissues compared to normal tissues and in cell lines with different site of origin: oral squamous carcinoma originated from human tongue, oral squamous carcinoma SCC-9 isolated from lymph nodes and a skin-derived squamous carcinoma. Next, we showed that oral squamous carcinoma cell line had a reduced ability to adhere to extracellular matrix proteins and increased sensibility to cisplatin when treated with chondroitinase. By specific target agrin and perlecan protein levels with siRNA, we showed that OSCC cells have decreased cell adhesion and migration and increased sensibility to cisplatin treatment. Overall, our findings opened new avenues to better understand the role of agrin and perlecan, as well as their involvement in carcinogenesis, which may offer a novel approach to cancer therapy by targeting the tumor microenvironment. Proteoglycans, essential macromolecules of the tumor microenvironment, have their expression altered during malignant transformation and tumor progression. Agrin and perlecan are two of the major HSPG identified in the basement membrane, and their functional roles in modulation of cancer growth have been reviewed elsewhere. In this study, we showed for the first time that agrin and perlecan are highly expressed in OSCCs, and the function of these proteins in oral cancer associated processes was investigated. Not only the expression of agrin and perlecan was shown to be higher in OSCC tissues compared to control tissues, but also their expression might be associated with different sites of origin, where higher expression of agrin was found in cell line originated from primary site.