Immunohistochemical Expression of CLAUDIN-1 and MMP-9 in Oral Premalignant Lesions and Squamous Cell Carcinoma

Abstract

Oral epithelial dysplasia (OED) is the diagnostic term used to describe the histopathologic changes seen in a chronic, progressive, and premalignant disorder of the oral mucosa. Clinically it may present as leukoplakia, erythroplakia, or leukoerythroplakia. Epithelial dysplasia may also be seen in verrucous or papillary leukoplakias or in the margins of a chronic mucosal ulcer. It is also consistently seen in the mucosa adjacent to the tumor in patients with invasive squamous cell carcinoma. OED is the histologic marker of premalignancy and as such it is predictive of an increased rate of development of squamous cell carcinoma. OSCC is a malignant neoplasm derived from the stratified squamous epithelium of the oral mucosa. It occurs at various sites, the most frequent being the lip, lateral edges of the tongue and floor of the oral cavity. The incidence of OSCC increases with age, with the majority of OSCC occuring in patients over 40 years. At the time of diagnosis, the majority of patients present advanced disease stages and approximately one third of them show LNM. Despite the currently available therapeutic strategies, which include the excision of malignant tissue and combination of radiotherapy and chemotherapy, the five-year survival rate is only 50%. In addition, a high percentage of patients have a poor response to therapy and high recurrence rates. Claudins are considered to be the main tight junction-forming proteins.These proteins comprise a family of 24 members and CLDN-1 has been shown to be essential for the function of tight junctions.CLDN-1 has been associated with the pathogenesis of neoplastic processes, since alterations in these structures may lead to increased nutrient diffusion and influence other factors that promote the development of tumors such as human carcinomas.Biochemical and molecular changes in cells precede the establishment of cancer, and the dysregulation of different proteins might be involved in this process. Immunoreactivity for CLDN-1 can be seen in different potentially malignant lesions and carcinomas. There are, however, tissue type-specific differences in their expression. Investigators have shown the overexpression of these proteins in epithelial dysplasias,cervical intraepithelial neoplasia and oral squamous cell carcinoma. A potential mechanism by which alterations in the expression of CLDN-1 may contribute to oral carcinogenesis is through destabilization of tight junctions, resulting in loss of adhesion properties known to be involved in early steps of invasion and metastasis.Few studies have investigated the expression of claudins in oral potentially malignant lesions, especially oral epithelial dysplasias (OEDs). MMP-9 is the most widely distributed member of MMPs, which cleaves type IV collagen, the main component of BM. The ability of MMP-9 to initiate BM destruction and further degradation of ECM suggests its importance in tumor invasion and metastasis. Stromal cells typically synthesize MMP-9, which can then act on the stroma and regulate the tissue microenvironment as well as the tumor cells themselves. MMP-9 has been associated with cancer cells invasion, proliferation, angiogenesis, EMT and immune surveillance. Many studies have proposed that MMP-9 may serve as a novel biomarker for tumor progression and invasion in various malignant lesions.