Background: Oral cancer, predominantly oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. Despite advances in the treatment, the mortality rate of this disease has not improved significantly over the past several decades. This is often due to the treatment failure for progressive, recurrent disease that is resistant to chemotherapy. One of the hallmark features of cancer is its resistance to apoptosis. Here, we present the molecular mechanisms of apoptosis resistance that leads to drug resistance in OSCC.
Methods: The human OSCC cell lines, SAS and Ca9-22, and their respective 5-FU-resistant cell lines, SAS/FR2 and Ca9-22/FR2 were used in this study. These 5-FU-resistant cell lines were established by continuous exposure to increasing concentrations of 5-FU over 2 years. On the basis of a DNA and microRNA (miRNA) microarray data using above parental and 5-FU-resistant cell lines, we focused on the cellular inhibitor of apoptosis protein 2 (cIAP2), fibronectin (FN), and one of miRNAs, miR-30a.
Results: In the in vitro experiments, the downregulation of cIAP2 significantly enhanced the sensitivity of the 5-FU-resistant cells to 5-FU, with a significant increase in apoptosis. The upregulation of miR-30a in the parent cells significantly enhanced the resistance to 5-FU, with a significant decrease in apoptosis. On the other hand, the cells cultured on FN-coated dish showed higher resistance to 5-FU than the cells on noncoated dish, mediated through activated Akt signaling. Furtheremore, the immunohistochemical analysis demonstrated a high cIAP2 tumor expression to significantly correlate with the pathological response to 5-FU-based chemoradiotherapy.
Conclusion: Our results demonstrate that not only aberrant expressions of cIAP2, FN, and miR-30a but also cell adhesion-mediated apoptosis resistance may represent a potentially useful therapeutic target for improving the treatment and survival of OSCC patients, particularly in the setting of 5-FU resistance.