Survivin and oral squamous cell carcinoma: a review

• ¹ Polytechnical University of Marche, Department of Clinical Specialistic and Dental Sciences, Italy
• ² University of Foggia, Department of Clinical and Experimental Medicine, Italy

Aim. Apoptosis, a phenomenon that allows the programmed destruction of damaged or unwanted cells, involves the interplay of a large number of proteins, that are deregulated in various human pathologies, including cancer. Survivin, a member of the family of inhibitor of apoptosis (IAP), is a 16.5 kDa protein composed of 142-amino acid encoded by a single gene located on the human 17q25 chromosome, that exists physiologically as a functional homodimer. This protein is well known to induce apoptosis by inhibiting, both directly and indirectly, the activity of caspases 3, 7 and 9. Survivin is expressed in most human neoplasms and has been reported to contribute to cancer initiation and drug resistance in a wide variety of human tumors. This review will summarize the most important information about the role of survivin in oral squamous cell carcinoma (OSCC) and will focus on its potential predictive/prognostic impact for disease progression and its future eventual therapeutic use. Materials and Methods. Literature research of the past years regarding the role of survivin in OSCC. Results. Survivin is expressed in more than 80% of OSCC and its degree of expression is directly related to an aggressive phenotype. Especially, survivin expression usually increases in poorly differentiated tumours, and high survivin expression results related to poor survival rates. Furthermore, an inverse correlation between cytoplasmic and nuclear survivin expression and HPV-associated OSCC has been reported, suggesting that HPV-carcinogenesis interferes with active nuclear import of survivin. Besides, the levels of survivin in OSCC tissues result greatly higher than those in corresponding noncancerous tissues; in fact, the staining of survivin protein in OSCC tissues is deeper than that typical of nontumor tissues. Some authors suggest that physiological cutaneous and oral mucosa specimens are negative for survivin expression, while OSCC cells displays a positive cytoplasmic reactivity of 20–100%. Other immunohistochemical studies detected survivin expression in basal and parabasal cells of normal oral mucosa. Survivin expression detected by real-time RT-PCR is present in all samples of normal mucosa, although at a low rate. Thus, it is not easy to predict how oral potentially malignant lesions could behave. There are low and high survivin expression lesions in the same quantities among leucoplakias in their sample, suggesting the presence of a progressive deregulation of survivin expression paralleling oncogenesis. Other surveys instead report opposite results with significant difference between potentially malignant and normal mucosa, but not between cancer and potentially malignant lesions. Several authors agree in maintaining that survivin expression rates can be considered a putative predictive value that appears among lesions evolving into OSCC compared with lesions not evolving in malignancies. Survivin mRNA levels are overexpressed in OSCC, in epithelial dysplasia and in lymph node metastases compared to normal mucosa. Moreover, the high level of survivin in OSCC tissues is significantly correlated with poorer tumor differentiation, higher tumor stage, and lymph node metastasis, but not with other clinicopathologic features, including gender, age, smoking, and tumor size. Some authors instead observed no correlation between survivin expression and differentiation of OSCCs, assuming that survivin plays a minor role in terms of dedifferentiation in OSCC itself. Several authors reported that the role of survivin is associated with angiogenesis in OSCC. However, even if all precise molecular mechanisms underlaying the aberrant expression of survivin in cancer cells are not well defined, the diverse functional roles assigned to survivin in cancer cells can be explained, at least in part, by the presence of splice variants. Five alternative splice variants of survivin (“wild-type”, 2α, β/2B, 3B, and ΔEx3) have been identified, each one probably characterized by a different apoptotic function and cell localization. Survivin protein expression pattern showed nuclear and cytoplasm localization. The nuclear localization of survivin is related to unfavorable prognosis in many malignancies; however, other studies do not agree with these observations. This difference may be associated with the tumour types examined or may be due to the parameters applied to classify a tumour as “nuclear” versus “cytoplasmic” with respect to survivin expression. The preferential nuclear versus cytoplasmic survivin seems to be linked with a good prognosis and the difference between cytoplasmic and nuclear survivin was significantly associated with the survival of the patients and was found to be the strongest predictor for disease-free survival. The different subcellular localization of survivin-ΔEx3 (nuclear) and survivin-2B (cytoplasmic) suggests their potential different roles in tumor progression and tumorigenesis. In fact, survivin-2B might be an antagonist of survivin and survivin-ΔEx3. Discussion. OSCC has become a major public health issue: it is the most common malignant tumor of oral cavity and its incidence has been increasing. Even if there has been progress in diagnosis and therapy, the prognosis remains unfavorable; with a 5-year survival rate of 35-50%. The altered functions of cell cycle regulatory proteins commonly found in OSCC suggest that studies of programmed cell death processes can lead to new strategies for both diagnosis and treatment. According to different researchers, the relationship between survivin expression and tumorigenesis or prognosis and development of OSCC exists. These contrasting results regarding the role of Survivin in OSCC, probably related to the techniques employed on the different nature of the potentially malignant lesions analyzed in the study. In conclusion, survivin is a unique member of IAP proteins that is upregulated in many tumor types, but the presence of splice variants and different subcellular pools complicate the understanding of this molecule. For these reasons, it is important to carry out further studies to clarify the role of survivin splice variants. At the present state-of-the-art survivin-based treatments, the favorable results from gene therapy pre-clinical studies did not meet expectations in the clinical trials. The anticancer immunotherapy with peptide vaccines remain the most intriguing approach but are also far from any practical clinical application in the immediate future. Combined therapies using survivin-based strategies and concomitant/previous chemotherapy seem to be close to a realistic clinical application.