Dynamic intracellular survivin in oral squamous cell carcinoma: underlying molecular mechanism and potential as an early prognostic marker

Abstract

Survivin functions as an apoptosis inhibitor and a regulator of cell division in many tumours. The intracellular localization of survivin in tumours has been suggested as a prognostic marker. However, current reports are inconsistent and the underlying molecular mechanisms are not understood. The present study has examined the localization and prognostic value of nuclear and cytoplasmic survivin in the pre-therapeutic biopsies from 71 oral and oropharyngeal squamous carcinoma (OSCC) patients. Statistical analysis indicated that preferential nuclear versus cytoplasmic survivin correlated with favourable versus unfavourable disease outcome. Uni- and multi-variate analysis showed that in contrast to total survivin expression, the difference between nuclear and cytoplasmic survivin was a strong predictor for relapse-free survival (p=0.0003). As a potential underlying molecular mechanism, it is shown in OSCC cell lines that predominantly cytoplasmic survivin mediates protection against chemo- and radio-therapy-induced apoptosis. Importantly, the cytoplasmic localization of survivin is regulated by its nuclear export signal (NES), and export-deficient nuclear survivin is not cytoprotective. This study suggests that the difference between cytoplasmic and nuclear survivin is an indicator for survivin activity in tumour cells. Thus, this difference may serve as a predictive marker of outcome in OSCC patients undergoing multi-modality therapy. The pharmacogenetic interference with survivin's cytoplasmic localization is also to be pursued as a potential therapeutic strategy.

Nuclear survivin expression is associated with HPV-independent carcinogenesis and is an indicator of poor prognosis in oropharyngeal cancer

“…Active nuclear import is mediated by nuclear localisation signals (NLS), which interact with import receptors (Weis, 2003). Mutations in the NLS or enhanced binding to nuclear components may account for pronounced nuclear survivin (Engels et al, 2007). The nuclear expression patterns of survivin were significantly correlated with HPV-negative tumours in our series, which suggests that the HPVdependent carcinogenesis interferes with the active nuclear import of survivin.…”

Immunohistochemical characteristics of cystic odontogenic lesions: a comparative study

“…Recently, some studies demonstrated that over-expression of survivin is associated with the more aggressive and invasive phenotype of oral squamous cell carcinoma (30,31 (9). They also documented that there was no or only weak survivin staining in radicular or apical cysts.…”

“…In the article of de Oliveira et al (27), survivin staining patterns in DCs and KCOTs is also similar to our observations. Furthermore, some authors hypothesized that cytoplasmic survivin expression is responsible for poor prognosis and for the resistance to therapy in oral squamous cell carcinoma (31). Although effects of nuclear vs. cytoplasmic expression of survivin are still ambiguous, some investigators have reported that predominantly nuclear survivin over-expression is a negative prognostic factor in oropharyngeal squamous cell carcinomas (32).…”

Upregulation of vimentin and aberrant expression of E-cadherin/β-catenin complex in oral squamous cell carcinomas: correlation with the clinicopathological features and patient outcome

“…Immunoreactivity was semiquantitatively evaluated on the basis of staining intensity and distribution using the immunoreactive score: 37,38 Immunoreactive score ¼ intensity score  proportion score. The intensity score was defined as 0, negative; 1, weak; 2, moderate; or 3, strong, and the proportion score was defined as 0, negative; 1, o10%; 2, 11-50%; 3, 51-80%; or 4, 480% positive cells.…”