Nuclear Survivin expression is correlated with malignant behaviors of head and neck cancer together with Aurora-B
Introduction
Survivin is a member of the IAP family, contains only a single BIR repeat and lacks a RING finger domain.1, 2 Survivin plays an important role in the suppression of apoptosis by either directly or indirectly inhibiting the activity of caspases.3 Survivin is strongly expressed in fetal and cancer tissues.2, 4, 5, 6, 7, 8 It is well known that Survivin expression is correlated with resistance against cancer therapy-induced apoptosis and poor survival of patients.9 Besides its role as IAP, Survivin appears to function as a subunit of the CPC and concerts the other subunits of CPC such as Aurora-B, INCENP, and Borealin to regulate cell division.10, 11, 12, 13, 14, 15 Aurora-B is the enzymatic core of the complex, whereas Survivin and INCENP dictate the timing and localization of the kinase activity.11 CPC corrects attachment errors between chromosomes and the mitotic spindle, regulates the quality-control checkpoint, and ensures the correct completion of cytokinesis.9 In cancer cells, the high expression of Aurora-B and INCENP is observed as well as Survivin.14 We previously showed the overexpression of Aurora-B in nucleus and its correlation with cell proliferation and metastasis in HNSCC.16 However, it is still unclear whether abnormal regulation of Survivin influences CPC function or not in cancer.
As mentioned above, Survivin has dual functional roles. It has been revealed that Survivin is detected as a cytoplasmic and nuclear protein in cancer.17 Nuclear Survivin is suspected to control cell division, whereas cytoplasmic Survivin is considered cytoprotective. The intracellular localization of Survivin in tumor cells and its significance as a prognostic marker were analyzed in many patient-based studies, albeit with opposing conclusions. Previous studies showed that overexpression of cytoplasmic Survivin is associated with a poor outcome in various cancers including HNSCC, although some reports consider nuclear Survivin to be associated with poor survival.4, 5, 6, 7, 8, 18, 19, 20, 21 Thus, the clinico-pathological significance of nuclear expression of Survivin is controversial in cancer. In addition, there are no reports regarding the abnormal Survivin expression as a CPC in cancer. Here we examined the relationship between the nuclear Survivin and Aurora-B in HNSCC. Moreover, we compared nuclear Survivin expression with clinico-pathological findings and examined the functional correlation between Survivin and Aurora-B in HNSCC.
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Patients and tissue samples
HNSCC tissues were obtained from 19 patients who underwent surgery at Dental Hospital, Peradeniya and OMF unit, Kandy hospital, Sri Lanka. These tissue specimens were immediately frozen and stored in −80 °C. Informed consent was obtained from all patients for this study. Fifty cases (27 males and 23 females) of paraffin-embedded HNSCC cases, including 16 cases with lymph node metastasis, were selected from the pathological files of Hiroshima University Hospital, Japan and University of
Survivin and Aurora-B expression in nuclear and cytoplasmic fraction of HNSCC cell lines and tissues
First, we examined Survivin and Aurora-B expression by using nuclear and cytoplasmic fractions of 5 HNSCC cell lines and 19 HNSCC tissues by Western blot analysis. Survivin expression was observed in both nuclear and cytoplasmic fraction of all 5 HNSCC cells (Fig. 1A), and high expression of Survivin was observed in 11 of 19 HNSCC tissues (Fig. 1B). Aurora-B expression was observed only in the nuclear fraction (Fig. 1A and B). In normal tissue, both Survivin and Aurora-B expression was not
Discussion
It is well known that Survivin overexpression is associated with a poor outcome in various cancers.9 Survivin is detected as a cytoplasmic and nuclear protein in cancer. Survivin has a nuclear export signals (NES) in the linker region between BIR domain and the COOH-terminal a helix.17, 23, 24 In fact, several studies have shown that nuclear accumulation of cytoplasmic Survivin upon treatment with leptomycin B.23, 24 It previously has been reported that cytoplasmic Survivin overexpression was
Conflict of interest statement
None declared.
Acknowledgements
We thank Dr. Masaaki Tatsuka (Prefectural University of Hiroshima) and Dr. Fumio Shimamoto (Prefectural University of Hiroshima) for helpful discussion. Supported by in part by Grants-in-Aid from the Ministry of Education, Science and Culture of Japan to YK, IO and TT and in part by Grant-in-Aid for Japan Society for the Promotion of Science Fellows to GQ.
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The noncanonical function of borealin, a component of chromosome passenger complex, promotes glycolysis via stabilization of survivin in squamous cell carcinoma cells
2024, Biochemical and Biophysical Research CommunicationsSensitization of head and neck squamous cell carcinoma to apoptosis by combinational SMAC mimetic and Fas ligand-Fc treatment in vitro
2020, Journal of Cranio-Maxillofacial SurgeryCitation Excerpt :The targeted suppression of survivin led to inhibited cell proliferation and induced apoptosis (Zhang et al., 2016). In accordance with this, different groups have indicated that survivin plays an important role in HNSCC therapy and that its downregulation results in enhanced radiosensitivity (Khan et al., 2010; Qi et al., 2010). Comparing the indicated SMAC mimetics as monotherapies, BV-6 seems most effective, with the overall lowest IC50.
Comprehensive pharmacogenomic profiling of human papillomavirus-positive and -negative squamous cell carcinoma identifies sensitivity to aurora kinase inhibition in KMT2D mutants
2018, Cancer LettersCitation Excerpt :Aurora B expression was higher in oral squamous cell carcinoma than in normal epithelium and also correlated with nodal metastasis and poor differentiation [38]. Aurora B expression has not consistently correlated with stage and outcome in HNSCC and CESC [39–41]. Both Aurora B inhibition and Aurora A silencing induced apoptosis in HNSCC cell lines [41,42].
O-linked N-acetylglucosamine cycling regulates mitotic spindle organization
2013, Journal of Biological ChemistryCitation Excerpt :At the same time, the Chromosomal Passenger Protein Complex (CPC), composed of the proteins AurB, Survivin, Borealin, and the inner centromere protein (INCENP), localize to the spindle midzone to ensure the proper phosphorylation of substrates involved in condensation of chromosomes, correction of microtubule-kinetochore attachments, and the activation of the spindle assembly checkpoint (9–11). As the enzymatic core of the CPC, activation of AurB is of extreme importance during mitosis (12, 13) and altered AurB activity can lead to improper chromosome segregation and cell division (14, 15). In addition to phosphorylation, the post-translational modification of proteins with O-linked N-acetylglucosamine (O-GlcNAc) regulates cell cycle progression (16, 17).
Aurora kinases in head and neck cancer
2013, The Lancet OncologyCitation Excerpt :In cancer cells, AURKA and AURKB mRNA expression is affected by histone acetylation.81 Combined pharmacological blockade of aurora kinases and histone deacetylases has been shown to be synergistic in preclinical models of B-cell lymphoma,82 and has led to the testing of this combination therapy in patients with Hodgkin's, B-cell non-Hodgkin, or peripheral T-cell lymphoma (NCT01567709). This approach might have promise in SCCHN.