Chromatin bound by survivin regulates the glycolytic switch in interferon-γ producing CD4+ T cells

Upon activation, CD4+ T cells adapt metabolically to fulfill their effector function in autoimmunity. Here we show that nuclear survivin is essential for transcriptional regulation of glucose utilization. We found that the glycolytic switch in interferon (IFN) g–producing CD4+ cells is dependent on a complex of survivin with interferon regulatory factor 1 (IRF1), and Smad3 and was reversed by survivin inhibition. Transcriptome analysis of CD4+ cells and sequencing of survivin-bound chromatin identified a hub of metabolism regulating genes whose transcription depended on survivin. Direct binding of survivin to IRF1 and SMAD3 promoted IRF1-mediated transcription, repressed SMAD3 activity, and lowered PFKFB3 production. Inhibiting survivin upregulated PFKFB3, restored glycolysis, and reduced glucose uptake, improving control over IFNg-dependent T-cell functions. Thus, IRF1-survivin-SMAD3 interactions are important for metabolic adaptation of CD4+ cells and provide an attractive strategy to counteract IFNg-dependent inflammation.

Survivin and cortactin expression in sinonasal schneiderian (inverted) papilloma and associated carcinoma

Background: Sinonasal inverted (schneiderian) papilloma (IP) is histologically benign but shows a propensity for malignant transformation. Survivin, a member of the inhibitor of the apoptosis family of proteins that controls cell division, apoptosis, metastasis, and, probably, also neoangiogenesis, is overexpressed in essentially all human cancers. Overexpression of the multidomain protein cortactin has also been associated with increased cell migration, invasion, and metastatic potential in several malignancies. Objective: The aim of the present study was to preliminarily investigate survivin and cortactin expression in a consecutive series of sinonasal IPs, and IP-associated squamous cell carcinomas (SCC). Methods: Immunohistochemical expression of nuclear survivin and cortactin was measured in 19 consecutive sinonasal IPs and 3 IP-associated SCCs. Results: The mean ± standard deviation nuclear survivin expression was 9.4 ± 9.2% and 31.7% ± 15.4% in sinonasal IPs and SCCs, respectively (p < 0.0001). Results of cortactin immunostaining was strongly positive in the cytoplasm of both sinonasal IPs and SCCs: no significant difference emerged between the IP and SCC epithelial components. Conclusion: Nuclear survivin expression was significantly higher in SCCs than in IPs. Prospective, multi-institutional prognostic studies, preferably on an international scale (given the few cases treated at single institutions), are needed to confirm the role of survivin in IP malignant transformation.

Nuclear survivin expression correlates with endoglin-assessed microvascularisation in laryngeal carcinoma

AimsSurvivin—a member of the family of inhibitor of apoptosis proteins that control cell division, apoptosis and metastasis—is overexpressed in virtually all human cancers, including laryngeal squamous cell carcinoma (LSCC). Recent findings also correlate survivin expression with the regulation of angiogenesis. The novel main aim of this study was a preliminary investigation into the potential role of survivin expression in LSCC neoangiogenesis, as determined by endoglin-assessed microvascular density (MVD).MethodsImmunohistochemical expression of nuclear survivin and endoglin-assessed MVD were ascertained by image analysis in 75 consecutive LSCCs.ResultsStatistical analysis disclosed a strong direct correlation between nuclear survivin expression and MVD. Patients whose nuclear survivin expression was ≥6.0% had a significantly higher LSCC recurrence rate, and a significantly shorter disease-free survival (DFS) than those with a nuclear survivin expression <6.0%. The LSCC recurrence rate was also higher and the DFS shorter in patients with endoglin-assessed MVD ≥6.89%. The OR for recurrence was 2.79 in patients with LSCC with a nuclear survivin expression ≥6.0%, and 12.31 in those with an MVD≥6.89%.ConclusionsSurvivin-targeting strategies to enhance tumour cell response to apoptosis and inhibit tumour growth should receive more attention with a view to developing agents for use in multimodality advanced LSCC treatment, or combined with conventional chemotherapy. Given the present preliminary evidence in LSCC, survivin targeting should also be further investigated for anti-angiogenic purposes, to reduce tumour blood flow and induce cancer necrosis.

Immunohistochemical Expression of Survivin and Its Relationship with Cell Apoptosis and Proliferation in Ameloblastomas

Ameloblastoma behavior is related to the potential of tumor cells to inhibit apoptosis and to initiate a proliferative phase. This study was performed to compare the immunoexpression of Survivin with Bcl-2, Bax, and Ki-67 and to associate them with the histopathological type of each variant of ameloblastoma.Material and Methods. Using the World Health Organization (WHO) criteria for ameloblastoma, 110 cases were selected. The cases were classified as solid/multicystic and unicystic ameloblastomas. Cellular counts of cytoplasmic immunoexpression were assessed for cytoplasmic Survivin, Bcl-2, and Bax, while the nuclear immunoexpression of Survivin and Ki-67 was assessed using label index.Results. Cytoplasmic Survivin and Bcl-2 showed higher percentages of immunoexpression in solid multicystic ameloblastomas compared to unicystic ameloblastomas (P<0.05). Bax, Ki-67, and nuclear Survivin were expressed in higher percentages in unicystic ameloblastomas.Conclusions. Cytoplasmic Survivin and Bcl-2 immunoexpression levels were elevated in relation to Bax immunoexpression, suggesting aggressive ameloblastoma behavior, while Ki-67 and nuclear Survivin immunoexpression may be associated with the type of tumor morphology that influences cellular counts or with the greater capacity for cellular proliferation and tumor growth.