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Nuclear localization of signal transducer and activator of transcription 3 in head and neck squamous cell carcinoma is associated with a better prognosis.

ABSTRACT: A high frequency of head and neck squamous cell cancers (HNSCC) contain constitutively activated signal transducer and activator of transcription 3 (STAT3). To further elucidate the prognostic role of STAT3 in HNSCC, the expression pattern of STAT3 was correlated with outcome in two independent data sets.STAT3 protein expression analysis was done on a test cohort of 102 patients with HNSCC recruited between 1992 and 2005. Automated quantitative analysis was used to assess STAT3 protein expression. We evaluated associations with clinicopathologic parameters and survival prognosis. Associations were validated in a second, independent cohort of 58 patients with confirmed HNSCC enrolled in the Early Detection Research Network-sponsored study who underwent surgical resection with curative intent at the University of Pittsburgh Medical Center between 2000 and 2004.STAT3 displayed mixed nuclear and cytoplasmic staining. Survival analysis showed that high nuclear STAT3 expression (top tertile versus the rest) was associated with longer progression-free survival (n = 70, mean survival of 88.9 versus 46.7 months, P = 0.012 for the first cohort; n = 37, mean survival of 60.3 versus 33.0 months, P = 0.009 for the second cohort). After best model selection in the multivariable analysis context, only STAT3 was significant, revealing a lower risk of progression and death for patients with high nuclear STAT3-expressing tumors (hazard ratio, 0.28; 95% confidence interval, 0.10-0.82; P = 0.019; and hazard ratio, 0.23; 95% confidence interval, 0.07-0.76; P = 0.016, respectively).Our results indicate that high nuclear STAT3 expression levels by automated quantitative analysis are associated with favorable outcome in HNSCC.

SUBMITTER: Pectasides E

PROVIDER: S-EPMC3030188 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Nuclear localization of signal transducer and activator of transcription 3 in head and neck squamous cell carcinoma is associated with a better prognosis.

Pectasides Eirini E Egloff Ann-Marie AM Sasaki Clarence C Kountourakis Panteleimon P Burtness Barbara B Fountzilas George G Dafni Urania U Zaramboukas Thomas T Rampias Theodoros T Rimm David D Grandis Jennifer J Psyrri Amanda A

Clinical cancer research : an official journal of the American Association for Cancer Research 20100406 8

<h4>Purpose</h4>A high frequency of head and neck squamous cell cancers (HNSCC) contain constitutively activated signal transducer and activator of transcription 3 (STAT3). To further elucidate the prognostic role of STAT3 in HNSCC, the expression pattern of STAT3 was correlated with outcome in two independent data sets.<h4>Experimental design</h4>STAT3 protein expression analysis was done on a test cohort of 102 patients with HNSCC recruited between 1992 and 2005. Automated quantitative analysi ...[more]

PMID: 20371693

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Project description:STAT (signal transducer and activator of transcription) proteins play a critical role in cellular response to a wide variety of cytokines and growth factors by regulating specific nuclear genes. STAT-dependent gene transcription can be finely tuned through the association with co-factors in the nucleus. We showed previously that STAT5 (including 5a and 5b) specifically interacts with a mitochondrial enzyme PDC-E2 (E2 subunit of pyruvate dehydrogenase complex) in both leukemic T cells and cytokine-stimulated cells. However, the functional significance of this novel association remains largely unknown. Here we report that PDC-E2 may function as a co-activator in STAT5-dependent nuclear gene expression. Subcellular fractionation analysis revealed that a substantial amount of PDC-E2 was constitutively present in the nucleus of BaF3, an interleukin-3 (IL-3)-dependent cell line. IL-3-induced tyrosine-phosphorylated STAT5 associated with nuclear PDC-E2 in co-immunoprecipitation analysis. These findings were confirmed by confocal immunofluorescence microscopy showing constant nuclear localization of PDC-E2 and its co-localization with STAT5 after IL-3 stimulation. Similar to mitochondrial PDC-E2, nuclear PDC-E2 was lipoylated and associated with PDC-E1. Overexpression of PDC-E2 in BaF3 cells augmented IL-3-induced STAT5 activity as measured by reporter assay with consensus STAT5-binding sites. Consistent with the reporter data, PDC-E2 overexpression in BaF3 cells led to elevated mRNA levels of endogenous SOCS3 (suppressor of cytokine signaling 3) gene, a known STAT5 target. We further identified two functional STAT5-binding sites in the SOCS3 gene promoter important for its IL-3-inducibility. The observation that both cis-acting elements were essential to detect the stimulatory effect by PDC-E2 strongly supports the role of PDC-E2 in up-regulating the transactivating ability of STAT5. All together, our results reveal a novel function of PDC-E2 in the nucleus. It also raises the possibility of nuclear-mitochondrial crosstalk through the interaction between STAT5 and PDC-E2.

Dataset Information

Nuclear localization of signal transducer and activator of transcription 3 in head and neck squamous cell carcinoma is associated with a better prognosis.

Publications

Nuclear localization of signal transducer and activator of transcription 3 in head and neck squamous cell carcinoma is associated with a better prognosis.

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