Nuclear Localization of Signal Transducer and Activator of Transcription 3 in Head and Neck Squamous Cell Carcinoma Is Associated with a Better Prognosis

Abstract

Purpose: 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.Experimental Design: 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.Results: 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).Conclusions: Our results indicate that high nuclear STAT3 expression levels by automated quantitative analysis are associated with favorable outcome in HNSCC.

The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma

“…6E). Importantly, our findings may explain the accumulating controversies regarding the tumor suppressor function of STAT3 in various cancer types (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). For instance, there are many publications in which the immune-detection of pSTAT3 Y705 or nuclear STAT3 was found to significantly correlate with a better outcome (9)(10)(11)(12)(13)(14).…”

“…The oncogenic potential of STAT3 has been well documented; specifically, the constitutively activated STAT3 mutant (commonly labeled STAT3C) can effectively induce malignant transformation (4), and many human cancers harbor constitutively active STAT3 (1)(2)(3). Nevertheless, accumulating evidence from both experimental and clinical studies has suggested that STAT3 may also carry a tumor suppressor role in specific contexts (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). For instance, in a mouse model of intestine adenoma, tissue-specific STAT3 gene knockout was found to enhance tumor invasion and promote tumor progression (5,6).…”

“…STAT3 expression was found to be reduced in the majority of skin squamous cell carcinomas compared with adjacent nonmalignant tissues (8). Moreover, nuclear-STAT3 or pSTAT3 Y705 was shown to correlate with a better prognosis in multiple cancers, such as head and neck squamous cell carcinoma, salivary gland cancer, low-grade or node-negative breast cancer, colorectal cancer, and nasopharyngeal carcinoma (9)(10)(11)(12)(13)(14). In a recent review article, we have speculated that the molecular basis of how STAT3 can function as a tumor suppressor and oncoprotein may be related to the existence of two STAT3 isoforms, STAT3a and STAT3b (3).…”

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

“…Thus, after being identified as an oncogene in some cancer types, 31,33 recent work has highlighted its role as tumor suppressor in glioma, hepatoma, breast, intestinal, head and neck and thyroid cancer. 11,30,[34][35][36][37][38] Interestingly, Couth et al 11 found that an autocrine IL6/gp130/JAK loop is responsible for keeping high levels of phospho-STAT3 phosphorylation in thyroid carcinoma cell lines, which in turn suppress tumorigenesis.…”

Comparative Prognostic Value of Epidermal Growth Factor Quantitative Protein Expression Compared with FISH for Head and Neck Squamous Cell Carcinoma

“…TMAs were deparaffinized and stained as previously described (14). In brief, slides were deparaffinized in 2 changes of xylene and rehydrated through changes of ethanol with decreasing concentrations.…”