Biology of Human Tumors The Opposing Function of STAT3 as an Oncoprotein andTumor Suppressor Is Dictatedby the Expression Status of STAT3b in Esophageal Squamous Cell Carcinoma

Purpose: STAT3 is known to have both oncogenic and tumor suppressive effects, but the regulation of these opposing effects is elusive. We hypothesized that STAT3b, one of the two STAT3 isoforms, is the key determinant in this context. Experimental Design: The prognostic significance of STAT3b and phospho-STAT3a (pSTAT3a) was evaluated in 286 cases of patients with esophageal squamous cell carcinoma (ESCC). STAT3b-induced changes in the chemosensitivity to cisplatin and 5-fluorouracil were assessed both in vitro and in vivo. STAT3b-induced changes in the frequency of cancer stemcells were evaluated using Hoechst and CD44 staining. How STAT3b regulates STAT3a was determined using immunoprecipitation, confocal microscopy, DNA-binding, and chromatin immunoprecipitation-PCR. Results: STAT3b expression is an independent protective prognostic marker in patients with ESCC, which strongly correlated with longer overall survival (P 1⁄4 0.0009) and recurrence-free survival (P 1⁄4 0.0001). STAT3b significantly decreased the cancer stem cell population, and sensitized ESCC cells to cisplatin and 5fluorouracil in tumor xenografts.Mechanistically, STAT3bmarkedly attenuated the transcription activity of STAT3a via inducing STAT3a:STAT3b heterodimers. However, the heterodimer formation decreased the binding between STAT3a and PTPN9 (better known as PTP-MEG2), a protein tyrosine phosphatase, thereby promoting the phosphorylation of STAT3a and enhancing its nuclear translocationandDNAbinding.Correlatingwith this, high STAT3b expression converts the prognostic value of pSTAT3a from unfavorable to favorable in patients with ESCC. Conclusions: STAT3b suppresses chemoresistance and cancer stemness by blocking the transcriptional activity of STAT3a. The paradoxical increase in pSTAT3a induced by STAT3b carries important implications as to how the biologic and prognostic significance of STAT3 in cancers should be interpreted. Clin Cancer Res; 22(3); 691–703. 2015 AACR.