The opposing function of STAT3 as an oncoprotein and tumor suppressor is dictated by the expression status of STAT3β in esophageal squamous cell carcinoma
A partir de 286 échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde de l'œsophage, puis menée in vitro et in vivo, cette étude met en évidence le rôle joué par l'une des deux isoformes de STAT3 (STAT3bêta) dans la fonction exercée par STAT3, suppresseur de tumeurs ou oncogène
Purpose: STAT3 is known to have both oncogenic and tumor suppressive effects, but the regulation of these opposing effects is elusive. We hypothesized that STAT3β, one of the two STAT3 isoforms, is the key determinant in this context. Experimental Design: The prognostic significance of STAT3β and phospho-STAT3αY705 (pSTAT3αY705) was evaluated in 286 cases of esophageal squamous cell carcinoma (ESCC) patients. STAT3β-induced changes in the chemosensitivity to cisplatin and 5-flurouracil were assessed both in vitro and in vivo. STAT3β-induced changes in the frequency of cancer stem cells were evaluated using Hoechst and CD44 staining. How STAT3β regulates STAT3α was determined using immunoprecipitation, confocal microscopy, DNA-binding and ChIP-PCR. Results: STAT3β expression is an independent protective prognostic marker in ESCC patients, which strongly correlated with longer overall survival (P=0.0009) and recurrence-free survival (P=0.0001). STAT3β significantly decreased the cancer stem cell population, and sensitized ESCC cells to cisplatin and 5-flurouracil in tumor xenografts. Mechanistically, STAT3β markedly attenuated the transcription activity of STAT3α via inducing STAT3α:STAT3β heterodimers. However, the heterodimer formation decreased the binding between STAT3α and PTP-MEG2, a protein tyrosine phosphatase, thereby promoting the phosphorylation of STAT3αY705 and enhancing its nuclear translocation and DNA binding. Correlating with this, high STAT3β expression converts the prognostic value of pSTAT3αY705 from unfavorable to favorable in ESCC patients. Conclusions: STAT3β suppresses chemoresistance and cancer stemness by blocking the transcriptional activity of STAT3α. The paradoxical increase in pSTAT3αY705 induced by STAT3β carries important implications as to how the biological and prognostic significance of STAT3 in cancers should be interpreted.