The mu-opioid receptor (MOR), a membrane-bound G protein-coupled receptor, is the main target for opioids in the nervous system. MOR1 has been found in several types of cancer cells and reported to be involved in tumor progression and metastasis. However, the expression and clinical significance of MOR1 in esophageal squamous cell carcinoma (ESCC) remain unclear. In our study, the expression of MOR1 was confirmed in ESCC cell lines (KYSE180, KYSE150, and EC109) by Western blot. MOR1 was also detected on tissue microarrays of ESCC samples in 239 cases using immunohistochemical staining. We found that MOR1 was mainly located in the cytoplasm and occasionally occurred in the membrane or nucleus of ESCC cells. Moreover, results indicated that MOR1 expression in the cytoplasm was associated with lymph node metastasis (R = 0.164, P = 0.008, Kendall's tau-b-test). No more associations were found between MOR1 expression status and other clinical parameters. However, no statistical significant differences were found between MOR1 expression in the cytoplasm, nucleus/membrane, and the overall survival of ESCC patients (P = 0.848; P = 0.167; P = 0.428, respectively, log-rank test). Our results suggest that the cytoplasmic MOR1 may be a high-risk factor for lymph node metastasis of ESCC patients. We also hypothesize that MOR1 agonists used in ESCC patients should be prudent, and opioid receptor antagonists may be novel therapeutic drugs for ESCC patients.

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 Y705 (pSTAT3a Y705 ) 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 stem cells 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 ¼ 0.0009) and recurrence-free survival (P ¼ 0.0001). STAT3b significantly decreased the cancer stem cell population, and sensitized ESCC cells to cisplatin and 5-fluorouracil in tumor xenografts. Mechanistically, STAT3b markedly 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 Y705 and enhancing its nuclear translocation and DNA binding. Correlating with this, high STAT3b expression converts the prognostic value of pSTAT3a Y705 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 Y705 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. Ó2015 AACR.

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