A three-lncRNA signature predicts overall survival and disease-free survival in patients with esophageal squamous cell carcinoma.

BACKGROUND: Increasing evidence shows that dysregulated long non-coding RNAs (lncRNAs) can serve as potential biomarkers for cancer prognosis. However, lncRNA signatures, as potential prognostic biomarkers for esophageal squamous cell carcinoma (ESCC), have been seldom reported. METHODS: Based on our previous transcriptome RNA sequencing analysis from 15 paired ESCC tissues and adjacent normal tissues, we selected 10 lncRNAs with high score rank and characterized the expression of those lncRNAs, by qRT-PCR, in 138 ESCC and paired adjacent normal samples. These 138 patients were divided randomly into training (n = 77) and test (n = 59) groups. A prognostic signature of lncRNAs was identified in the training group and validated in the test group and in an independent cohort (n = 119). Multivariable Cox regression analysis evaluated the independence of the signature in overall survival (OS) and disease-free survival (DFS) prediction. GO and KEGG pathway analysis, combined with cell transwell and proliferation assays, are applied to explore the function of the three lncRNAs. RESULTS: A novel three-lncRNA signature, comprised of RP11-366H4.1.1 (ENSG00000248370), LINC00460 (ENSG00000233532) and AC093850.2 (ENSG00000230838), was identified. The signature classified patients into high-risk and low-risk groups with different overall survival (OS) and disease-free survival (DFS). For the training group, median OS: 23.1 months vs. 39.1 months, P < 0.001; median DFS: 15.2 months vs. 33.3 months, P < 0.001. For the test group, median OS: 23 months vs. 59 months, P < 0.001; median DFS: 16.4 months vs. 50.8 months, P < 0.001. For the independent cohort, median OS: 22.4 months vs. 60.4 months, P < 0.001). The signature indicates that patients in the high-risk group show poor OS and DFS, whereas patients with a low-risk group show significantly better outcome. The independence of the signature was validated by multivariable Cox regression analysis. GO and KEGG pathway analysis for 588 protein-coding genes-associated with the three lncRNAs indicated that the three lncRNAs were involved in tumorigenesis. In vitro assays further demonstrated that the three lncRNAs promoted the migration and proliferation of ESCC cells. CONCLUSIONS: The three-lncRNA signature is a novel and potential predictor of OS and DFS for patients with ESCC.

Plasma Riboflavin Level is Associated with Risk, Relapse, and Survival of Esophageal Squamous Cell Carcinoma.

Riboflavin is an essential micronutrient for normal cellular activity, and deficiency may result in disease, such as cancer. We performed a case-control study to explore the association of riboflavin levels with risk and prognosis of esophageal squamous cell carcinoma (ESCC). Plasma riboflavin levels, as measured by enzyme-linked immunosorbent assay (ELISA), in ESCC patients were significantly lower than in those of healthy controls (7.04 ± 6.34 ng/ml vs. 9.32 ± 12.40 ng/ml; P < 0.05). Moreover, there was an inverse relationship between riboflavin level and risk of ESCC (odds ratio (OR) = 0.97, 95% confidence interval (CI) = 0.95-0.99, P =  0.02). The 5-year relapse-free and overall survival rates were significantly lower when riboflavin levels were ≤0.8 ng/ml than >0.8 ng/ml (relapse-free survival rate: 29.4% vs. 54.8%; overall survival rate: 28.6% vs. 55.6%). Plasma riboflavin level was an independent protective factor for both relapse-free (hazard ratio (HR) = 0.325, 95% CI = 0.161-0.657, P = 0.002) and overall survival of ESCC patients (HR = 0.382, 95% CI = 0.190-0.768, P = 0.007). In conclusion, plasma riboflavin levels are significantly related to risk and prognosis of ESCC patients, suggesting that moderate supplementation of riboflavin will decrease risk and prevent recurrence of ESCC and also improve prognosis of ESCC patients.

The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3ß 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 STAT3ß, one of the two STAT3 isoforms, is the key determinant in this context. EXPERIMENTAL DESIGN: The prognostic significance of STAT3ß and phospho-STAT3α(Y705) (pSTAT3α(Y705)) was evaluated in 286 cases of patients with esophageal squamous cell carcinoma (ESCC). STAT3ß-induced changes in the chemosensitivity to cisplatin and 5-fluorouracil were assessed both in vitro and in vivo. STAT3ß-induced changes in the frequency of cancer stem cells were evaluated using Hoechst and CD44 staining. How STAT3ß regulates STAT3α was determined using immunoprecipitation, confocal microscopy, DNA-binding, and chromatin immunoprecipitation-PCR. RESULTS: STAT3ß expression is an independent protective prognostic marker in patients with ESCC, which strongly correlated with longer overall survival (P = 0.0009) and recurrence-free survival (P = 0.0001). STAT3ß significantly decreased the cancer stem cell population, and sensitized ESCC cells to cisplatin and 5-fluorouracil in tumor xenografts. Mechanistically, STAT3ß markedly attenuated the transcription activity of STAT3α via inducing STAT3α:STAT3ß heterodimers. However, the heterodimer formation decreased the binding between STAT3α and PTPN9 (better known as PTP-MEG2), a protein tyrosine phosphatase, thereby promoting the phosphorylation of STAT3α(Y705) and enhancing its nuclear translocation and DNA binding. Correlating with this, high STAT3ß expression converts the prognostic value of pSTAT3α(Y705) from unfavorable to favorable in patients with ESCC. CONCLUSIONS: STAT3ß suppresses chemoresistance and cancer stemness by blocking the transcriptional activity of STAT3α. The paradoxical increase in pSTAT3α(Y705) induced by STAT3ß carries important implications as to how the biologic and prognostic significance of STAT3 in cancers should be interpreted.