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Background: Radiation-induced bystander effect (RIBE) can promote tumor metastasis contributing to the failure of radiotherapy for esophageal squamous cell carcinoma (ESCC). Aberrant expression of DJ-1 has been identified in ESCC; however, the relationship between DJ-1 and RIBE in ESCC remains unknown. Methods: We detected DJ-1 in the serum and cell supernatants by enzyme-linked immunosorbent assay (ELISA) and evaluated tumor metastasis by phenotypic experiments in vivo and in vitro. RNA-seq, mass spectrometry, western blot (WB), immunoprecipitation (IP), and dual-luciferase reporter assays were performed to explore the underlying mechanisms. Results: DJ-1 was highly expressed in the serum of patients with ESCC receiving radiotherapy and was significantly overexpressed in the medium of ESCC cells receiving irradiation. DJ-1 promoted tumor metastasis via the TGF-β1 pathway. Mechanistic studies revealed that DJ-1 bound to HSC70 to promote Smad3 phosphorylation and nuclear aggregation in a protein-interaction manner, which activated the transcription of Thrombospondin-1 (TSP1). Subsequently, the activation of TGF-β1 by TSP1 re-promoted Smad3 phosphorylation and nuclear aggregation, constituting a positive feedback loop to strengthen the metastasis of ESCC cells, which was effectively blocked by LY2109761 and LSKL. Moreover, higher levels of serum DJ-1 in patients with ESCC were related to a poorer prognosis of radiotherapy. Conclusions: Irradiation can induce ESCC cells secreting DJ-1. Secreted DJ-1 enters bystander cells to initiate activation of the TGF-β1 pathway via the DJ-1/HSC70/Smad3 signaling axis. The TSP1/TGF-β1/Smad3 positive feedback pathway constitutes the core pathway that promotes ESCC metastasis. DJ-1 is a useful biomarker for predicting the efficacy of radiotherapy and a potential therapeutic target for reversing RIBE in ESCC. Schematic diagram showing the underlying mechanism that irradiation-induced secretion of DJ-1 accelerates the metastasis of bystander ESCC cells. [ABSTRACT FROM AUTHOR]

This study was aimed to evaluate the clinical values of single markers and combination in the diagnosis, short-term efficacy and recurrence risk assessment of esophageal squamous cell carcinoma (ESCC). Methods: Totally 50 patients with I-IVa stage ESCC, 50 healthy controls and 11 patients with recurrent esophageal cancer after comprehensive treatment were enrolled. Serum biomarkers were collected and evaluated. Serum concentrations of carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) and neuron specific enolase (NSE) were measured by enzyme-linked immunosorbent assay before and after treatment. Results: The diagnostic efficacy ROC curve area of CEA, CYFRA21-1 and NSE in esophageal cancer was 0.70, 0.71 and 0.64(all P <0.05), respectively, the sensitivity was 80%, 88.89% and 60% respectively, and the specificity was 53%, 58.5% and 58% respectively. The sensitivity and specificity of the combined detection were 68% and 78% respectively. The area under ROC curve was 0.75. CEA, CYFRA21-1 and NSE were significantly higher than the healthy control group and thus can be used as diagnostic markers of esophageal cancer (all P <0.05). After standard treatment, the clinical CR and PR rate of patients with positive CYFRA21-1 or NSE before treatment was significantly lower than that of patients with negative CYFRA21-1 or NSE (X2 = 4.52,P =0.03). A significant negative correlation was found between N stage and clinical efficacy (HR 2.48, 95%CI 1.07-5.73). After comprehensive treatment, the serum CYFRA21-1 and NSE levels in recurrent patients also increased significantly(all P<0.05), indicating these two markers play obvious roles in recurrence monitoring. Conclusion: CYFRA21-1 and NSE may help to predict the response of ESCC to CRT, and play important roles in the diagnosis and recurrence monitoring of esophageal cancer. These markers have a diagnostic value of esophageal cancer when combined with CEA. [ABSTRACT FROM AUTHOR]