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  2. Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop

Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop

  • J Exp Clin Cancer Res. 2022 Aug 26;41(1):259. doi: 10.1186/s13046-022-02471-6.
Junjie Gu  # 1 2 Yuanyuan Sun  # 1 2 Jiahang Song  # 1 2 Ruiling Zhao  # 1 3 Xiaoke Di 2 Yumeng Zhang 1 2 Xiaolin Ge 2 Shu Zhang 4 Yun Gu 5 Xinchen Sun 6
Affiliations

Affiliations

  • 1 The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
  • 2 Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, No.300 Guangzhou Road, Nanjing, 210029, China.
  • 3 Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 4 Core Facility Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 5 Department of Thoracic Surgery, Lian Shui People's Hospital, Huai'an, 223400, China. guyunlcph@foxmail.com.
  • 6 Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, No.300 Guangzhou Road, Nanjing, 210029, China. sunxinchen@njmu.edu.cn.
  • # Contributed equally.
Abstract

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.

Keywords

DJ-1; Esophageal squamous cell carcinoma; HSC70; Radiation-induced bystander effect; Smad3; TGF-β1; TSP1; Tumor metastasis.

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