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

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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.

Graphical Abstract

Schematic diagram showing the underlying mechanism that irradiation-induced secretion of DJ-1 accelerates the metastasis of bystander ESCC cells.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13046-022-02471-6.

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Most cited references 42

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Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Ahmedin Jemal, Lindsey A Torre, Rebecca Siegel … (2018)

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.

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JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles

Jaime Castro-Mondragon, Rafael Riudavets-Puig, Ieva Rauluseviciute … (2021)

JASPAR ( http://jaspar.genereg.net/ ) is an open-access database containing manually curated, non-redundant transcription factor (TF) binding profiles for TFs across six taxonomic groups. In this 9th release, we expanded the CORE collection with 341 new profiles (148 for plants, 101 for vertebrates, 85 for urochordates, and 7 for insects), which corresponds to a 19% expansion over the previous release. We added 298 new profiles to the Unvalidated collection when no orthogonal evidence was found in the literature. All the profiles were clustered to provide familial binding profiles for each taxonomic group. Moreover, we revised the structural classification of DNA binding domains to consider plant-specific TFs. This release introduces word clouds to represent the scientific knowledge associated with each TF. We updated the genome tracks of TFBSs predicted with JASPAR profiles in eight organisms; the human and mouse TFBS predictions can be visualized as native tracks in the UCSC Genome Browser. Finally, we provide a new tool to perform JASPAR TFBS enrichment analysis in user-provided genomic regions. All the data is accessible through the JASPAR website, its associated RESTful API, the R/Bioconductor data package, and a new Python package, pyJASPAR, that facilitates serverless access to the data.

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Deciphering the complex role of thrombospondin-1 in glioblastoma development

Thomas Daubon, Céline Léon, Kim Clarke … (2019)

We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process.

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Author and article information

Contributors

Yun Gu: guyunlcph@foxmail.com

Xinchen Sun: sunxinchen@njmu.edu.cn

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J Exp Clin Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 26 August 2022

Publication date PMC-release: 26 August 2022

Publication date Collection: 2022

Volume: 41

Electronic Location Identifier: 259

Affiliations

[1 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, The First School of Clinical Medicine, , Nanjing Medical University, ; Nanjing, China

[2 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of Radiation Oncology, , The First Affiliated Hospital of Nanjing Medical University, ; No.300 Guangzhou Road, Nanjing, 210029 China

[3 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of Endocrinology, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, China

[4 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, 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

Article

Publisher ID: 2471

DOI: 10.1186/s13046-022-02471-6

PMC ID: 9413943

PubMed ID: 36008860

SO-VID: b364a6e1-5385-42dd-9477-479c8293318b

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 22 April 2022

Date accepted : 20 August 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82073344

Award ID: 81874217

Award ID: 81672983

Award Recipient : Xinchen Sun

Funded by: General Project of Huai’an Health Scientific Research

Award ID: HAWJ202030

Award Recipient : Yun Gu

Funded by: the Jiangsu Provincial Health and Health Commission Scientific Research Project

Award ID: Z2021036

Award Recipient : Yun Gu

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: dj-1,tgf-β1,hsc70,smad3,tsp1,esophageal squamous cell carcinoma,radiation-induced bystander effect,tumor metastasis

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: dj-1, tgf-β1, hsc70, smad3, tsp1, esophageal squamous cell carcinoma, radiation-induced bystander effect, tumor metastasis

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

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Universal stem cells

Most cited references 42

Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles

Deciphering the complex role of thrombospondin-1 in glioblastoma development

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