Radiotherapy-induced cell death activates paracrine HMGB1-TLR2 signaling and accelerates pancreatic carcinoma metastasis

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Xuelian Chen, Lirong Zhang, Yujie Jiang, Lian Song, Yanfang Liu, Fang Cheng, Xin Fan, Xiongfeng Cao, Aihua Gong, Dongqing Wang, Haitao Zhu
Publisher: BMC
Publication year: 2018
Journal: Journal of Experimental and Clinical Cancer Research
Journal acronym: J EXP CLIN CANC RES
Volume number: 37
Number of pages: 15
ISSN: 1756-9966


Abstract

Background: Dying cells after irradiation could promote the repopulation of surviving cancer cells leading to tumor recurrence. We aim to define the role of dying cells in promoting pancreatic cancer cells metastasis following radiotherapy.Methods: Using the transwell system as the in vitro co-culture model, a small number of untreated pancreatic cancer cells were seeded in the upper chamber, while a larger number of lethally treated pancreatic cancer cells were seeded in the lower chamber. A series of experiments were conducted to investigate the role of dying-cell-derived HMGB1 on the invasion of pancreatic cancer in vitro and cancer metastasis in vivo. We then designed shRNA knockdown and Western blot assays to detect signaling activity.Results: We found that dying pancreatic cancer cells significantly promote the invasion of pancreatic cancer cells in vitro and cancer metastasis in vivo. HMGB1 gene knockdown attenuated the migration-stimulating effect of irradiated, dying cells on living pancreatic cancer cells. Finally, we showed that dying-cell-derived HMGB1 functions in a paracrine manner to affect cancer-cell migration dependent on acquiring an epithelial-mesenchymal transition (EMT) phenotype and PI3K/pAkt activation. This process is mediated by the receptor for TLR2.Conclusion: Our study indicates that, during radiotherapy, dying pancreatic cancer cells activate paracrine signaling events that promote the mobility of surviving tumor cells. We suggest a strategy to inhibit HMGB1 for preventing pancreatic carcinoma relapse and metastasis.


Keywords

HMGB1, metastasis, Pancreatic carcinoma, Radiotherapy

Last updated on 2019-16-10 at 02:36