J Cancer 2021; 12(2):518-529. doi:10.7150/jca.51049

Research Paper

High mobility group box 1 regulates gastric cancer cell proliferation and migration via RAGE-mTOR/ERK feedback loop

Tuo Tang1,2, Shengnan Wang1,2, Tianyu Cai3, Zhenyu Cheng3, Yu Meng1,2, Shimei Qi1,2✉, Yao Zhang1,2✉, Zhilin Qi1,2✉

1. Department of Biochemistry and Molecular Biology.
2. Anhui Province Key Laboratory of Active Biological Macro-molecules.
3. School of Clinical Medicine, Wannan Medical College, Wuhu, Anhui 241002, P.R. China.

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Citation:
Tang T, Wang S, Cai T, Cheng Z, Meng Y, Qi S, Zhang Y, Qi Z. High mobility group box 1 regulates gastric cancer cell proliferation and migration via RAGE-mTOR/ERK feedback loop. J Cancer 2021; 12(2):518-529. doi:10.7150/jca.51049. Available from https://www.jcancer.org/v12p0518.htm

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Abstract

Gastric cancer (GC) is a common malignancy tumour in China. Despite various therapeutic approaches to improve the survival rate of GC patients, the effectiveness of currently available treatments remains unsatisfactory. High mobility group box 1 (HMGB1) is reported to play a role in tumour development. However, the molecular mechanisms involved in HMGB1-mediated regulation of proliferation and migration of GC cells remain unclear. In the present study, we demonstrated that HMGB1 is highly expressed in GC cells and tissue. In HGC-27 GC cells, HMGB1 overexpression or HMGB1 RNA interference both demonstrated that HMGB1 could promote GC cell proliferation and migration. Investigation of the underlying molecular mechanisms revealed that HMGB1 enhanced cyclins expression, induced epithelial-to-mesenchymal transition and matrix metalloproteinase (MMPs) expression and promoted RAGE expression as well as RAGE-mediated activation of Akt/mTOR/P70S6K and ERK/P90RSK/CREB signalling pathways. We also found that inhibition of ERK and mTOR using specific inhibitors reduced recombinant human HMGB1-induced RAGE expression, suggesting that the RAGE-mTOR/ERK positive feedback loop is involved in HMGB1-induced GC cell proliferation and migration. Our study highlights a novel mechanism by which HMGB1 promotes GC cell proliferation and migration via RAGE-mediated Akt-mTOR and ERK-CREB signalling pathways which also involves the RAGE-mTOR/ERK feedback loop. These findings indicate that HMGB1 is a potential therapeutic target for GC.

Keywords: High mobility group box 1 (HMGB1), gastric cancer, proliferation, migration, RAGE, Akt/mTOR, ERK