HMGB1 regulates SNAI1 during NSCLC metastasis, both directly, through transcriptional activation, and indirectly, in a RSF1-IT2-dependent manner.

Abstract

High-mobility group protein B1 (HMGB1) has important functions in cancer cell proliferation and metastasis. However, the mechanisms of HMGB1 function in non-small-cell lung cancer (NSCLC) remain unclear. This study aimed to investigate the underlying mechanism of HMGB1-dependent tumor cell proliferation and NSCLC metastasis. Firstly, we found high HMGB1 expression in NSCLC and showed that HMBG1 promoted proliferation, migration, and invasion of NSCLC cells. HMGB1 could bind to SNAI1 promoter and activate the expression of SNAI1. In addition, HMGB1 could transcriptionally regulate the lncRNA RSF1-IT2. RSF1-IT2 was found to function as ceRNA, sponging miR-129-5p, which targets SNAI1. Notably, HMGB1 was also identified as a target of miR-129-5p, which indicates the establishment of a positive feedback loop. Consequently, high expression of RSF1-IT2 and SNAI1 was found to closely correlate with tumor progression in both HMGB1-overexpressing xenograft nude mice and patients with NSCLC. Taken together, our findings provide new insights into molecular mechanisms of HMGB1-dependent tumor metastasis. Components of the HMGB1-RSF1-IT2-miR-129-5p-SNAI1 pathway may have a potential as prognostic and therapeutic targets in NSCLC.

• Authors: Xiao-Jin Wu, Yuan-Yuan Chen, Wen-Wen Guo, Tao Li, Hai-Bei Dong, Wei Wang, Min Xie, Gao-Lei Ma, Dong-Sheng Pei
• Journal: Molecular oncology (Mol Oncol) Vol. 14 Issue 6 Pg. 1348-1364 (06 2020) ISSN: 1878-0261 [Electronic] United States
• PMID: 32306523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• HMGB1 Protein
• MicroRNAs
• Mirn129 microRNA, human
• RNA, Long Noncoding
• SNAI1 protein, human
• Snail Family Transcription Factors

Topics

• Animals
• Base Sequence
• Carcinoma, Non-Small-Cell Lung (genetics, pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Down-Regulation (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• HMGB1 Protein (metabolism)
• Humans
• Lung Neoplasms (genetics, pathology)
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Models, Biological
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Prognosis
• Proportional Hazards Models
• RNA, Long Noncoding (genetics, metabolism)
• Regression Analysis
• Snail Family Transcription Factors (genetics, metabolism)
• Transcriptional Activation (genetics)
• Up-Regulation (genetics)