High mobility group Box-1 inhibits cancer cell motility and metastasis by suppressing activation of transcription factor CREB and nWASP expression.

Zhenghong Zuo,Yulei Wang,Charles P Lin,Wei Dai,Bowen Li,Jingxia Li,Chuanshu Huang,Xun Che

doi:10.18632/oncotarget.2150

Zhenghong Zuo, Yulei Wang + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.2150

Copy DOI

Abstract

The ability to metastasize is a hallmark of malignant tumors, and metastasis is the principal cause of death of cancer patients. The High Mobility Group Box-1 (HMGB1) is a multifunction protein that serves as both a chromatin protein and an extracellular signaling molecule. Our current study demonstrated a novel mechanism of HMGB1 in the regulation of cancer cell actin polymerization, cell skeleton formation, cancer cell motility and metastasis. We found that knockdown of HMGB1 in human lung cancer A549 cells significantly increased cell β-actin polymerization, cell skeleton formation, cancer cell migration and invasion in vitro, as well as metastasis in vivo. And this increase could be inhibited by treatment of HMGB1 knockdown cells with recombinant human HMGB1. Further studies discovered that HMGB1 suppressed phosphorylation, nuclear translocation, and activation of CREB, by inhibiting nuclear translocation of PKA catalytic subunit. This reduces nWASP mRNA transcription and expression, further impairing cancer cell motility. Our findings on the novel mechanism underlying the HMGB1 anti-metastatic effect on cancer provides significant insight into the understanding of the nature of HMGB1 in cancer invasion and metastasis, further serving as key information for utilization of HMGB1 and its regulated downstream components as new targets for cancer therapy.

Highlights

Cancer metastasis, one of the major reasons for failure of cancer patient therapy, involves complex processes, including basement membrane degradation, cell migration, stromal invasion, angiogenesis, intravasation, adhesion, extravasation, and colonization [1, 2]
Our current studies demonstrated that knockdown of endogenous High Mobility Group Box-1 (HMGB1) increased A549 cancer cell migration is accompanied by induction of actin polymerization, cell skeleton formation and nWASP expression, suggesting that an inhibitory effect of HMGB1 on cancer cell migration and filament formation might be due to its regulation of nWASP expression
As actin acts as the basic structure and source of motile force of cell movement, our finding provides insight into the understanding of HMGB1 in the regulation of cancer cell motility, invasion, and metastasis

Summary

Introduction

One of the major reasons for failure of cancer patient therapy, involves complex processes, including basement membrane degradation, cell migration, stromal invasion, angiogenesis, intravasation, adhesion, extravasation, and colonization [1, 2]. These processes are regulated by numerous metastasis promoting and suppressing genes [3]. NWASP has been revealed as one of the signaling molecules linking actin dynamics to delamination, a cellular process with potential association with cancer cell migration

Methods

Results

Conclusion