Elsevier

Laboratory Investigation

Volume 89, Issue 8, August 2009, Pages 948-959
Laboratory Investigation

Research Article
Non-histone nuclear factor HMGB1 is phosphorylated and secreted in colon cancers

https://doi.org/10.1038/labinvest.2009.47Get rights and content
Under an Elsevier user license
open archive

Abstract

The high mobility group box 1 (HMGB1) protein, a non-histone nuclear factor, is overexpressed and localizes to the cytoplasm in some cancer cells. However, the mechanism of cytoplasmic HMGB1 transport, extracellular secretion, and its role in cancer progression is not clear. To simulate the activated state of HMGB1, we mutated serine residues of nuclear localization signals (NLSs) to glutamic acid and performed transfection assays. We carried out a kinase inhibitor study and evaluated the cell migration by invasion assay. We showed that phosphorylated HMGB1 localizes in the cytoplasm of colon cancer cells and also showed the interaction of PKC and HMGB1 by immunoprecipitation analysis. Concurrent mutations at six serine residues (35, 39, 42, 46, 53, and 181) to glutamic acid induced the nuclear to cytoplasmic transport of HMGB1, which was detected in the culture medium. We also observed that the secretion of HMGB1 correlated with increased cancer cell invasiveness. Our results suggest that phosphorylated HMGB1 is transported to the cytoplasm, is subsequently secreted from the cell, and has a role in tumor progression through the activation of genes related to cell migration.

Keywords

HMGB1 phosphorylation
HMGB1 secretion
colon cancer cells
PKC
invasion

Cited by (0)

Supplementary Information accompanies the paper on the Laboratory Investigation website (http://www.laboratoryinvestigation.org)

Hyun Ju Kang and Hanna Lee: These two authors contributed equally to this work.

Supplementary information

The online version of this article (doi:10.1038/labinvest.2009.47) contains supplementary material, which is available to authorized users.