Research Papers:

Novel chemokine-like activities of histones in tumor metastasis

Ruochan Chen _, Yangchun Xie, Xiao Zhong, Yongmin Fu, Yan Huang, Yixiang Zhen, Pinhua Pan, Haichao Wang, David L. Bartlett, Timothy R. Billiar, Michael T. Lotze, Herbert J. Zeh, III, Xue-Gong Fan, Daolin Tang and Rui Kang

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Oncotarget. 2016; 7:61728-61740. https://doi.org/10.18632/oncotarget.11226

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Ruochan Chen1,2, Yangchun Xie2, Xiao Zhong1, Yongmin Fu1, Yan Huang1, Yixiang Zhen1, Pinhua Pan3, Haichao Wang4, David L. Bartlett2, Timothy R. Billiar2, Michael T. Lotze2, Herbert J. Zeh III2, Xue-Gong Fan1, Daolin Tang2,5, Rui Kang2

1Department of Infectious Diseases and State Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China

2Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA

3Department of Pneumology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China

4Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA

5Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, China

Correspondence to:

Xue-Gong Fan, email: [email protected]

Daolin Tang, email: [email protected]

Rui Kang, email: [email protected]

Keywords: histone, TLR4, NF-κB, metastasis, hepatocellular carcinoma

Received: May 07, 2016    Accepted: July 28, 2016    Published: August 11, 2016


Histones are intracellular nucleosomal components and extracellular damage-associated molecular pattern molecules that modulate chromatin remodeling, as well as the immune response. However, their extracellular roles in cell migration and invasion remain undefined. Here, we demonstrate that histones are novel regulators of tumor metastasis with chemokine-like activities. Indeed, exogenous histones promote both hepatocellular carcinoma (HCC) cell migration and invasion through toll-like receptor (TLR)4, but not TLR2 or the receptor for advanced glycosylation end product. TLR4-mediated activation of nuclear factor-κB (NF-κB) by extracellular signal-regulated kinase (ERK) is required for histone-induced chemokine (e.g., C-C motif ligand 9/10) production. Pharmacological and genetic inhibition of TLR4-ERK-NF-κB signaling impairs histone-induced chemokine production and HCC cell migration. Additionally, TLR4 depletion (by using TLR4-/- mice and TLR4-shRNA) or inhibition of histone release/activity (by administration of heparin and H3 neutralizing antibody) attenuates lung metastasis of HCC cells injected via the tail vein of mice. Thus, histones promote tumor metastasis of HCC cells through the TLR4-NF-κB pathway and represent novel targets for treating patients with HCC.

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