Novel chemokine-like activities of histones in tumor metastasis
| Autor: | Yixiang Zhen, Xiao Zhong, Ruochan Chen, Timothy R. Billiar, Xue Gong Fan, Haichao Wang, Daolin Tang, Yongmin Fu, Yan Huang, Pinhua Pan, Yangchun Xie, Rui Kang, Herbert J. Zeh, David L. Bartlett, Michael T. Lotze |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Chemokine Glycosylation NF-κB Metastasis Histones Mice chemistry.chemical_compound 0302 clinical medicine Cell Movement TLR4 Neoplasm Metastasis RNA Small Interfering Extracellular Signal-Regulated MAP Kinases biology Liver Neoplasms Cell migration hepatocellular carcinoma Chromatin Nucleosomes 3. Good health Histone Oncology 030220 oncology & carcinogenesis RNA Interference Chemokines Signal transduction Signal Transduction Research Paper Carcinoma Hepatocellular histone Chromatin remodeling 03 medical and health sciences Cell Line Tumor medicine Animals metastasis Neoplasm Invasiveness business.industry medicine.disease Toll-Like Receptor 2 Mice Inbred C57BL Toll-Like Receptor 4 TLR2 030104 developmental biology chemistry Immune System Immunology biology.protein business Neoplasm Transplantation |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Ruochan Chen 1, 2 , Yangchun Xie 2 , Xiao Zhong 1 , Yongmin Fu 1 , Yan Huang 1 , Yixiang Zhen 1 , Pinhua Pan 3 , Haichao Wang 4 , David L. Bartlett 2 , Timothy R. Billiar 2 , Michael T. Lotze 2 , Herbert J. Zeh, III 2 , Xue-Gong Fan 1 , Daolin Tang 2, 5 , Rui Kang 2 1 Department of Infectious Diseases and State Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China 2 Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA 3 Department of Pneumology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China 4 Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA 5 Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510150, China Correspondence to: Xue-Gong Fan, email: xgfan@hotmail.com Daolin Tang, email: tangd2@upmc.edu Rui Kang, email: kangr@upmc.edu Keywords: histone, TLR4, NF-κB, metastasis, hepatocellular carcinoma Received: May 07, 2016 Accepted: July 28, 2016 Published: August 11, 2016 ABSTRACT 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. |
| Databáze: | OpenAIRE |
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