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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common solid tumor and the third leading cause of cancer-related mortality worldwide, in Asia [1]
We found that TLR4-mediated nuclear factor-κB (NF-κB) activation is required for the chemokine-like activity of histones in hepatocellular carcinoma (HCC) cells
We demonstrated that histones, as nuclear damage-associated molecular pattern molecules (DAMPs), promote the migration and invasion of HCC cells via activation of NF-κB-dependent chemokine production and release (Figure 7D)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common solid tumor and the third leading cause of cancer-related mortality worldwide, in Asia [1]. Curative resection has prolonged the five-year survival rate of HCC patients, recurrence and metastasis following curative resection are sadly common [2]. Tumor progression with metastasis is the main cause of death in HCC patients, which underlying regulatory mechanisms promote this process are still not fully understood [3]. The tumor microenvironment is recognized as a key factor in multiple stages of HCC [4]; it is composed of a several cell types and factors including stellate cells, myeloid and lymphoid cells, cytokines, chemokines, and growth factors, as well as damage-associated molecular pattern molecules (DAMPs). DAMPs are elevated in the serum of cancer patients, they may have different biological effects during tumorigenesis and interfere with the efficacy of cancer therapy via binding to respective receptors important for cancer progression [7, 8]
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