Abstract
H1 histamine receptor (H1HR) belongs to the family of rhodopsin-like G-protein-coupled receptors. Recent studies have shown that H1HR expression is increased in several types of cancer. However, its functional roles in tumor progression remain largely unknown, especially in hepatocellular carcinoma (HCC). We found that H1HR is frequently unregulated in HCC, which is significantly associated with both recurrence-free survival and overall survival in HCC patients. Functional experiments revealed that H1HR promoted both the growth and metastasis of HCC cells by inducing cell cycle progression, formation of lamellipodia, production of matrix metalloproteinase 2, and suppression of cell apoptosis. Activation of cyclic adenosine monophosphate-dependent protein kinase A was found to be involved in H1HR-mediated HCC cell growth and metastasis. In addition, we found that overexpression of H1HR was mainly due to the downregulation of miR-940 in HCC cells. Moreover, the H1HR inhibitor terfenadine significantly suppressed tumor growth and metastasis in an HCC xenograft nude mice model. Our findings demonstrate that H1HR plays a critical role in the growth and metastasis of HCC cells, which provides experimental evidence supporting H1HR as a potential drug target for the treatment of HCC.
Highlights
These authors contributes : Jing Zhao, Yiran Hou
We found that cells with positive GPC3 and CD68 staining exhibited H1 histamine receptor (H1HR) positive staining, indicating that H1HR was expressed in both hepatocellular carcinoma (HCC) cells and infiltration myeloid cells (Supplementary Fig. S1A)
The Cancer Genome Atlas (TCGA)-based survival analysis indicated that overexpressed H1HR predicted a poor survival only in HCC patients with high CD68 expression levels, but not in HCC patients with low CD68 expression levels (Supplementary Fig. S1C, D), which further suggest that increased infiltration of myeloid may aggravate the oncogenic effects exerted by H1HR in HCC
Summary
Histamine is a ubiquitous messenger molecule with multiple physiological activities that released from neurons, mast cells, and enterochromaffin-like cells [1]. It exerts various biological effects through its four cognate G proteincoupled histamine receptors: H1, H2, H3, and H4 (H1HR, H2HR, H3HR, and H4HR, respectively) [2]. Activated PKC and PKA phosphorylate a number of substrates involved in cell signal transduction. We systematically investigated the expression and functional roles of H1HR in HCC as well as its clinical implication. Our study facilitates an understanding of the pathological roles of H1HR and provides experimental evidence for H1HR as a potential therapeutic target in HCC
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