Upregulated histamine receptorH3 promotes tumor growth and metastasis in hepatocellular carcinoma.

Deliang Yu,Jibin Li,Jianjun Zhu,Yuhong Wang,Qinchuan Zhao,Jing Hu,Jing Zhao

doi:10.3892/or.2019.7119

Abstract

Histamine receptor H3 (HRH3) is mainly expressed in the central nervous system, where it is involved in the regulation of the release of various neurotransmitters in the brain. Recent studies have demonstrated that the expression of HRH3 is upregulated in several types of cancer. However, the functional effect of HRH3 on tumor progression remains largely unknown, particularly in hepatocellular carcinoma (HCC). In the present study, the expression of HRH3 in 96 HCC patients was first evaluated, and its clinical significance was analyzed. Subsequently, the functional roles of HRH3 in HCC growth and metastasis were systematically explored in vitro and in vivo using its agonist (imetit) or antagonist (clobenpropit). It was observed that HRH3 was significantly upregulated in HCC tissues, while its expression was significantly associated with recurrence‑free survival and overall survival in HCC patients. Functional experiments also demonstrated that HRH3 upregulation facilitated the growth and metastasis of HCC cells by inducing the formation of lamellipodia. These findings revealed that HRH3 serves an important role in the growth and metastasis of HCC cells, which provides experimental evidence supporting the application of HRH3 as a potential therapeutic target in HCC treatment.

Highlights

Histamine is a biogenic amine that is released throughout the entire body of an organism via the autocrine and/or paracrine mechanisms [1,2,3]
Reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) and western blot analysis data demonstrated that Histamine receptor H3 (HRH3) was significantly upregulated in Hepatocellular carcinoma (HCC) tissues when compared with peritumor tissues (Fig. 1A and B)
The results in the present study demonstrated that HRH3 was significantly upregulated in HCC tissues and contributed to tumor progression, suggesting that increased HRH3 level may serve as a potential prognostic marker for HCC patients

Summary

Introduction

Histamine is a biogenic amine that is released throughout the entire body of an organism via the autocrine and/or paracrine mechanisms [1,2,3]. The multiple actions of histamine are mediated by its receptors, including H1, H2, H3 and H4, which belong to the family of G protein‐coupled receptors [4,5]. Histamine receptor H3 (HRH3) is an integral membrane protein that regulates neurotransmitter release [6]. Decrease in HRH3 function was linked to epileptic activity in the temporal neocortex and hippocampus of patients with pharmacoresistant mesial temporal lobe epilepsy [8]. Clobenpropit, an HRH3 antagonist, was observed to significantly lower the multiplicity of colonic adenocarcinoma, suggesting that HRH3 may be a possible oncoprotein and potential target in tumor therapies [10]. The functional roles of HRH3 in tumor growth and metastasis remain largely unknown, in HCC

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