Deletion and Down-Regulation of HRH4 Gene in Gastric Carcinomas: A Potential Correlation with Tumor Progression

BackgroundHistamine is an established growth factor for gastrointestinal malignancies. The effect of histamine is largely determined locally by the histamine receptor expression pattern. Histamine receptor H4 (HRH4), the newest member of the histamine receptor family, is positively expressed on the epithelium of the gastrointestinal tract, and its function remains to be elucidated. Previously, we reported the decreased expression of HRH4 in colorectal cancers and revealed its correlation with tumor proliferation. In the current study, we aimed to investigate the abnormalities of HRH4 gene in gastric carcinomas (GCs).
Methodology/Principal FindingsWe analyzed H4R expression in collected GC samples by quantitative PCR, Western blot analysis, and immunostaining. Our results showed that the protein and mRNA levels of HRH4 were reduced in some GC samples, especially in advanced GC samples. Copy number decrease of HRH4 gene was observed (17.6%, 23 out of 131), which was closely correlated with the attenuated expression of H4R. In vitro studies, using gastric cancer cell lines, showed that the alteration of HRH4 expression on gastric cancer cells influences tumor growth upon exposure to histamine.
Conclusions/SignificanceWe show for the first time that deletion of HRH4 gene is present in GC cases and is closely correlated with attenuated gene expression. Down-regulation of HRH4 in gastric carcinomas plays a role in histamine-mediated growth control of GC cells.

研究背景
组胺是胃肠道恶性肿瘤公认的生长因子。组胺的生物学效应在很大程度上由局部的组胺受体表达谱所决定。组胺受体H4（Histamine Receptor H4, HRH4）作为组胺受体家族的最新成员，在胃肠道上皮细胞中呈阳性表达，但其具体生理功能仍有待阐明。此前本团队已报道结直肠癌组织中HRH4表达下调，并揭示其与肿瘤增殖的相关性。本研究旨在探究胃癌（Gastric Carcinomas, GCs）中HRH4基因的异常改变。

研究方法与主要结果
本研究通过定量聚合酶链反应（qPCR）、蛋白质印迹（Western blot）及免疫染色技术，对收集的胃癌样本中H4R的表达水平进行检测。结果显示，部分胃癌样本中HRH4的蛋白与mRNA表达水平均出现下调，尤以进展期胃癌样本更为显著。在131例受试样本中，共23例（17.6%）检测到HRH4基因拷贝数缺失，该异常与H4R表达减弱密切相关。体外细胞实验以胃癌细胞系为模型，结果表明胃癌细胞中HRH4的表达改变可影响组胺介导的肿瘤生长过程。

结论与意义
本研究首次证实胃癌组织中存在HRH4基因缺失现象，且该缺失与基因表达下调显著相关。胃癌组织中HRH4表达下调，可参与组胺介导的胃癌细胞生长调控过程。