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Abstract
BackgroundEarlier studies have reported the production of histamine in colorectal cancers (CRCs). The effect of histamine is largely determined locally by the histamine receptor expression pattern. Recent evidence suggests that the expression level of histamine receptor H4 (HRH4) is abnormal in colorectal cancer tissues. However, the role of HRH4 in CRC progression and its clinical relevance is not well understood. The aim of this study is to evaluate the clinical and molecular phenotypes of colorectal tumors with abnormal HRH4 expression.MethodsImmunoblotting, real-time PCR, immunofluorescence and immunohistochemistry assays were adopted to examine HRH4 expression in case-matched CRC samples (n = 107) and adjacent normal tissues (ANTs). To assess the functions of HRH4 in CRC cells, we established stable HRH4-transfected colorectal cells and examined cell proliferation, colony formation, cell cycle and apoptosis in these cells.ResultsThe protein levels of HRH4 were reduced in most of the human CRC samples regardless of grade or Dukes classification. mRNA levels of HRH4 were also reduced in both early-stage and advanced CRC samples. In vitro studies showed that HRH4 over-expression caused growth arrest and induced expression of cell cycle proteins in CRC cells upon exposure to histamine through a cAMP -dependent pathway. Furthermore, HRH4 stimulation promoted the 5-Fu-induced cell apoptosis in HRH4-positive colorectal cells.ConclusionThe results from the current study supported previous findings of HRH4 abnormalities in CRCs. Expression levels of HRH4 could influence the histamine-mediated growth regulation in CRC cells. These findings suggested a potential role of abnormal HRH4 expression in the progression of CRCs and provided some new clues for the application of HRH4-specific agonist or antagonist in the molecular therapy of CRCs.
Highlights
Earlier studies have reported the production of histamine in colorectal cancers (CRCs)
It was found that histamine receptor H4 (HRH4) mRNA levels were significantly reduced in the CRCs (Figure 1C, p < 0.001), and there was a statistical difference between the group of early-stage CRCs and advanced CRCs (p < 0.05)
We showed that HRH4 activation could promote the 5-Fu-mediated cell apoptosis in colon cancer cells, which may provide new clues for histamine receptor-targeted therapies of CRCs
Summary
Earlier studies have reported the production of histamine in colorectal cancers (CRCs). Recent evidence suggests that the expression level of histamine receptor H4 (HRH4) is abnormal in colorectal cancer tissues. The aim of this study is to evaluate the clinical and molecular phenotypes of colorectal tumors with abnormal HRH4 expression. Colorectal cancer is the uncontrolled growth of malignant cells in the colon or rectum. It is currently the third most common cancer in the Chinese population, responsible for about 130,000 deaths per year. Histamine levels in cells and tissues are regulated by the activity of histidine decarboxylase (HDC), the only enzyme responsible for the generation of histamine from L-histidine. It has been shown that the levels of HDC mRNA protein and its enzymatic activity are significantly increased in both experimental and human tumors, including colorectal carcinoma [10,13,14,15]
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