Integrative genomic analyses of the histamine H1 receptor and its role in cancer prediction

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Abstract
The human histamine receptor H1 (HRH1) gene is located on chromosome 3p25 and encodes for a 487 amino acid G protein-coupled receptor (GPCR) with a long third intracellular loop (IL3). The HRH1 predominantly couples to Gαq/11 proteins, leading to the activation of phospholipase C (PLC) and subsequent release of the second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG) followed by the activation of PKC and the release of [Ca2+]i. In the present study, we identified HRH1 genes from 14 vertebrate genomes and found that HRH1 exists in all types of vertebrates including fish, amphibians, birds and mammals. We identified 88 SNPs including 4 available alleles disrupting an existing exonic splicing enhancer and 84 SNPs causing missense mutation, which may impact the effect of histamine on the HRH1 protein. We found that the human HRH1 gene was expressed in many tissues or organs, and predominant expression of HRH1 was shown in the bone marrow, whole blood, lymph node, thymus, brain, cerebellum, retina, spinal cord, heart, smooth muscle, skeletal muscle, small intestine, colon, adipocytes, kidney, liver, lung, pancreas, thyroid salivary gland, skin, ovary, uterus, placenta, prostate and testis. When searched in the PrognoScan database, human HRH1 was also found to be expressed in bladder cancer, blood cancer, brain cancer, breast cancer, colorectal cancer, eye cancer, head and neck cancer, lung cancer, ovarian cancer, skin cancer and soft tissue cancer tissues. The relationship between the expression of HRH1 and prognosis was found to vary in different types of cancers, even in the same cancer from different databases. This implies that the function of HRH1 in these tumors may be multidimensional. GR, STAT5A and c-Myb regulatory transcription factor binding sites were identified in the HRH1 gene upstream (promoter) region, which may be involved in the effect of HRH1 in tumors.

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