Dataset Information

Deletion and down-regulation of HRH4 gene in gastric carcinomas: a potential correlation with tumor progression.

ABSTRACT:

Background

Histamine 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 findings

We 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/significance

We 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.

SUBMITTER: Zhang C

PROVIDER: S-EPMC3282702 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Deletion and down-regulation of HRH4 gene in gastric carcinomas: a potential correlation with tumor progression.

Zhang Chao C Xiong Yi Y Li Jiana J Yang Yang Y Liu Li L Wang Wen W Wang Luo L Li Manhui M Fang Zhengyu Z

PloS one 20120220 2

<h4>Background</h4>Histamine 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 correlatio ...[more]

PMID: 22363581

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Project description:BackgroundLatexin, also known as endogenous carboxypeptidase inhibitor (CPI), has been found to inhibit mouse stem cell populations and lymphoma cell proliferation, demonstrating its potential role as a tumor suppressor. Our previous study also suggested a correlation between latexin expression and malignant transformation of immortalized human gastric epithelial cells. Here, we examined latexin expression in human gastric carcinomas and investigated the effect of differential latexin expression on proliferation of gastric cancer cells in vitro and in vivo.MethodsMonoclonal antibody against human latexin was prepared and immunohistochemical analysis was performed to detect latexin expression in 41 paired gastric carcinomas and adjacent normal control tissues. Human gastric cancer cells MGC803 (latexin negative) stably transfected with LXN gene and BGC823 cells (latexin positive) stably transfected with antisense LXN gene were established for anchorage-dependent colony formation assay and tumorigenesis assay in nude mice. Differentially expressed genes in response to exogeneous latexin expression were screened using microarray analysis and identified by RT-PCR. Bisulfite sequencing was performed to analyze the correlation of the methylation status of LXN promoter with latexin expression in cell lines.ResultsImmunohistochemical analysis showed significantly reduced latexin expression in gastric carcinomas (6/41, 14.6%) compared to control tissues (31/41, 75.6%) (P < 0.05). Overexpression of LXN gene in MGC803 cells inhibited colony formation and tumor growth in nude mice. Conversely, BGC823 cells transfected with antisense LXN gene exhibited enhanced tumor growth and colony formation. Additionally, several tumor related genes, including Maspin, WFDC1, SLPI, S100P, and PDGFRB, were shown to be differentially expressed in MGC803 cells in response to latexin expression. Differential expression of Maspin and S100P was also identified in BGC823 cells while latexin expression was downregulated. Further bisulfite sequencing of the LXN gene promoter indicated CpG hypermethylation was correlated with silencing of latexin expression in human cells.ConclusionsLatexin expression was reduced in human gastric cancers compared with their normal control tissues. The cellular and molecular evidences demonstrated the inhibitory effect of latexin in human gastric cancer cell growth and tumorigenicity. These results strongly suggest the possible involvement of latexin expression in tumor suppression.

Project description:Despite improvements in the early diagnosis, prognosis and therapeutic strategies for gastric cancer (GC), human GC remains one of the most frequently diagnosed malignant tumors in the world, and the survival rate of GC patients remains very poor. Thus, a suitable therapeutic strategy for GC is important for prolonging survival. Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis, including angiogenesis, inflammation, immunosuppression and metastasis. Importantly, these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch. The development, relapse and spreading of tumors depend on new vessels that provide the nutrition, growth factors and oxygen required for continuous tumor growth. Therefore, a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis. Recently, several antiangiogenic agents have been identified, and their potential for the clinical management of GC has been tested. Here, we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC. We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor (VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC. However, most antiangiogenic agents have reported no benefit to overall survival (OS) compared to chemotherapy alone in local or advanced GC. In phase III clinical trials, only ramucirumab (anti-VEGFR blocker) and apatinib (VEGFR-TKI blocker) have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2nd-line agent combined with chemotherapy treatment in advanced GC. By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC, this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.

Dataset Information

Deletion and down-regulation of HRH4 gene in gastric carcinomas: a potential correlation with tumor progression.

Background

Methodology/principal findings

Conclusions/significance

Publications

Deletion and down-regulation of HRH4 gene in gastric carcinomas: a potential correlation with tumor progression.

Similar Datasets

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