Human Cancer Biology Contrasting Expression Patterns of Histone mRNA and microRNA 760 in Patients with Gastric Cancer

Purpose:Recent studies revealed that both disseminated tumor cells and noncancerous cells contributed to cancer progression cooperatively in the bone marrow. Here, RNA-seq analysis of bone marrow from gastric cancer patients was performed to identify prognostic markers for gastric cancer. Experimental Design: Bone marrow samples from eight gastric cancer patients (stages I and IV: n 1⁄4 4 each)were used for RNA-seq analysis. Results were validated through quantitative real-time PCR (qRT-PCR) analysis of HIST1H3D expression in 175 bone marrow, 92 peripheral blood, and 115 primary tumor samples from gastric cancer patients.miR-760 expression was assayed using qRT-PCR in 105 bone marrow and 96 primary tumor samples. Luciferase reporter assays were performed to confirm whether histone mRNAs were direct targets of miR-760. miR-760 expression was also evaluated in noncancerous cells from gastric cancer patients. Results: RNA-seq analysis of bone marrow samples from gastric cancer patients revealed higher expression of multiple histone mRNAs in stage IV patients. HIST1H3D expression in the bone marrow, peripheral blood, andprimary tumor of stage IVpatients was higher than that in stage I patients (P1⁄4 0.0284, 0.0243, and0.0006, respectively). In contrast,miR-760was downregulated in the bonemarrowandprimary tumor of stage IV patients compared with stage I patients (P 1⁄4 0.0094 and 0.0018, respectively). Histone mRNAandmiR-760 interacted directly. Furthermore,miR-760was downregulated in noncancerousmucosa in stage IV gastric cancer patients. Conclusion:HistonemRNAwas upregulated, whereasmiR-760was downregulated in the bonemarrow and primary tumor of advanced gastric cancer patients, suggesting that the histonemRNA/miR-760 axis had a crucial role in the development of gastric cancer. Clin Cancer Res; 1–12. 2013 AACR.

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