Contrasting expression patterns of histone mRNA and microRNA 760 in patients with gastric cancer

Clin Cancer Res. 2013 Dec 1;19(23):6438-49. doi: 10.1158/1078-0432.CCR-12-3186. Epub 2013 Oct 4.


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 = 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, and primary tumor of stage IV patients was higher than that in stage I patients (P = 0.0284, 0.0243, and 0.0006, respectively). In contrast, miR-760 was downregulated in the bone marrow and primary tumor of stage IV patients compared with stage I patients (P = 0.0094 and 0.0018, respectively). Histone mRNA and miR-760 interacted directly. Furthermore, miR-760 was downregulated in noncancerous mucosa in stage IV gastric cancer patients.

Conclusion: Histone mRNA was upregulated, whereas miR-760 was downregulated in the bone marrow and primary tumor of advanced gastric cancer patients, suggesting that the histone mRNA/miR-760 axis had a crucial role in the development of gastric cancer.

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / secondary
  • Aged
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Bone Marrow / metabolism
  • Cell Line, Tumor
  • Female
  • Gastric Mucosa / metabolism
  • Gene Expression Regulation, Neoplastic
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Kaplan-Meier Estimate
  • Lymphatic Metastasis
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Staging
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Proportional Hazards Models
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sequence Analysis, RNA
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / mortality
  • Stomach Neoplasms / pathology
  • Transcriptome


  • Biomarkers, Tumor
  • Histones
  • MIRN760 microRNA, human
  • MicroRNAs
  • RNA, Messenger