Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype

Abstract

Gastric cancer is composed of disease subgroups with heterogeneous clinical and biological behaviors. A previous study identified two subgroups with distinct gene-expression profiles strongly associated with prognosis. To identify molecular biologic differences between these two subgroups, we performed an integrative analysis of mRNA, microRNA, and protein expression. Array technologies were used to generate and analyze microRNA and protein expression profiles of samples from patients with gastric cancer. MicroRNA and protein expression patterns were compared between gastric cancer tissue and normal gastric tissue and also between two different prognostic groups. Aberrantly expressed microRNA and associated mRNA in patients with poor-prognosis gastric cancer were validated by quantitative RT-PCR and immunochemistry. Four microRNAs were aberrantly expressed in the two prognostic groups and in cancer vs. non-cancer tissues (P < 0.05). In the poor-prognosis subgroup, miR-196b, miR-135b, and miR-93 were up-regulated and miR-29c* down-regulated. miR-196b expression positively correlated with HOXA10 expression (r = 0.726; P < 0.001), which was significantly increased in poor-prognosis patients (P < 0.001). In gastric cancer vs. non-cancer tissues 46/124 proteins were expressed differently (P < 0.05); COX2 (P < 0.001) and cyclin B1 (P = 0.017) were clearly over-expressed in the poor-prognosis group.Integrative analysis of the transcriptome profile facilitates interpretation of the molecular biologic heterogeneity of cancer. Co-activation of miR-196b and HOXA10 characterized a poor-prognosis subgroup of patients with gastric cancer. The relevance of hematopoietic progenitor cell and gastric cancer development/progression warrants further investigation. HOXA10 maybe a key regulator of tumor progression and prognosis in patients with gastric cancer.