MicroRNA-148a is downregulated in gastric cancer, targets MMP7, and indicates tumor invasiveness and poor prognosis.
Bottom Line: Downregulation of miR-148a was significantly correlated with an advanced clinical stage, lymph node metastasis, and poor clinical outcome.Custom oligonucleotide array analysis revealed that MMP7 expression was markedly downregulated in miR-148a-overexpressing GC cells; MMP7 was found to be a direct and functional target of miR-148a, participating in cell invasion.These results suggest that miR-148a contributes to the maintenance of homeostasis in normal stomach tissue and plays an important role in GC invasion by regulating MMP7 expression.
Affiliation: Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.Show MeSH
Related in: MedlinePlus
Mentions: To confirm the localization of miR-148a expression, in situ hybridization (ISH) was carried out using GC tissues. We could detect the miR-148a expression only in fundic glands and pyloric glands. However, neither cancer cells nor stromal tissues expressed miR-148a (Fig. 1a). Then, to further understand the relationship between miR-148a expression and clinicopathologic parameters, we examined the miR-148a expression levels in 61 formalin-fixed paraffin-embedded samples of primary GC and their corresponding non-neoplastic gastric mucosa by qRT-PCR. In this sample set, miR-148a expression levels were also significantly downregulated in GC tissue compared with corresponding non-neoplastic mucosa (Fig. S2). The expression level of miR-148a was evaluated using the tumor : normal ratio of miR-148a. The relationship between the miR-148a expression level and clinicopathologic parameters of GC is summarized in Table S1. We also evaluated the association between miR-148a expression levels and cancer-specific mortality. In all cases and in 41 advanced GC patients, the GC tissues with lower expression levels of miR-148a showed significantly worse prognosis than those with high expression (Fig. 1b,c). In order to further evaluate the association of miR-148a expression with cancer-specific mortality, we used both univariate and multivariate Cox proportional hazards analyses (Table 2). According to the univariate analysis, T grade, N grade, stage, and miR-148a expression were significantly associated with cancer-specific mortality. According to the multivariate model, expression of miR-148a was an independent prognostic classifier of cancer-specific mortality. These results indicate that loss of miR-148a may play important roles in GC progression.
Affiliation: Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.