Hypermethylation of potential tumor suppressor miR-34b/c is correlated with late clinical stage in patients with soft tissue sarcomas

Abstract

Soft tissue sarcomas (STSs) are comparatively rare malignant tumors with poor prognosis. STSs predominantly arise from mesenchymal differentiation. MicroRNA-34b/c, the transcriptional targets of tumor suppressor p53, possesses tumor suppressing property. Hypermethylation of miR-34b/c has been associated with tumorigenesis and the progression of various cancers. To determine whether aberrant miR-34b/c methylation occurs in STSs, we quantitatively evaluated the methylation level of miR-34b/c in 57 STS samples and 20 cases of peripheral blood from healthy volunteers serving as normal controls by using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. We found that miRNA34b/c is more frequently methylated in STSs (0.157±0.028) than in normal controls (0.098±0.012, p=0.038). Furthermore, the methylation levels of CpG_1.2.3, CpG_4.5.6.7, and CpG_11.12.13 of miR-34b/c were significantly higher in the STS group than in the normal control group (p<0.001). No significant differences in the methylation levels within miR-34b/c were observed between specific reciprocal translocations in STSs and nonspecific reciprocal translocations in STSs (0.146±0.039 vs. 0.168±0.035, p>0.05). The methylation levels of miR-34b/c in STSs were associated with clinical stage. The methylation levels of CpG_1.2.3, CpG_4.5.6.7, CpG_9.10, CpG_11.12.13, and CpG_14 in tumor-stage III/IV tissues were significantly higher than those in tumor-stage I/II tissues. Our findings indicated that DNA hypermethylation of the miR-34b/c is a relatively common event in STSs and is significantly correlated with late clinical stage in patients with STSs. Hypermethylation of the miR-34b/c may be pivotal in the oncogenesis and progression of STSs and may be a potential prognostic factor for STSs.

Keywords: Methylation; MircroRNA-34b/c; Soft tissue sarcomas; Translocation; Tumorigenesis.