RNA methyltransferase NSUN2 enhances vasculogenic mimicry and malignant progression of cervical cancer through upregulation of MMP-9.

Vasculogenic mimicry (VM), which creates an endothelium-independent tumor microcirculation, is associated with tumor metastasis and drug resistance, which are key challenges in the clinical treatment of cervical cancer (CC). The malignant progression of a variety of tumors is supported by the 5-methylcytidine (m(5)C) modification of RNA. In the present study, potential relationships between VM formation and the m(5)C modification in CC were investigated. Immunohistochemistry of CC tissues and a tissue microarray revealed that VM is prevalent in CC tissues but not in paracancerous tissues, and VM formation is associated with a poor prognosis in CC. Matrix metalloproteinase-9 (MMP-9) is highly expressed in CC tissues and in cell lines exposed to hypoxia. Using dot blotting and methylated RNA immunoprecipitation analyses, the m(5)C modification was shown to be enriched in bulk RNA and in MMP-9 mRNA isolated from VM-competent cultured CC cells. The NOP2/Sun RNA methyltransferase 2 (NSUN2) was highly expressed in CC tissues and cells and its expression was associated with poor prognosis in CC. Genetic interference with NSUN2 expression decreased VM formation in CC cells and it led to lower MMP-9 expression, suggesting that NSUN2 stabilizes MMP-9 mRNA. This model, in which NSUN2 enhances VM by increasing MMP-9 expression, identified novel potential markers for early diagnosis of CC and potential therapeutic targets in the future.