RBM15-mediating MDR1 mRNA m(6)A methylation regulated by the TGF-beta signaling pathway in paclitaxel-resistant ovarian cancer

Ovarian cancer (OC) lacks effective biomarkers for diagnosis at an early stage and often develops chemoresistance after the initial treatment at an advanced stage. RNA-binding motif protein 15 (RBM15) is an RNA m(6)A methylation mediator that serves an oncogenic role in some cancers. However, the function and molecular mechanisms of RBM15 in ovarian tumorigenesis and chemoresistance remain to be elucidated. The present study identified the overexpression of RBM15 in OC tissues and paclitaxel (PTX)-resistant cells using reverse transcription-quantitative (q)PCR, western blotting and immunohistochemistry. Clinical data analyses showed that high expression of RBM15 was associated with poor prognosis in patients with OC. Overexpression of RBM15 led to an increase in cell viability and colony formation and a decrease in cell sensitivity to PTX and apoptosis, whereas the knockdown of RBM15 resulted in the inhibition of cell viability and colony formation in vitro and tumor formation in vivo and increased cell apoptosis and sensitivity to PTX in a time- and dose-dependent manner. Furthermore, RBM15 knockdown reduced the spheroid formation of PTX-resistant OC cells. Silencing of RBM15 decreased multidrug resistance 1 (MDR1) mRNA m(6)A methylation detected by the methylated RNA immunoprecipitation-qPCR assay and downregulated the expression of a chemo-drug efflux pump MDR1 at the mRNA and protein levels. Finally, RBM15 expression was suppressed by the activation of the TGF-beta signaling pathway. Thus, the findings revealed a TGF-beta/RBM15/MDR1 regulatory mechanism. Targeting RBM15 may provide a novel therapeutic strategy for the treatment of PTX-resistant OC.

Automated summary

This study identified the overexpression of RBM15 in ovarian cancer tissues and paclitaxel-resistant cells, and high expression of RBM15 was associated with poor prognosis in ovarian cancer patients. Overexpression of RBM15 led to increased cell viability and colony formation, decreased sensitivity to paclitaxel, and decreased apoptosis. Knockdown of RBM15 inhibited cell viability and colony formation, increased sensitivity to paclitaxel, and reduced tumor formation and sphere formation of paclitaxel-resistant ovarian cancer cells.