Abstract
The RNA component of mitochondrial RNA-processing endoribonuclease (RMRP) was recently shown to play a role in cancer development. However, the function and mechanism of RMRP during cancer progression remain incompletely understood. Here, we report that RMRP is amplified and highly expressed in various malignant cancers, and the high level of RMRP is significantly associated with their poor prognosis, including breast cancer. Consistent with this, ectopic RMRP promotes proliferation and migration of TP53-mutated breast cancer cells, whereas depletion of RMRP leads to inhibition of their proliferation and migration. RNA-seq analysis reveals AKT as a downstream target of RMRP. Interestingly, RMRP indirectly elevates AKT expression by preventing AKT mRNA from miR-206-mediated targeting via a competitive sequestering mechanism. Remarkably, RMRP endorses breast cancer progression in an AKT-dependent fashion, as knockdown of AKT completely abolishes RMRP-induced cancer cell growth and migration. Altogether, our results unveil a novel role of the RMRP-miR-206-AKT axis in breast cancer development, providing a potential new target for developing an anti-breast cancer therapy.
Highlights
The past decade has witnessed the growing importance of the non-coding RNAs as critical regulators of almost all biological aspects of human cancer (Esteller, 2011; Wolin and Maquat, 2019)
We found that the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP) gene is amplified and overexpressed in a variety of human cancers, and the high level of RMRP is significantly associated with poor prognosis of multiple cancers, including breast cancer
The expression of RMRP was preferentially upregulated in cancerous tissues compared to normal tissues (Figure 1B and Supplementary Figure 1A) by mining the Gene Expression Omnibus (GEO) and UALCAN databases (Chandrashekar et al, 2017)
Summary
The past decade has witnessed the growing importance of the non-coding RNAs (ncRNA) as critical regulators of almost all biological aspects of human cancer (Esteller, 2011; Wolin and Maquat, 2019). Long non-coding RNAs (lncRNA) and microRNAs (miRNA) constitute the majority of ncRNA (Garzon et al, 2009; Gibb et al, 2011). LncRNAs are a group of ncRNAs with >200 nucleotides (Schmitt and Chang, 2016), while miRNAs represent a group of small regulatory RNAs with 18-23 nucleotides in length (Garneau et al, 2007; Fabian et al, 2010). Activation of AKT by RMRP have been proposed to illustrate how lncRNAs might function in cancer (Schmitt and Chang, 2016; He et al, 2019). It has been shown that a number of highly expressed lncRNAs are able to act as competitive endogenous RNAs (ceRNAs) to sequester microRNAs (miRNAs) away from their mRNA targets (Tay et al, 2014). Because of the increasingly complex network with the addition of ncRNAs in cancer, more efforts are needed to thoroughly dissect the molecular basis underlying the role of lncRNAs in disease development
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