LncRNA RNA Component of Mitochondrial RNA-Processing Endoribonuclease Promotes AKT-Dependent Breast Cancer Growth and Migration by Trapping MicroRNA-206

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.

The emerging role of long noncoding RNA RMRP in cancer development and targeted therapy

“…Both univariate and multivariate analyses and Kaplan-Meier survival analysis revealed that higher expression of RMRP predicted worse prognoses in CRC patients 3 . In a later study, we further reported that RMRP expression was upregulated in various human cancers, when compared with normal tissues, and upregulation of RMRP was significantly associated with unfavorable prognoses in breast cancer, head and neck carcinoma, lung adenocarcinoma, pancreatic ductal adenocarcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma 4 . However, a few studies have reported that RMRP may be downregulated in cancers and may be associated with a favorable prognosis, thereby suggesting that RMRP may have divergent roles in the context of different pathological or stressful conditions.…”

“…RMRP prevents miR-206 from directly targeting AKT mRNA for degradation by competitively binding to miR-206. More importantly, overexpression of RMRP aborts miR-206-induced repression of breast cancer cell growth and migration, while ablation of AKT completely restores RMRP-induced malignant phenotypes 4 . In agreement with our study, miR-206 was also shown to indirectly repress AKT activity by targeting EGFR, MET, PIK3C2α, HDAC6, ATG3, STC2, ROCK1, IGF-1, or FAM83A.…”

“…Because miR-206 has been shown to inactivate multiple oncogenic signal transduction pathways in cancer, it is not surprising that RMRP is also able to regulate these pathways by counteracting miR-206. We recently reported that RMRP promoted breast cancer cell growth and migration by activating the AKT pathway 4 . RMRP prevents miR-206 from directly targeting AKT mRNA for degradation by competitively binding to miR-206.…”

Advanced Analysis and Validation of a microRNA Signature for Fanconi Anemia

“…In FA patients, a defective process in hematopoietic stem and progenitor cells (HSPCs) is observed before the onset of clinical BMF, where DNA damage and replicative stress elicit p53 activity that results in a late p21/Cdkn1a-dependent G0/G1 cell-cycle. This exacerbated p53/p21 response to cellular stress and DNA damage accumulation could be a central mechanism for the progressive HSPC depletion in FA patients, and indeed, p53 knockout can rescue the HSPC defects in FA models both in vitro and in vivo [29]. Since p53 pathway signaling appears as a core signaling in FA, we quantified the expression of TP53, p21, and CDK6, which are target genes of different pathways regulated by miRNA-1246 and miRNA-206 [29][30][31].…”

A Novel Aging-Related Prognostic lncRNA Signature Correlated with Immune Cell Infiltration and Response to Immunotherapy in Breast Cancer

“…These lncRNAs have crucial effects in all kinds of biological processes, including cell multiplication, differentiation, invasion, apoptosis, and metastasis [11]. Aging-related lncRNAs (ARlncRNAs) participate in the genesis, metastasis, invasion, chemotherapy resistance, and prognosis of BC [12][13][14][15]. These studies focus on a single lncRNA in BC.…”