Long non‐coding RNA RACGAP1P promotes breast cancer invasion and metastasis via miR‐345‐5p/RACGAP1‐mediated mitochondrial fission

• Published in: Molecular oncology 2021-02, Vol.15 (2), p.543-559
• Main Authors: Zhou, Danmei, Ren, Kehan, Wang, Meili, Wang, Jigang, Li, Ermin, Hou, Chenjian, Su, Ying, Jin, Yiting, Zou, Qiang, Zhou, Ping, Liu, Xiuping
• Format: Article
• Language: English
• Subjects: Analysis; Breast cancer; Colon cancer; DNA microarrays; Genes; Glyceraldehyde-3-phosphate dehydrogenase; Laboratory animals; Liver cancer; Metastases; Metastasis; MicroRNAs; MiR‐345‐5p; Mitochondria; mitochondrial fission; Neomycin; Non-coding RNA; Prostate cancer; Proteins; RACGAP1; RACGAP1P; Ribonucleic acid; RNA; Therapeutic targets; Wound healing
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12866

In this study, we illustrate the potential mechanism of RACGAP1P implicated in breast cancer invasion and metastasis. In breast cancer cells, RACGAP1P could competitively bind to miR‐345‐5p, which targets RACGAP1, and therefore up‐regulate RACGAP1. RACGAP1P overexpression promoted mitochondrial fission‐mediated cell invasion via the RACGAP1P/miR‐345‐5p/RACGAP1/Drp1 network. Long non‐coding RNAs (lncRNAs) are emerging as key molecules in various cancers, yet their potential roles in the pathogenesis of breast cancer are not fully understood. Herein, using microarray analysis, we revealed that the lncRNA RACGAP1P, the pseudogene of Rac GTPase activating protein 1 (RACGAP1), was up‐regulated in breast cancer tissues. Its high expression was confirmed in 25 pairs of breast cancer tissues and 8 breast cell lines by qRT‐PCR. Subsequently, we found that RACGAP1P expression was positively correlated with lymph node metastasis, distant metastasis, TNM stage, and shorter survival time in 102 breast cancer patients. Then, in vitro and in vivo experiments were designed to investigate the biological function and regulatory mechanism of RACGAP1P in breast cancer cell lines. Overexpression of RACGAP1P in MDA‐MB‐231 and MCF7 breast cell lines increased their invasive ability and enhanced their mitochondrial fission. Conversely, inhibition of mitochondrial fission by Mdivi‐1 could reduce the invasive ability of RACGAP1P‐overexpressing cell lines. Furthermore, the promotion of mitochondrial fission by RACGAP1P depended on its competitive binding with miR‐345‐5p against its parental gene RACGAP1, leading to the activation of dynamin‐related protein 1 (Drp1). In conclusion, lncRNA RACGAP1P promotes breast cancer invasion and metastasis via miR‐345‐5p/RACGAP1 pathway‐mediated mitochondrial fission.