M6A RNA methylation-mediated RMRP stability renders proliferation and progression of non-small cell lung cancer through regulating TGFBR1/SMAD2/SMAD3 pathway

• Published in: Cell death and differentiation Vol. 30; no. 3; pp. 605 - 617
• Main Authors: Yin, Hang, Chen, Lin, Piao, Shiqi, Wang, Yiru, Li, Zhange, Lin, Yuan, Tang, Xueqing, Zhang, Huijuan, Zhang, Haiyang, Wang, Xiaoyuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2023; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/109; 13/2; 13/31; 13/51; 13/89; 14/32; 42; 45; 631/67/1612/1350; 631/67/68; Apoptosis; Biochemistry; Biomedical and Life Sciences; Carcinoma, Non-Small-Cell Lung - genetics; Cell Biology; Cell Cycle Analysis; Cell Line, Tumor; Cell migration; Cell proliferation; Cell Proliferation - genetics; Cisplatin; Gene Expression Regulation, Neoplastic; Genomes; Humans; Life Sciences; Lung cancer; Lung Neoplasms - pathology; Malignancy; Mesenchyme; Methylation; MicroRNAs - metabolism; Mitochondria; N6-methyladenosine; Non-coding RNA; Non-small cell lung carcinoma; Radiation therapy; Receptor, Transforming Growth Factor-beta Type I - metabolism; Ribonuclease MRP; RNA processing; RNA Stability; RNA, Long Noncoding - genetics; Smad2 protein; Smad2 Protein - metabolism; Smad3 protein; Smad3 Protein - genetics; Small cell lung carcinoma; Stem Cells
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-021-00888-8

Non-small cell lung cancer (NSCLC) has the highest mortality rate among all malignancies worldwide. The role of long noncoding RNAs (lncRNAs) in the progression of cancers is a contemporary research hotspot. Based on an integrative analysis of The Cancer Genome Atlas database, we identified lncRNA-RNA Component of Mitochondrial RNA Processing Endoribonuclease (RMRP) as one of the most highly upregulated lncRNAs that are associated with poor survival in NSCLC. Furthermore, N(6)-methyladenosine (m6A) was highly enriched within RMRP and enhanced its RNA stability. In vitro and in vivo experiments showed that RMRP promoted NSCLC cell proliferation, invasion, and migration. In terms of mechanism, RMRP recruited YBX1 to the TGFBR1 promotor region, leading to upregulation of the transcription of TGFBR1. The TGFBR1/SMAD2/SMAD3 pathway was also regulated by RMRP. In addition, RMRP promoted the cancer stem cells properties and epithelial mesenchymal transition, which promote the resistance to radiation therapy and cisplatin. Clinical data further confirmed a positive correlation between RMRP and TGFBR1. In short, our work reveals that m6A RNA methylation-mediated RMRP stability renders proliferation and progression of NSCLC through regulating TGFBR1/SMAD2/SMAD3 pathway.