Newly identified lncRNA-45 promotes breast cancer metastasis through activating the mTOR signaling pathway

Background: Metastasis, a complex multi-stage process, is the primary cause of breast cancer-related death. Unfortunately, the molecular mechanisms underlying tumor metastasis have not been fully elucidated thus far. Long noncoding RNAs (lncRNAs) dictate the behaviours of tumor cells via multiple signaling pathways, resulting in tumor cell migration and invasion, as well as all stages of cancer progression. LncRNAs function as regulators in shaping cellular activities directly through influencing key genes involved in biological processes of the tumor, and representing promising novel targets in cancer diagnosis and therapy. We therefore sought to define the correlations between lncRNA expression and breast cancer metastasis, especially to investigate the functional pathway underlying lncRNA-mediated tumor invasion and metastasis process. Results: In this study, we compared the lncRNA transcriptome profiles between primary breast cancer 4T1 cells and high metastatic 4T1- LG12 cells. We found that many differently expressed lncRNAs greatly correlated to the metastatic propensity of 4T1-LG12 cells, particularly lncRNA-45, a new lncRNA without functional annotations, which was found to be the most upregulated lncRNA transcribed by an internal region within the regulatory associated with protein of mechanistic target of rapamycin kinase (mTOR) complex 1 (Rptor) gene. LncRNA-45 was uncovered to be involved in the epithelial-to-mesenchymal transition process of breast cancer cells, as evidenced by the observation that lncRNA-45 knockdown significantly suppressed the invasive capability of parental 4T1-LG12 cells. Molecular mechanistic investigation showed that reduced activity of mTORC1-associated pathway led to a decrease of total ribosomal protein S6 kinase, polypeptide 1 (S6K1) content and enhancement of autophagy, consequently compromising the metastatic propensity in lncRNA-45 knockdown cells. Conclusions: Overall, our experiments uncovered that the newly identified lncRNA-45 played a regulatory role in breast cancer cell metastasis. (c) 2022 Published by Elsevier Inc.

Automated summary

In this study, the transcriptome profiles of lncRNAs were compared between primary breast cancer 4T1 cells and highly metastatic 4T1-LG12 cells. It was found that many differentially expressed lncRNAs were strongly correlated with the metastatic propensity of 4T1-LG12 cells. Among them, lncRNA-45, a newly identified lncRNA, was the most upregulated lncRNA transcribed by an internal region within the Rptor gene. Functional investigation revealed that lncRNA-45 played a regulatory role in the epithelial-to-mesenchymal transition process of breast cancer cells and its knockdown significantly suppressed the invasive capability of 4T1-LG12 cells.