Long Non-coding RNA LOXL1-AS1 Drives Breast Cancer Invasion and Metastasis by Antagonizing miR-708-5p Expression and Activity

Abstract

LOXL1-AS1, a recently characterized long non-coding RNA (lncRNA), has been reported to modulate tumor progression in several types of cancer. However, the expression and role of LOXL1-AS1 in breast cancer remain unclear. In this study, we sought to identify novel lncRNA regulators engaged in breast cancer metastasis. To this end, we examined 42 cancer-related lncRNAs between MCF7 (with low metastatic potential) and MDA-MB-231 (with high metastatic potential) cells. These lncRNAs have been found to affect the invasiveness of several cancer types, but they are still undefined in breast cancer. Among the 42 candidates, LOXL1-AS1 is significantly increased in MDA-MB-231 cells relative to MCF7 cells. We also show that LOXL1-AS1 is upregulated in breast cancer tissues and cells compared to noncancerous counterparts. Increased LOXL1-AS1 expression is correlated with tumor stage and lymph node metastasis in breast cancer patients. Biologically, overexpression of LOXL1-AS1 enhances and knockdown of LOXL1-AS1 suppresses breast cancer cell migration and invasion. In vivo studies demonstrate that depletion of LOXL1-AS1 inhibits breast cancer metastasis. Mechanistically, LOXL1-AS1 sponges miR-708-5p to increase nuclear factor κB (NF-κB) activity. LOXL1-AS1 can also interact with EZH2 protein to enhance EZH2-mediated transcriptional repression of miR-708-5p. Rescue experiments indicate that co-expression of miR-708-5p attenuates LOXL1-AS1-induced invasiveness in breast cancer. In addition, there is a negative correlation between LOXL1-AS1 and miR-708-5p expression in breast cancer specimens. Overall, LOXL1-AS1 upregulation facilitates breast cancer invasion and metastasis by blocking miR-708-5p expression and activity. LOXL1-AS1 serves as a potential therapeutic target for breast cancer treatment.