Long non-coding RNAs regulated by TGFβ: lncRNA-HIT mediated TGFβ-induced epithelial to mesenchymal transition in mammary epithelia

Abstract Long noncoding RNAs (lncRNAs) are emerging as key regulators in various biological processes. Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by tumor cells to depart from the primary tumor site, invade surrounding tissue, and establish distant metastases. Transforming growth factor beta (TGFβ) signaling has been shown to be a major inducer of EMT and to facilitate breast cancer metastasis. However, lncRNA in this process remains largely unknown. Here we report lncRNA profile in the mouse mammary epithelial NMuMG cells upon TGFβ induction of EMT. Among 10,802 lnRNAs profiled, over 600 were up-regulated and down-regulated during the EMT, respectively. Further, we identify that lncRNA-HIT (HOXA antisense transcript induced by TGFβ) mediates TGFβ function, i.e., depletion of lncRNA-HIT inhibits TGFβ-induced migration, invasion, and EMT in NMuMG. LncRNA-HIT is also significantly elevated in the highly metastatic 4T1 cells. Knockdown of lncRNA-HIT in 4T1 results in decrease of cell migration and invasion. Moreover, lncRNA-HIT is conserved in human and elevated expression associates with more invasive human breast carcinoma in patients. Collectively, these data suggest that a subset of lncRNAs such as lncRNA-HIT play a significant role in regulation of EMT and breast cancer invasion and metastasis, and could be potential therapeutic targets in breast cancers.