Abnormal long noncoding RNA (lncRNA) expression plays an important role in tumor invasion and metastasis. Here, we show that lncRNA LY6E divergent transcript (LY6E-DT) levels are increased in breast cancer (BC) tissues. Transcription factor SP3 binds directly to the LY6E-DT promoter, activating its transcription. Moreover, LY6E-DT N6-methyladenosine modification by methyltransferase-like protein 14 (METTL14) promotes its expression, dependent on the “reader” insulin-like growth factor 2 mRNA binding protein 1(IGF2BP1)-dependent pathway. Notably, we discovered that the lncRNA LY6E-DT encodes a conserved 153-aa protein, “Metastatic-Related Protein” (MRP). Both LY6E-DT and MRP promote BC invasion and metastasis, and MRP expression could distinguish BC patients with lymph node metastasis from those without. Mechanistically, MRP binds heterogeneous nuclear ribonucleoproteins C1/C2 (HNRNPC), enhancing the interaction between HNRNPC and epidermal growth factor receptor (EGFR) mRNA, increasing EGFR mRNA stability and protein expression and subsequently activating the phosphatidylinositol 3‑kinase/protein kinase B signaling (PI3K) pathway. LncRNA LY6E-DT promotes the interaction between Y box binding protein 1 (YBX1) and importin α1 and increases YBX1 protein entry into the nucleus, where it transcriptionally activates zinc finger E-box-binding homeobox 1(ZEB1). Our findings uncover a novel regulatory mechanism underlying BC invasion orchestrated by LY6E-DT and its encoded MRP.

长链非编码RNA（lncRNA）异常表达在肿瘤侵袭和转移中发挥重要作用。在这里，我们发现乳腺癌（BC）组织中的lncRNA LY6E分歧转录物（LY6E-DT）水平增加。转录因子 SP3 直接与 LY6E-DT 启动子结合，激活其转录。此外，LY6E-DT N6-甲基腺苷通过甲基转移酶样蛋白 14 (METTL14) 的修饰可促进其表达，这依赖于“读取器”胰岛素样生长因子 2 mRNA 结合蛋白 1 (IGF2BP1) 依赖性途径。值得注意的是，我们发现 lncRNA LY6E-DT 编码保守的 153 个氨基酸蛋白，“转移相关蛋白”(MRP)。 LY6E-DT和MRP均促进BC侵袭和转移，MRP表达可以区分有淋巴结转移的BC患者和无淋巴结转移的BC患者。从机制上讲，MRP 结合异质核核糖核蛋白 C1/C2 (HNRNPC)，增强 HNRNPC 与表皮生长因子受体 (EGFR) mRNA 之间的相互作用，增加 EGFR mRNA 稳定性和蛋白表达，随后激活磷脂酰肌醇 3 激酶/蛋白激酶 B 信号传导。 PI3K）途径。 LncRNA LY6E-DT 促进 Y 盒结合蛋白 1 (YBX1) 和输入蛋白 α1 之间的相互作用，并增加 YBX1 蛋白进入细胞核，在细胞核中转录激活锌指 E 盒结合同源盒 1 (ZEB1)。我们的研究结果揭示了一种由 LY6E-DT 及其编码的 MRP 精心策划的 BC 入侵背后的新型调控机制。