Cancer stem cells (CSCs) are considered the roots of cancer metastasis and recurrence (CSCs), due in part to their self‐renewal and therapy resistance properties. However, the underlying mechanisms for the regulation of CSC stemness are poorly understood. Recently, increasing evidence shows that long non‐coding RNAs (lncRNAs) are critical regulators for cancer cell function in various malignancies including breast cancer, but how lncRNAs regulate the function of breast cancer stem cells (BCSCs) remains to be determined. Herein, using lncRNA/mRNA microarray assays, a novel lncRNA (named lnc030) is identified, which is highly expressed in BCSCs in vitro and in vivo, as a pivotal regulator in maintaining BCSC stemness and promoting tumorigenesis. Mechanistically, lnc030 cooperates with poly(rC) binding protein 2(PCBP2) to stabilize squalene epoxidase (SQLE) mRNA, resulting in an increase of cholesterol synthesis. The increased cholesterol in turn actives PI3K/Akt signaling, which governs BCSC stemness. In summary, these findings demonstrate that a new, lnc030‐based mechanism for regulating cholesterol synthesis and stemness properties of BCSCs. The lnc030‐SQLE‐cholesterol synthesis pathway may serve as an effective therapeutic target for BCSC elimination and breast cancer treatment.

中文翻译：

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一种新型长链非编码 RNA lnc030 通过稳定 SQLE mRNA 和增加胆固醇合成来维持乳腺癌干细胞干细胞

癌症干细胞 (CSC) 被认为是癌症转移和复发 (CSC) 的根源，部分原因在于它们的自我更新和治疗抵抗特性。然而，人们对调节 CSC 干性的潜在机制知之甚少。最近，越来越多的证据表明，长链非编码 RNA (lncRNA) 是包括乳腺癌在内的各种恶性肿瘤中癌细胞功能的关键调节因子，但 lncRNA 如何调节乳腺癌干细胞 (BCSC) 的功能仍有待确定。在此，使用 lncRNA/mRNA 微阵列分析，鉴定出一种新的 lncRNA（命名为 lnc030），它在体外和体内的 BCSCs 中高度表达，作为维持 BCSC 干性和促进肿瘤发生的关键调节因子。机械地，lnc030 与 poly(rC) 结合蛋白 2(PCBP2) 协同作用以稳定角鲨烯环氧酶 (SQLE) mRNA，导致胆固醇合成增加。胆固醇升高反过来激活 PI3K/Akt 信号传导，从而控制 BCSC 干性。总之，这些研究结果表明，一种基于 lnc030 的新机制可用于调节 BCSCs 的胆固醇合成和干性特性。lnc030-SQLE-胆固醇合成途径可作为 BCSC 消除和乳腺癌治疗的有效治疗靶点。