Breast cancer is the most prevalent malignancy among women worldwide. Paclitaxel (Taxol) is a widely applied chemotherapeutic agent against breast cancer. Although Taxol therapy has achieved improvements recently, development of chemoresistance of breast cancer patients is a major obstacle, leading to therapeutic failure. Long non-coding RNAs (lncRNAs) play pivotal roles in tumorigenesis and progresses of breast cancer. However, the biological roles and molecular targets of lncRNA NEAT1 in Taxol-resistant breast cancer remain unclear. Here, we report that NEAT1 is significantly upregulated in breast tumors and cell lines. In addition, silencing NEAT1 effectively sensitizes breast cancer cells to Taxol. Bioinformatical analysis and luciferase assay demonstrated that miR-23a-3p could be sponged and downregulated by NEAT1. We demonstrated that miR-23a-3p was downregulated and functioned as a tumor suppressor in breast cancer. Furthermore, in the established Taxol-resistant MDA-MB-231 breast cancer cell line, we detected significantly increased NEAT1 expression and downregulated miR-23a-3p expression. Importantly, FOXA1 was identified and validated as a direct target of miR-23a-3p in breast cancer cells. Rescue experiments demonstrated that the restoration of miR-23a-3p in NEAT1-overexpressing Taxol-resistant breast cancer cells successfully overcame the NEAT1-promoted Taxol resistance. Taken together, our results revealed the clinical roles and molecular mechanisms for the NEAT1-mediated chemoresistance, providing new insights into the development of non-coding RNA-based therapeutic strategies for enhancing the anti-cancer effects of traditional chemotherapeutic drugs.

中文翻译：

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lncRNA NEAT1通过海绵化miR-23a-3p-FOXA1轴促进乳腺癌对紫杉醇的耐药性

乳腺癌是全世界女性中最常见的恶性肿瘤。紫杉醇（Taxol）是一种广泛应用的乳腺癌化疗药物。尽管紫杉醇疗法最近取得了进步，但乳腺癌患者的化疗耐药性的发展是一个主要障碍，导致治疗失败。长链非编码 RNA (lncRNA) 在乳腺癌的肿瘤发生和进展中起关键作用。然而，lncRNA NEAT1 在紫杉醇耐药性乳腺癌中的生物学作用和分子靶点仍不清楚。在这里，我们报告 NEAT1 在乳腺肿瘤和细胞系中显着上调。此外，沉默 NEAT1 可以有效地使乳腺癌细胞对紫杉醇敏感。生物信息学分析和荧光素酶测定表明 miR-23a-3p 可以被 NEAT1 吸收和下调。我们证明了 miR-23a-3p 在乳腺癌中被下调并作为肿瘤抑制因子发挥作用。此外，在已建立的紫杉醇抗性 MDA-MB-231 乳腺癌细胞系中，我们检测到 NEAT1 表达显着增加和 miR-23a-3p 表达下调。重要的是，FOXA1 被鉴定并验证为乳腺癌细胞中 miR-23a-3p 的直接靶标。救援实验表明，在 NEAT1 过表达的紫杉醇抗性乳腺癌细胞中恢复 miR-23a-3p 成功地克服了 NEAT1 促进的紫杉醇抗性。总之，我们的结果揭示了 NEAT1 介导的化学抗性的临床作用和分子机制，