Wei Xinyu, Tao Shuang, Mao Huilan, Zhu Haitao, Mao Lingyu, Pei Wenhao, Shi Xiuru, Shi Yingxiang, Zhang Shiwen, Wu Yulun, Wei Ke, Wang Jing, Pang Siyan, Wang Wenrui, Chen Changjie, Yang Qingling
Anhui Province Key Laboratory of Translational Cancer Research, Clinical Testing and Diagnose Experimental Center, Bengbu Medical College, Anhui 233030, China.
Anhui Province Key Laboratory of Translational Cancer Research, Department of Life Sciences, Bengbu Medical College, Anhui 233030, China.
Gene. 2023 Apr 15;860:147230. doi: 10.1016/j.gene.2023.147230. Epub 2023 Jan 27.
The lncRNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) has been associated with the development, metastasis and drug resistance of breast cancer (BC). However, the mechanisms underlying NEAT1-induced paclitaxel resistance in the microenvironment of BC remain unclear. In this study, NEAT1 expression was found to be high in paclitaxel-resistant BC cells (SKBR3/PR cells) and exosomes derived from these cells. NEAT1 promoted the migration of BC cells and their resistance to paclitaxel, whereas its downregulation reduced the drug resistance. In addition, downregulation of NEAT1 decreased the migration and proliferation of BC cells by inhibiting the expression of CXCL12 by reducing the adsorption of miR-133b. Furthermore, inhibition of miR-133b reversed the interference of NEAT1 and CXCL12 in paclitaxel resistance, migration and proliferation of BC cells. Knockdown of NEAT1 in a xenograft-bearing mouse model remarkably inhibited cancer progression and improved the response to paclitaxel. Altogether, this study revealed that SKBR3/PR cell-derived exosomal lncRNA NEAT1 can induce paclitaxel resistance and cell migration and growth in the tumour microenvironment of BC and may serve as a new target for the clinical treatment of BC.
长链非编码RNA核旁斑组装转录本1（lncRNA NEAT1）与乳腺癌（BC）的发生、转移及耐药性相关。然而，在BC微环境中，NEAT1诱导紫杉醇耐药的机制仍不清楚。本研究发现，在紫杉醇耐药的BC细胞（SKBR3/PR细胞）及其来源的外泌体中，NEAT1表达较高。NEAT1促进BC细胞的迁移及其对紫杉醇的耐药性，而其表达下调则降低耐药性。此外，NEAT1表达下调通过减少miR-133b的吸附抑制CXCL12的表达，从而降低BC细胞的迁移和增殖。此外，抑制miR-133b可逆转NEAT1和CXCL12对BC细胞紫杉醇耐药性、迁移和增殖的干扰。在荷瘤小鼠模型中敲低NEAT1可显著抑制肿瘤进展并改善对紫杉醇的反应。总之，本研究表明，SKBR3/PR细胞来源的外泌体长链非编码RNA NEAT1可在BC肿瘤微环境中诱导紫杉醇耐药及细胞迁移和生长，可能成为BC临床治疗的新靶点。
