BANCR-containing extracellular vesicles enhance breast cancer resistance.

IF 4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Biological Chemistry Pub Date : 2025-04-01 Epub Date: 2025-02-11 DOI:10.1016/j.jbc.2025.108304

Xinming Song, Shen Liu, Ying Zeng, Yilin Cai, Haiqing Luo

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Abstract

Extracellular vesicles (EVs) are nano-sized particles secreted by many cell types-including tumor cells-and play key roles in cellular communication by transporting functional RNAs. This study aims to elucidate the role of long noncoding RNA BRAF-activated nonprotein coding RNA (BANCR) in EVs derived from breast cancer (BC) cells in trastuzumab resistance. Differentially expressed long noncoding RNA and downstream targets in BC-resistant samples were identified. SKBR-3 cells were treated with trastuzumab to generate resistant cells (SKBR-3TR), and EVs from these cells (SKBR-3TR-EVs) were isolated and characterized. Functional studies of BANCR were performed in SKBR-3 and SKBR-3TR cells. Coculturing SKBR-3 cells with SKBR-3TR-EVs assessed changes in cell behavior. A xenograft model in nude mice examined in vivo tumorigenicity and trastuzumab resistance. BANCR was highly expressed in SKBR-3TR cells and EVs, linked to trastuzumab resistance. SKBR-3TR-EVs transferred BANCR to SKBR-3 cells, where BANCR inhibited miR-34a-5p, reducing its expression. High-mobility group A1 (HMGA1) was identified as a miR-34a-5p target. BANCR activated the HMGA1/Wnt/β-catenin pathway by inhibiting miR-34a-5p, promoting resistance. In vivo experiments showed that BANCR inhibition delayed tumorigenesis and reversed trastuzumab resistance. BC cell-derived EVs containing BANCR may enhance resistance to trastuzumab by regulating the miR-34a-5p/HMGA1/Wnt/β-catenin axis, presenting a potential target for BC therapy.

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含有bancr的细胞外囊泡增强乳腺癌抵抗能力。

细胞外囊泡（EVs）是包括肿瘤细胞在内的许多细胞类型分泌的纳米级颗粒，通过运输功能性rna在细胞通讯中发挥关键作用。本研究旨在阐明lncRNA BANCR在乳腺癌（BC）细胞衍生的ev中在曲妥珠单抗耐药中的作用。鉴定bc耐药样本中差异表达的lncrna和下游靶点。用曲妥珠单抗处理SKBR-3细胞以产生耐药细胞（SKBR-3TR），并从这些细胞（SKBR-3TR- ev）中分离并表征ev。在SKBR-3和SKBR-3TR细胞中进行了BANCR的功能研究。将SKBR-3细胞与skbr - 3tr - ev共培养，评估细胞行为的变化。裸鼠异种移植物模型检测了体内致瘤性和曲妥珠单抗耐药性。BANCR在SKBR-3TR细胞和ev中高度表达，与曲妥珠单抗耐药有关。skbr - 3tr - ev将BANCR转移到SKBR-3细胞中，其中BANCR抑制miR-34a-5p，降低其表达。HMGA1被鉴定为miR-34a-5p靶点。BANCR通过抑制miR-34a-5p激活HMGA1/Wnt/β-catenin通路，促进耐药。体内实验表明，BANCR抑制延缓肿瘤发生并逆转曲妥珠单抗耐药性。含有BANCR的BC细胞源性ev可能通过调节miR-34a-5p/HMGA1/Wnt/β-catenin轴增强对曲珠单抗的耐药性，这是BC治疗的潜在靶点。

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来源期刊

Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry

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4.20%

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1233

期刊介绍： The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.