Isoliquiritigenin reduces brain metastasis by circNAV3-ST6GALNAC5-EGFR axis in triple-negative breast cancer

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-04-21 DOI:10.1016/j.canlet.2025.217734

Yi Xie , Jindong Xie , Guoxian Huang , Jinhui Zhang , Cailu Song , Yongzhou Luo , Hailin Tang , Yuhui Tang , Xiangsheng Xiao , Chi Zhang , Zeyu Shuang , Xing Li

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引用次数: 0

Abstract

Brain metastasis (BM) is a serious complication of increasing incidence in patients with advanced breast cancer, which is characterized by swift deterioration in quality of life with few efficient therapy strategies. There is an urgent clinical requirement to devise potent therapeutic strategies for the prevention and management of brain metastases. Here, we report isoliquiritigenin (ISL), a key bioactive substance extracted from licorice root, which effectively inhibited triple-negative breast cancer (TNBC) brain metastasis (BM) by downregulation of circNAV3. CircRNAs expression analyses and functional studies, coupled with clinical significance investigations identified circNAV3 as a key molecule promoting TNBC BM. Functionally, circNAV3 could promote proliferation, migration, invasion, angiogenesis and capacity to penetrate the blood-brain barrier of TNBC cells. Mechanistically, circNAV3 could competitively bind with miR-4262, hence intercepting the suppressive effect of miR-4262 on ST6GALNAC5. Subsequently, this interplay enhanced EGFR sialylation and activation, initiating the PI3K/Akt pathway and ultimately fostering the development of TNBC brain metastases. In conclusion, our research establishes that ISL impede the initiation and advancement of TNBC brain metastasis by modulation of circNAV3/miR-4262/ST6GALNAC5/EGFR axis, laying a theoretical groundwork for the therapeutic use of ISL in this scenario.

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异尿酸原通过circNAV3-ST6GALNAC5-EGFR轴减少三阴性乳腺癌脑转移

脑转移是晚期乳腺癌患者发病率上升的严重并发症，其特点是生活质量迅速恶化，缺乏有效的治疗策略。临床迫切需要制定有效的治疗策略来预防和管理脑转移。在这里，我们报道了一种从甘草根中提取的关键生物活性物质ISL，它通过下调circNAV3有效抑制三阴性乳腺癌（TNBC）脑转移（BM）。CircRNAs的表达分析和功能研究，结合临床意义研究发现circrnav3是促进TNBC BM的关键分子。在功能上，circNAV3可以促进TNBC细胞的增殖、迁移、侵袭、血管生成和穿透血脑屏障的能力。在机制上，circNAV3可以竞争性地与miR-4262结合，从而阻断miR-4262对ST6GALNAC5的抑制作用。随后，这种相互作用增强了EGFR唾液化和激活，启动了PI3K/Akt通路，最终促进了TNBC脑转移的发展。总之，我们的研究确定了ISL通过调节circNAV3/miR-4262/ST6GALNAC5/EGFR轴阻碍TNBC脑转移的发生和进展，为ISL在这种情况下的治疗应用奠定了理论基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.