Circular RNA circBNC2 inhibits tumorigenesis by modulating ferroptosis and acts as a nanotherapeutic target in prostate cancer

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-01-24 DOI:10.1186/s12943-025-02234-9

Xiang Pan, Kailai Chen, Wei Gao, Meiqi Xu, Fanlong Meng, Mengyuan Wu, Zi Qi Wang, Yun Qi Li, Wanhai Xu, Manjie Zhang, Yakun Luo

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Abstract

Metastasis is a leading cause of cancer-related death in castration-resistant prostate cancer (CRPC) patients. Circular RNAs (circRNAs) have emerged as key regulators of the metastasis of various cancers. However, the functional effects and regulatory mechanisms of circRNAs in metastatic CRPC (mCRPC) remain largely unknown. The expression of circBNC2 in prostate cancer (PCa), CRPC and neuroendocrine prostate cancer (NEPC) tissues was analyzed through bioinformatics analysis. Functional assays, including cell proliferation, migration, invasion and ferroptosis, were conducted in vitro and in vivo. The interactions between circBNC2, miR-4298, and ACSL6 were explored via luciferase reporter assays, RNA immunoprecipitation, and western blotting analysis. In addition, for the first time in PCa, we developed novel nanobowls (NBs) loaded with docetaxel (DTX) and circBNC2 (Dc-NBs) and evaluated the antitumor efficacy of Dc-NBs in a photothermal therapy (PTT) strategy. We identified a novel tumor-suppressive circRNA, circBNC2, in human PCa, CRPC and NEPC samples via bioinformatic analysis. CircBNC2 expression was significantly downregulated in PCa tissues and PCa cell lines. Functional assays demonstrated that circBNC2 inhibited PCa cell proliferation and migration both in vitro and in vivo. Mechanistically, circBNC2 acted as a sponge for miR-4298, and ACSL6 was identified as a direct target of the circBNC2/miR-4298 axis. Moreover, we demonstrated that ACSL6 is essential for mediating circBNC2-regulated ferroptosis in PCa cells. More importantly, we demonstrated the nanodelivery of Dc-NBs, which exhibited significant antitumor effects in both subcutaneous and metastatic PCa models. This study revealed the tumor-suppressive role of circBNC2 in mCRPC by driving ferroptosis via the circBNC2/miR-4298/ACSL6 axis. Additionally, we developed an efficient and safe PTT strategy based on a nanodelivery system that codelivers circBNC2 and DTX, highlighting its potential as a novel therapeutic approach for mCRPC.

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环状RNA circBNC2通过调节铁下垂抑制肿瘤发生，并作为前列腺癌的纳米治疗靶点

转移是去势抵抗性前列腺癌（CRPC）患者癌症相关死亡的主要原因。环状rna （circRNAs）已成为各种癌症转移的关键调节因子。然而，circRNAs在转移性CRPC （mCRPC）中的功能作用和调控机制在很大程度上仍然未知。通过生物信息学分析circBNC2在前列腺癌（PCa）、CRPC和神经内分泌前列腺癌（NEPC）组织中的表达情况。在体外和体内进行了细胞增殖、迁移、侵袭和铁下垂等功能测定。circBNC2、miR-4298和ACSL6之间的相互作用通过荧光素酶报告基因检测、RNA免疫沉淀和western blotting分析进行了探讨。此外，我们首次在前列腺癌中开发了装载多西他赛（DTX）和circBNC2 （Dc-NBs）的新型纳米碗（NBs），并评估了Dc-NBs在光热治疗（PTT）策略中的抗肿瘤效果。通过生物信息学分析，我们在人类PCa、CRPC和NEPC样本中发现了一种新的肿瘤抑制环状rna circBNC2。CircBNC2在PCa组织和细胞系中的表达显著下调。功能分析表明，circBNC2在体外和体内均能抑制PCa细胞的增殖和迁移。在机制上，circBNC2充当miR-4298的海绵，ACSL6被确定为circBNC2/miR-4298轴的直接靶点。此外，我们证明ACSL6在介导circbnc2调节的PCa细胞铁凋亡中是必不可少的。更重要的是，我们证明了dc - nb的纳米递送，在皮下和转移性PCa模型中都表现出显著的抗肿瘤作用。本研究通过circBNC2/miR-4298/ACSL6轴驱动铁凋亡，揭示了circBNC2在mCRPC中的肿瘤抑制作用。此外，我们开发了一种高效安全的PTT策略，该策略基于纳米递送系统，可共同递送circBNC2和DTX，突出了其作为mCRPC新治疗方法的潜力。

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

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

期刊介绍： Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.

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