Hypoxia induced cellular and exosomal RPPH1 promotes breast cancer angiogenesis and metastasis through stabilizing the IGF2BP2/FGFR2 axis.

IF 6.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Oncogene Pub Date : 2024-11-04 DOI:10.1038/s41388-024-03213-y

Wentao Ning, Jingyan Yang, Ruiqi Ni, Qianqian Yin, Manqi Zhang, Fangfang Zhang, Yue Yang, Yanfeng Zhang, Meng Cao, Liang Jin, Yi Pan

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Abstract

Metastasis is the major cause of breast cancer mortality, with angiogenesis and tumor-released exosomes playing key roles. However, the communication between breast cancer cells and endothelial cells and its role in tumor metastasis remains unclear. Here, we characterize a long noncoding RNA, RPPH1, which is upregulated in breast cancer tissues and positively associated with poor prognosis. Hypoxia microenvironment upregulates the expression of RPPH1 in breast cancer cells, and promotes its packaging into exosomes through hnRNPA1, leading to the maintenance of stemness and aggressive traits in cancer cells and angiogenesis in endothelial cells. The function of cellular and exosomal RPPH1 was confirmed in the MMTV-PyMT mouse model, in which ASO-RPPH1 therapy effectively inhibited tumor progression and metastasis. Mechanistically, RPPH1 protects IGF2BP2 from ubiquitination-induced degradation, stabilizes N6-methyladenosine (m6A)-modified FGFR2 mRNA, and activates the PI3K/AKT pathway. Our research unveils the role of RPPH1 in breast cancer metastasis and highlights its potential as a therapeutic target.

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缺氧诱导的细胞和外泌体 RPPH1 通过稳定 IGF2BP2/FGFR2 轴促进乳腺癌血管生成和转移。

转移是乳腺癌死亡的主要原因，其中血管生成和肿瘤释放的外泌体起着关键作用。然而，乳腺癌细胞与内皮细胞之间的通讯及其在肿瘤转移中的作用仍不清楚。在这里，我们研究了一种长非编码 RNA RPPH1，它在乳腺癌组织中上调，并与不良预后呈正相关。缺氧微环境会上调乳腺癌细胞中 RPPH1 的表达，并通过 hnRNPA1 促进其包装成外泌体，从而导致癌细胞干性和侵袭性特征的维持以及内皮细胞的血管生成。细胞和外泌体 RPPH1 的功能在 MMTV-PyMT 小鼠模型中得到了证实，其中 ASO-RPPH1 疗法有效抑制了肿瘤的进展和转移。从机理上讲，RPPH1能保护IGF2BP2免于泛素化诱导的降解，稳定N6-甲基腺苷（m6A）修饰的FGFR2 mRNA，并激活PI3K/AKT通路。我们的研究揭示了 RPPH1 在乳腺癌转移中的作用，并强调了其作为治疗靶点的潜力。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.