Rab1A-Mediated Exosomal Sorting of miR-200c Enhances Breast Cancer Lung Metastasis.

IF 3.3 4区 医学 Q2 ONCOLOGY
Yuting Liu, Jie Tang, Xiaolan Qiu, Lucy A Teng, Mukesh K Sriwastva, Xuedong Han, Zhi Li, Minmin Liu, Shuangyue Liu, Dongzhu Da, Zhi Li, Linlin Zhen, Yi Ren
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引用次数: 0

Abstract

Background: Recent therapeutic approaches have improved survival rate for women with breast cancer, but the survival rate for metastatic breast cancer is still low. Exosomes released by various cells are involved in all steps of breast cancer development.

Methods: We established the multimodal imaging report expression in breast cancer cells with lentivirus vectors pGluc and pBirA to investigate the secreted exosomes. Comparative microRNA (miRNA) analysis was performed with miRNA qPCR array in mice with breast cancer lung metastasis. The co-immunoprecipitation and chromatin immunoprecipitation assays were used to identify the mechanism of miRNA sorting to exosomes. The potential therapeutic strategy using an anti-sorting antibody was used to investigate breast cancer lung metastasis.

Results: We identified 26 high- and 32 low-expression level miRNAs in exosomes from metastasis compared to those from primary tumors and normal tissues. The tumor suppressors, including miR-200c and let-7a, were reduced in tumor tissues and metastasis but increased in the respective exosomes compared to normal tissues. Furthermore, the Ras-related protein (Rab1A) facilitated miR-200c sorting to exosomes circumventing the influence of tumor suppressor miR-200c on tumor cells, while the metastatic exosome cargo miR-200c inhibited F4/80+ macrophage immune response. Administration of anti-Rab1A antibody significantly repressed the trafficking of miR-200c to exosomes and breast cancer lung metastasis.

Conclusion: Our study has identified a novel molecular mechanism for breast cancer lung metastasis mediated by exosome cargo miRNAs and provided a new therapeutic strategy for cancer immunotherapy.

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rab1a介导的miR-200c外泌体分选增强乳腺癌肺转移
背景:最近的治疗方法提高了乳腺癌妇女的生存率,但转移性乳腺癌的生存率仍然很低。各种细胞释放的外泌体参与了乳腺癌发展的所有步骤。方法:利用慢病毒载体pGluc和pBirA在乳腺癌细胞中建立多模态成像报告表达,研究其分泌的外泌体。采用miRNA qPCR阵列对乳腺癌肺转移小鼠进行比较miRNA (miRNA)分析。采用免疫共沉淀法和染色质免疫共沉淀法鉴定miRNA外泌体分选的机制。使用抗分选抗体的潜在治疗策略被用于研究乳腺癌肺转移。结果:与原发肿瘤和正常组织相比,我们在转移的外泌体中鉴定出26个高表达和32个低表达的mirna。肿瘤抑制因子,包括miR-200c和let-7a,在肿瘤组织和转移中减少,但在各自的外泌体中与正常组织相比增加。此外,ras相关蛋白(Rab1A)促进miR-200c分选到外泌体,绕过肿瘤抑制因子miR-200c对肿瘤细胞的影响,而转移性外泌体货物miR-200c抑制F4/80+巨噬细胞免疫反应。抗rab1a抗体显著抑制miR-200c向外泌体的转运和乳腺癌肺转移。结论:我们的研究发现了外泌体载货mirna介导乳腺癌肺转移的一种新的分子机制,为癌症免疫治疗提供了新的治疗策略。
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
CiteScore
4.10
自引率
0.00%
发文量
40
审稿时长
16 weeks
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