Tumor-suppressive circRHOBTB3 is excreted out of cells via exosome to sustain colorectal cancer cell fitness.
Tumor-suppressive circRHOBTB3 is excreted out of cells via exosome to sustain colorectal cancer cell fitness.
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抑制肿瘤的 circRHOBTB3 通过外泌体从细胞中排出，以维持结直肠癌细胞的健康
DOI：
10.1186/s12943-022-01511-1
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发表时间：
2022-02-11
期刊：
影响因子：
37.3
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Chen C;Yu H;Han F;Lai X;Ye K;Lei S;Mai M;Lai M;Zhang H
阐明circRHOBTB 3在结直肠癌（CRC）发生发展中的生物学作用、环化过程及分泌途径。我们在公共数据库中对来自多种类型癌症患者的血清外泌体中的circRNA水平进行了全面分析，并通过RT-qPCR验证了CRC血清中的circRH 0 BTB 3水平高于健康供体。然后，在体外和体内研究circRHOBTB 3在结直肠癌中的功能。RNA-seq和RNA pull-down测定与质谱一起鉴定了circRH 0 BTB 3的下游信号和结合蛋白。最后，设计了反义寡核苷酸（ASO）以靶向circRHOBTB 3的环化和分泌元件用于CRC治疗。CRC患者血清中circRHOBTB 3水平升高，但组织样本中circRHOBTB 3水平下调，且下调与不良预后相关。此外，circRHOBTB 3通过抑制CRC中的代谢途径、细胞内ROS产生来发挥肿瘤抑制性circRNA的作用。发现了几个调节circRHOBTB 3环化和外泌体分泌的关键元件。此外，SNF 8被鉴定为将circRHOBTB 3分类到外泌体中。有趣的是，我们发现CRC细胞可以比正常细胞主动分泌更多的circRHOBTB 3。根据环化和外泌体分泌调控元件的序列，我们设计并合成了能够增加circRHOBTB 3表达并阻断circRHOBTB 3外泌体分泌的反义寡核苷酸。更重要的是，ASO在体内外均能抑制结直肠癌的生长和转移。circRHOBTB 3在CRC中发挥肿瘤抑制作用，并且必须从细胞中分泌出来以维持癌细胞适应性。靶向环化和外泌体分泌调控元件的ASO将成为一种新的抗肿瘤策略。在线版本包含补充材料，可通过10.1186/s12943-022-01511-1获得。
To clarify the biological roles, circularization process and secretion pathway of circRHOBTB3 in colorectal cancer (CRC) progression. We performed a comprehensive analysis of circRNA levels in serum exosomes from multiple types of cancer patients in public databases and verified the higher level of circRHOBTB3 in CRC sera versus healthy donors by RT-qPCR. Then, the function of circRHOBTB3 in CRC was investigated in vitro and in vivo. RNA-seq and RNA pull-down assays together with mass spectrometry identified the downstream signals and the binding proteins of circRHOBTB3. Finally, Antisense oligonucleotides (ASOs) were designed to target circularization and secretion elements of circRHOBTB3 for CRC therapy. circRHOBTB3 levels were increased in the sera but was downregulated in tissue samples in CRC, and the downregulation was associated with poor prognosis. Furthermore, circRHOBTB3 acts a tumor-suppressive circRNA by repressing metabolic pathways, intracellular ROS production in CRC. Several key elements were discovered to regulate circRHOBTB3 circularization and exosomal secretion. Moreover, SNF8 was identified that sorts circRHOBTB3 into exosomes. Interestingly, we found that CRC cells could actively secrete more circRHOBTB3 than normal cells. According to the sequence of regulatory elements for circularization and exosomal secretion, we designed and synthesized ASOs, which increased circRHOBTB3 expression and blocked circRHOBTB3 exosomal secretion. More importantly, ASOs could inhibit CRC growth and metastasis in vitro and in vivo. circRHOBTB3 plays a tumor-suppressive role in CRC and has to be excreted out of cells to sustain cancer cell fitness. ASOs targeting regulatory elements for circularization and exosomal secretion will become a novel antitumor strategy. The online version contains supplementary material available at 10.1186/s12943-022-01511-1.
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