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Molecular Cancer
Published in: Molecular Cancer 1/2022

Open Access 01-12-2022 | Metastasis | Research

Tumor-suppressive circRHOBTB3 is excreted out of cells via exosome to sustain colorectal cancer cell fitness

Authors: Chaoyi Chen, Hongfei Yu, Fengyan Han, Xuan Lai, Kehong Ye, Siqin Lei, Minglang Mai, Maode Lai, Honghe Zhang

Published in: Molecular Cancer | Issue 1/2022

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Abstract

Background & Aims

To clarify the biological roles, circularization process and secretion pathway of circRHOBTB3 in colorectal cancer (CRC) progression.

Methods

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.

Results

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.

Conclusions

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.
Appendix
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Metadata
Title
Tumor-suppressive circRHOBTB3 is excreted out of cells via exosome to sustain colorectal cancer cell fitness
Authors
Chaoyi Chen
Hongfei Yu
Fengyan Han
Xuan Lai
Kehong Ye
Siqin Lei
Minglang Mai
Maode Lai
Honghe Zhang
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2022
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-022-01511-1

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