Theranostics 2020; 10(18):8211-8226. doi:10.7150/thno.44419

Research Paper

Hypoxia induced exosomal circRNA promotes metastasis of Colorectal Cancer via targeting GEF-H1/RhoA axis

Haiou Yang1#, Haiyang Zhang1#, Yuchong Yang1#, Xinyi Wang1, Ting Deng1, Rui Liu1, Tao Ning1, Ming Bai1, Hongli Li1, Kegan Zhu1, Jialu Li2,3, Qian Fan1, Guoguang Ying1✉, Yi Ba1✉

1. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huan hu xi Road 18, Tianjin, 300060, China.
2. Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, China.
3. Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Jiao-Tong University School of Medicine, Renji Hospital, China.
#These authors contributed to this work equally.

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Citation:
Yang H, Zhang H, Yang Y, Wang X, Deng T, Liu R, Ning T, Bai M, Li H, Zhu K, Li J, Fan Q, Ying G, Ba Y. Hypoxia induced exosomal circRNA promotes metastasis of Colorectal Cancer via targeting GEF-H1/RhoA axis. Theranostics 2020; 10(18):8211-8226. doi:10.7150/thno.44419. Available from http://www.thno.org/v10p8211.htm

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Abstract

Hypoxia is one of the important properties of solid tumor. However, oxygen supply within tumors is generally heterogeneous according to the distance from the nearest blood vessel. The discrepancy of metastatic potential exists between hypoxic cancer cells and relatively normoxic cancer cells. But the molecular mechanism remains poorly understood.

Methods: Differential expression of circRNAs in plasma exosomes of CRC patients and normal subjects was performed by screening. Exosomes were isolated by ultra-centrifugation and RNA expressions were determined by RT-qPCR. The migratory capacity of cells was performed by high intension imaging, wound healing assay and transwell chamber migration assay.

Results: Circ-133 is enriched in the plasma exosomes of CRC patients and increased with the disease progression. Exosomal circ-133 derived from hypoxic cells delivered into normoxic cells and promoted cancer metastasis by acting on miR-133a/GEF-H1/RhoA axis. Meanwhile, animal experiments revealed that knockdown of circ-133 can inhibit tumor metastasis. Circ-133 is expected to be a new biomarker for monitoring tumor progression and might be a novel therapeutic target.

Conclusions: Hypoxia-derived exosomal circ-133 transported into normaxic cancer cells and promoted cell migration via miR-133a/GEF-H1/RhoA axis. This study reveals a potential mechanism for that the intra-tumor heterogeneity of oxygen promote cancer progression.

Keywords: exosomes, hypoxia, circRNAs, colorectal cancer, cancer metastasis