Tumor hypoxia and circular RNAs (circRNAs) are considered to play key roles in tumor progression and malignancy, respectively. Nevertheless, the biological functions and underlying mechanisms of specific circRNAs exposed to hypoxic microenvironments in colorectal cancer (CRC) remain largely elusive. Herein, a novel circRNA, circTDRD3, which is upregulated under hypoxic conditions, was identified. The expression of circTDRD3 was highly expressed in CRC tissues and positively correlated with overall survival, tumor size, lymph node invasion and clinical stage. CircTDRD3 facilitated CRC cell proliferation, migration and metastasis in vitro and in vivo. Mechanistically, circTDRD3 promoted HIF1α expression by sponging miR-1231, which facilitated CRC progression. Meanwhile, HIF1α directly combined with TDRD3 promoter to increase the expression of TDRD3 pre-mRNA. Then HIF1a-induced PTBP1 accelerated the formation of circTDRD3. Our findings reveal that circTDRD3 facilitates the proliferation and metastasis of CRC through a positive feedback loop mediated by the HIF1α/PTBP1/circTDRD3/miR-1231/HIF1α axis. Therefore, circTDRD3 may serve as a prognostic biomarker and therapeutic target for patients with CRC.
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The previously published sequencing data that were re-analyzed in the current study are available via the accession code GEO126094 and GEO138589. The post-hypoxia database analyzed in this study were shown in Supplementary Table S8.
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This work was supported by grants from the National Natural Science Foundation of China (Grant nos. 81772526 and 82072662), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (Grant no. 20191425), Shanghai Jiaotong University Medical Cross Fund (Grant no. YG2017MS28), Three year Action Plan for Clinical Skills and Clinical Innovation in Shanghai level Hospitals (Grant no. SHDC2020CR4022), Shanghai Anticancer Association Eyas Program (Grant no. SACA-CY21C08 to PZ) and China Postdoctoral Science Foundation (Grant no. 2021M702182 to PZ).
The authors declare no competing interests.
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Fu, Z., Zhang, P., Zhang, R. et al. Novel hypoxia-induced HIF1α-circTDRD3-positive feedback loop promotes the growth and metastasis of colorectal cancer. Oncogene 42, 238–252 (2023). https://doi.org/10.1038/s41388-022-02548-8