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Novel hypoxia-induced HIF1α-circTDRD3-positive feedback loop promotes the growth and metastasis of colorectal cancer

Abstract

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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Fig. 1: Identification and characterization of circTDRD3 in CRC.
Fig. 2: CircTDRD3 is upregulated in CRC tissues and closely related to unfavorable clinical features.
Fig. 3: CircTDRD3 knockdown suppresses CRC cell proliferation, migration and invasion in vitro.
Fig. 4: Depletion of circTDRD3 suppresses CRC cells proliferation and metastasis in vivo.
Fig. 5: HIF1α promotes transcriptionally pre-TDRD3 expresssion and synergizes with PTBP1 to induce the biogenesis of circTDRD3.
Fig. 6: CircTDRD3 acts as an efficient miR-1231 sponge in CRC.
Fig. 7: miR-1231 reverses the tumor-promoting roles of sh-circTDRD3 in RKO cells.
Fig. 8: CircTDRD3 modulated the miR-1231 direct target HIF1α.

Data availability

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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Acknowledgements

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).

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CH, PZ, BZ and ZF conceived this experiments and revised the manuscript. ZF contributed to the manuscript writing. ZF, PZ, RZ contributed to main experiments. SX and YZ contributed to bioinformatics analysis and experiments. ZF, BZ, YZ and ZL contributed to the raw data gathering and analyzing. All authors read and approved the final paper.

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Correspondence to Chen Huang.

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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

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