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Circ_03955 promotes pancreatic cancer tumorigenesis and Warburg effect by targeting the miR-3662/HIF-1α axis

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Abstract

Objectives

Former studies found that circRNAs play an important part in the occurrence of a variety of malignant biological characteristics that are critical for cancer progression. It has been shown that circ_03955 is highly expressed and implicated with quantities of biological processes in solid tumor. However, whether circ_03955 regulates the tumorigenesis and Warburg effect of pancreatic cancer (PC) remains largely unknown.

Materials and methods

The level of circ_03955 in PC tissues and cell lines was determined by real-time qPCR (RT-qPCR). Loss-of-function and gain-of-function assays were employed to investigate the biological role of circ_03955 in cell proliferation, apoptosis, and glycolysis. RT-qPCR, western blotting, bioinformatics analysis, luciferase reporter assay, and in vivo tumorigenicity assay were employed to determine the underlying mechanisms.

Results

In this study, it was investigated that circ_03955 was up-regulated in PC clinical samples as well as PC cell lines and associated with poor clinical outcomes of PC patients. Functional assays revealed that circ_03955 exerts a certain stimulative effect on the growth of PC cells in vitro and in vivo. Circ_03955 also inhibited apoptosis and promotes Warburg effect in PC cells. Mechanistically, bioinformatics analysis indicated that circ_03955 acts as a sponge for microRNA (miR)-3662, and hypoxia-inducible factor 1ɑ (HIF-1ɑ) was one of the transcriptional targets of miR-3662. Importantly, genetic promoting of HIF-1ɑ or downregulation of miR-3662 largely compromised circ_03955 depletion mediated tumor-inhibiting effects.

Conclusions

Taken together, circ_03955 functions as a tumor promoter through miR-3662/HIF-1α axis, which might provide a novel sight for PC treatment.

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Abbreviations

PC:

Pancreatic cancer

miR:

MicroRNA

HIF-1ɑ:

Hypoxia-inducible factor 1ɑ

RT-qPCR:

Real-time qPCR

circRNAs:

CircularRNAs

wt:

Wild-type

mut:

Mutant

References

  1. Mizrahi JD, Surana R, Valle JW, et al. Pancreatic cancer[J]. Lancet. 2020;395(10242):2008–20.

    Article  CAS  Google Scholar 

  2. Paternoster S, Falasca M. The intricate relationship between diabetes, obesity and pancreatic cancer[J]. Biochim Biophys Acta Rev Cancer. 2020;1873(1):188326.

    Article  CAS  Google Scholar 

  3. Yang J, Ren B, Yang G, et al. The enhancement of glycolysis regulates pancreatic cancer metastasis[J]. Cell Mol Life Sci. 2020;77(2):305–21.

    Article  CAS  Google Scholar 

  4. Pereira SP, Oldfield L, Ney A, et al. Early detection of pancreatic cancer[J]. Lancet Gastroenterol Hepatol. 2020;5(7):698–710.

    Article  Google Scholar 

  5. Yang X, Tian W, Wang S, et al. CircRNAs as promising biomarker in diagnostic and prognostic of lung cancer: an updated meta-analysis[J]. Genomics. 2021;113(1 Pt 1):387–97.

    Article  CAS  Google Scholar 

  6. Yang X, Ye T, Liu H, et al. Expression profiles, biological functions and clinical significance of circRNAs in bladder cancer[J]. Mol Cancer. 2021;20(1):4.

    Article  CAS  Google Scholar 

  7. Huang L, Han J, Yu H, et al. CircRNA_000864 upregulates B-cell translocation gene 2 expression and represses migration and invasion in pancreatic cancer cells by binding to miR-361-3p[J]. Front Oncol. 2020;10:547942.

    Article  Google Scholar 

  8. Zhang X, Tan P, Zhuang Y, et al. hsa_circRNA_001587 upregulates SLC4A4 expression to inhibit migration, invasion, and angiogenesis of pancreatic cancer cells via binding to microRNA-223[J]. Am J Physiol Gastrointest Liver Physiol. 2020;319(6):G703–17.

    Article  CAS  Google Scholar 

  9. Chen X, Jianjun Yu, Tian H, et al. Circle RNA hsa_circRNA_100290 serves as a ceRNA for miR-378a to regulate oral squamous cell carcinoma cells growth via Glucose transporter-1 (GLUT1) and glycolysis[J]. J Cell Physiol. 2019;234(11):19130–40.

    Article  CAS  Google Scholar 

  10. Wang Z, Deng M, Chen L, et al. Circular RNA Circ-03955 promotes epithelial-mesenchymal transition in osteosarcoma by regulating miR-3662/metadherin pathway[J]. Front Oncol. 2020;10:545460.

    Article  Google Scholar 

  11. Chao Xu, Yue Yu, Ding F. Microarray analysis of circular RNA expression profiles associated with gemcitabine resistance in pancreatic cancer cells[J]. Oncol Rep. 2018;40(1):395–404.

    Google Scholar 

  12. Riera Leal A, Ortiz-Lazareno PC, Jave-Suárez LF, et al. 17beta-estradiol-induced mitochondrial dysfunction and Warburg effect in cervical cancer cells allow cell survival under metabolic stress[J]. Int J Oncol. 2020;56(1):33–46.

    PubMed  Google Scholar 

  13. Cassim S, Vučetić M, Ždralević M, et al. Warburg and beyond: the power of mitochondrial metabolism to collaborate or replace fermentative glycolysis in cancer[J]. Cancers (Basel). 2020;12(5):1119.

    Article  CAS  Google Scholar 

  14. Wang XX, Yin GQ, Zhang ZH, et al. TWIST1 transcriptionally regulates glycolytic genes to promote the Warburg metabolism in pancreatic cancer[J]. Exp Cell Res. 2020;386(1):111713.

    Article  CAS  Google Scholar 

  15. Dai W, Meng X, Mo S, et al. FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer[J]. Cell Commun Signal. 2020;18(1):7.

    Article  CAS  Google Scholar 

  16. Liang L, Chen Y, Yu Y, et al. SLC25A18 has prognostic value in colorectal cancer and represses Warburg effect and cell proliferation via Wnt signaling[J]. Am J Cancer Res. 2020;10(5):1548–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Powrózek T, Krawczyk P, Kowalski DM, et al. Plasma circulating microRNA-944 and microRNA-3662 as potential histologic type-specific early lung cancer biomarkers[J]. Transl Res. 2015;166(4):315–23.

    Article  Google Scholar 

  18. Yasui K, Izumida M, Nakagawa T, et al. MicroRNA-3662 expression correlates with antiviral drug resistance in adult T-cell leukemia/lymphoma cells[J]. Biochem Biophys Res Commun. 2018;501(4):833–7.

    Article  CAS  Google Scholar 

  19. Maharry SE, Walker CJ, Liyanarachchi S, et al. Dissection of the major hematopoietic quantitative trait locus in chromosome 6q23.3 identifies miR-3662 as a player in hematopoiesis and acute myeloid leukemia[J]. Cancer Discov. 2016;6(9):1036–51.

    Article  CAS  Google Scholar 

  20. Xiao X, Han Y, Fan D, et al. MiR-3662 suppresses cell growth, invasion and glucose metabolism by targeting HK2 in hepatocellular carcinoma cells[J]. Neoplasma. 2020;67(4):773–81.

    Article  Google Scholar 

  21. Kanamori A, Matsubara D, Saitoh Y, et al. Mint3 depletion restricts tumor malignancy of pancreatic cancer cells by decreasing SKP2 expression via HIF-1[J]. Oncogene. 2020;39(39):6218–30.

    Article  CAS  Google Scholar 

  22. Liu C, Xing H, Guo C, et al. MiR-124 reversed the doxorubicin resistance of breast cancer stem cells through STAT3/HIF-1 signaling pathways[J]. Cell Cycle. 2019;18(18):2215–27.

    Article  CAS  Google Scholar 

  23. Zhang JG, Zhou HM, Zhang X, et al. Hypoxic induction of vasculogeni- mimicry in hepatocellular carcinoma: role of HIF-1 alpha, RhoA/ROCK and Rac1/PAK signaling[J]. BMC Cancer. 2020;20(1):32.

    Article  Google Scholar 

  24. Verduci L, Strano S, Yarden Y, et al. The circRNA-microRNA code: emerging implications for cancer diagnosis and treatment[J]. Mol Oncol. 2019;13(4):669–80.

    Article  Google Scholar 

  25. Li R, Jiang J, Shi H, et al. CircRNA: a rising star in gastric cancer[J]. Cell Mol Life Sci. 2020;77(9):1661–80.

    Article  CAS  Google Scholar 

  26. Chen Z, Wang Z, Guo W, et al. TRIM35 Interacts with pyruvate kinase isoform M2 to suppress the Warburgeffect and tumorigenicity in hepatocellular carcinoma[J]. Oncogene. 2015;34(30):3946–56.

    Article  CAS  Google Scholar 

  27. Liang G, Ling Y, Mehrpour M, et al. Autophagy-associated circRNA circCDYL augments autophagy and promotes breast cancer progression[J]. Mol Cancer. 2020;19(1):65.

    Article  CAS  Google Scholar 

  28. Zheng X, Huang M, Xing L, et al. The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer[J]. Mol Cancer. 2020;19(1):73.

    Article  CAS  Google Scholar 

  29. Tao T, Yuan S, Liu J, et al. Cancer stem cell-specific expression profiles reveal emerging bladder cancer biomarkers and identify circRNA_103809 as an important regulator in bladder cancer[J]. Aging (Albany NY). 2020;12(4):3354–70.

    Article  CAS  Google Scholar 

  30. Chen Z, Zuo X, Zhang Y, et al. MiR-3662 suppresses hepatocellular carcinoma growth through inhibition of HIF-1α-mediated Warburg effect[J]. Cell Death Dis. 2018;9(5):549.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the Scientific Research Fund of Hunan Provincial Education Department (No. 20A213 and No. 19B236) and Natural Science Foundation of Hunan Province (No. 2020JJ5221) for financial support.

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Authors and Affiliations

  1. Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang Avenue, Yueyang Tower District, Yueyang City, 414000, Hunan Province, China

    A. Liu

  2. Department of Gastrointestinal Surgery, The First People’s Hospital of Yueyang, Yueyang Avenue, Yueyang Tower District, Yueyang City, 414000, Hunan Province, China

    J. Xu

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Contributions

AL was responsible for doing the experiments, acquisition of data, and analysis and drafted the manuscript. JX was responsible for designing the experiments and supervising the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to J. Xu.

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The author declares that he has no competing interests.

Ethical approval and informed consent

The studies involving human participants were reviewed and approved by the protocol in this clinical experiment was authorized by the Clinical Research Ethics Committee of The First People’s Hospital of Yueyang. The patients/participants provided their written informed consent to participate in this study. The animal study was reviewed and approved by animal manipulates were authorized by the Animal Research Ethics Committee of The First People’s Hospital of Yueyang.

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Liu, A., Xu, J. Circ_03955 promotes pancreatic cancer tumorigenesis and Warburg effect by targeting the miR-3662/HIF-1α axis. Clin Transl Oncol 23, 1905–1914 (2021). https://doi.org/10.1007/s12094-021-02599-5

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  • DOI: https://doi.org/10.1007/s12094-021-02599-5

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