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CircRNA Circ-CCND1 Aggravates Hepatocellular Carcinoma Tumorigenesis by Regulating the miR-497-5p/HMGA2 Axis

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Abstract

Circular RNAs (circRNAs) are key regulators in hepatocellular carcinoma (HCC) tumorigenesis and development, yet it is unclear whether circ-CCND1 participates in regulating HCC progression. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for detecting the expressions of circ-CCND1, microRNA (miR) -497-5p, and high mobility group AT-hook 2 (HMGA2) mRNA in HCC tissues and cell lines. Subcellular fractionation assay was used to analyze the localization of circ-CCND1 in HCC cell lines. Loss-of-function experiments were conducted to examine the effects of circ-CCND1 on HCC cell proliferation, migration, and invasion. Dual-luciferase reporter gene assay was employed for detecting the targeting relationships of circ-CCND1 and miR-497-5p, as well as miR-497-5p and HMGA2, respectively. Western blot was used to detect the regulatory functions of circ-CCND1 and miR-497-5p on HMGA1 expression at protein level. Circ-CCND1 and HMGA2 expressions in HCC were significantly up-regulated and miR-497-5p expression was markedly decreased. High circ-CCND1 expression was associated with relatively large tumor size and lymph node metastasis in HCC patients. In addition, circ-CCND1 was mainly distributed in the cytoplasm of HCC cells. Functionally, knockdown of circ-CCND1 remarkably suppressed HCC cell proliferation, migration, and invasion. Mechanistically, miR-497-5p was a direct target of circ-CCND1 and miR-497-5p specifically modulated HMGA2 expression. Furthermore, miR-497-5p inhibitors and or HMGA2 overexpression partially counteracted the suppressing effect induced by si-circ-CCND1 on the malignant phenotype of HCC cells. Circ-CCND1 plays a cancer-promoting role in HCC by modulating the miR-497-5p/HMGA2 axis. Therefore, targeting circ-CCND1 is likely to be a promising therapeutic strategy for HCC.

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References

  1. Ulahannan, S. V., Duffy, A. G., McNeel, T. S., Kish, J. K., Dickie, L. A., Rahma, O. E., McGlynn, K. A., Greten, T. F., & Altekruse, S. F. (2014). Earlier presentation and application of curative treatments in hepatocellular carcinoma. Hepatology, 60, 1637–1644.

    Article  CAS  Google Scholar 

  2. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D. M., Forman, D., & Bray, F. (2015). Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer, 136, E359–E386.

    Article  CAS  Google Scholar 

  3. Graf, D., Vallbohmer, D., Knoefel, W. T., Kropil, P., Antoch, G., Sagir, A., & Haussinger, D. (2014). Multimodal treatment of hepatocellular carcinoma. European Journal of Internal Medicine, 25, 430–437.

    Article  Google Scholar 

  4. Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., Marzluff, W. F., & Sharpless, N. E. (2013). Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA, 19, 141–157.

    Article  CAS  Google Scholar 

  5. Shang, Q., Yang, Z., Jia, R., & Ge, S. (2019). The novel roles of circRNAs in human cancer. Molecular Cancer, 18, 6.

    Article  Google Scholar 

  6. Zhang, W., Zhu, L., Yang, G., Zhou, B., Wang, J., Qu, X., Yan, Z., Qian, S., & Liu, R. (2020). Hsa_circ_0026134 expression promoted TRIM25- and IGF2BP3-mediated hepatocellular carcinoma cell proliferation and invasion via sponging miR-127-5p. Biosci Reports, 40(7), BSR20191418.

    Article  CAS  Google Scholar 

  7. Sun, C., Li, G., & Liu, M. (2020). A novel circular RNA, circ_0005394, predicts unfavorable prognosis and contributes to hepatocellular carcinoma progression by regulating miR-507/E2F3 and miR-515-5p/CXCL6 signaling pathways. Oncotargets and Therapy, 13, 6171–6180.

    Article  CAS  Google Scholar 

  8. Zang, Y., Li, J., Wan, B., & Tai, Y. (2020). CircRNA circ-CCND1 promotes the proliferation of laryngeal squamous cell carcinoma through elevating CCND1 expression via interacting with HuR and miR-646. Journal of Cellular and Molecular Medicine, 24, 2423–2433.

    Article  CAS  Google Scholar 

  9. Park, J. H., & Shin, C. (2014). MicroRNA-directed cleavage of targets: Mechanism and experimental approaches. BMB Reports, 47, 417–423.

    Article  CAS  Google Scholar 

  10. Matboli, M., Labib, M. E., Nasser, H. E., El-Tawdi, A., Habib, E. K., & Ali-Labib, R. (2020). Exosomal miR-1298 and lncRNA-RP11-583F2.2 expression in hepato-cellular carcinoma. Current Genomics, 21, 46–55.

    Article  CAS  Google Scholar 

  11. Yahya, S., & Yahya, S. (2020). The effect of miR-98 and miR-214 on apoptotic and angiogenic pathways in hepatocellular carcinoma HepG2 cells. Indian Journal of Clinical Biochemistry, 35, 353–358.

    Article  CAS  Google Scholar 

  12. Expression of Concern: Upregulation of microRNA-497-5p inhibits colorectal cancer cell proliferation and invasion via targeting PTPN3. Biosci Rep 2020;40(6):BSR-20191123_EOC.

  13. Cheng, L., Xing, Z., Zhang, P., & Xu, W. (2020). Long non-coding RNA LINC00662 promotes proliferation and migration of breast cancer cells via regulating the miR-497-5p/EglN2 axis. Acta Biochimica Polonica, 67, 229–237.

    PubMed  CAS  Google Scholar 

  14. Duan, Y., Zhao, M., Jiang, M., Li, Z., & Ni, C. (2020). LINC02476 promotes the malignant phenotype of hepatocellular carcinoma by sponging miR-497 and increasing HMGA2 expression. Oncotargets and Therapy, 13, 2701–2710.

    Article  CAS  Google Scholar 

  15. Zhao, H., Yang, Y., Wang, Y., Feng, X., Deng, A., Ou, Z., & Chen, B. (2020). MicroRNA-497-5p stimulates osteoblast differentiation through HMGA2-mediated JNK signaling pathway. Journal of Orthopaedic Surgery and Research, 15(1), 515.

    Article  Google Scholar 

  16. Hui, Y., Yang, Y., Li, D., Wang, J., Di, M., Zhang, S., & Wang, S. (2020). LncRNA FEZF1-AS1 modulates cancer stem cell properties of human gastric cancer through miR-363-3p/HMGA2. Cell Transplantation, 29, 2138917763.

    Article  Google Scholar 

  17. Wang, Y. D., Mao, J. D., Wang, J. F., & Xu, M. Q. (2020). MiR-590 suppresses proliferation and induces apoptosis in pancreatic cancer by targeting high mobility group a2. Technology in Cancer Research & Treatment, 19, 1079195791.

    Google Scholar 

  18. Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., & Kjems, J. (2013). Natural RNA circles function as efficient microRNA sponges. Nature, 495, 384–388.

    Article  CAS  Google Scholar 

  19. Liu, J., Zhang, X., Yan, M., & Li, H. (2020). Emerging role of circular RNAs in cancer. Frontiers in Oncology, 10, 663.

    Article  CAS  Google Scholar 

  20. Ding, Q., He, K., Luo, T., Deng, Y., Wang, H., Liu, H., Zhang, J., Chen, K., Xiao, J., Duan, X., Huang, R., Xia, Z., Zhou, W., He, J., Yu, H., Jiao, X., & Xiang, G. (2016). SSRP1 Contributes to the malignancy of hepatocellular carcinoma and is negatively regulated by miR-497. Molecular Therapy, 24(5), 903–914.

    Article  CAS  Google Scholar 

  21. Unachukwu, U., Chada, K., & D’Armiento, J. (2020). High mobility group AT-Hook 2 (HMGA2) oncogenicity in mesenchymal and epithelial neoplasia. International Journal of Molecular Sciences, 21(9), 3151.

    Article  CAS  Google Scholar 

  22. Guo, H. H., Wang, Y. Z., Zhang, Z. K., Li, M. Z., Tian, X. D., & Yang, Y. M. (2020). High mobility group AT-hook 2 promotes tumorigenicity of pancreatic cancer cells via upregulating ANLN. Experimental Cell Research, 393, 2088.

    Article  CAS  Google Scholar 

  23. Wang, B., Pan, L. Y., Kang, N., & Shen, X. Y. (2020). PP4R1 interacts with HMGA2 to promote non-small-cell lung cancer migration and metastasis via activating MAPK/ERK-induced epithelial-mesenchymal transition. Molecular Carcinogenesis, 59, 467–477.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Hubei Yican Health Industry Co., Ltd (Wuhan, Hubei, China) for its linguistic assistance during the preparation of this manuscript.

Funding

Yunnan Provincial high-level health and family planning personnel training program (Yun health, science and education [2017] No.14); Basic research joint special general project of local universities in Yunnan Province(2018FH001-076, 2018FH001-080).

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Author notes

  1. Sheng Zheng and Jianhong Hou contributed equally and shared first authorship.

Authors and Affiliations

  1. Department of Gastroenterology, The Third People’s Hospital of Yunnan Province, Beijing Road No.292, Guandu District, Kunming, 650011, Yunnan, China

    Sheng Zheng, Hua Yang & Juan Yang

  2. Department of Liver and Gallbladder Surgery, The Third People’s Hospital of Yunnan Province, Kunming, 650011, Yunnan, China

    Jianhong Hou

  3. Department of Medical Laboratory, The Third People’s Hospital of Yunnan Province, Kunming, 650011, Yunnan, China

    Yefei Chang

  4. Department of Obstetrics and Gynecology, Kunming Dongfang Hospital of Yunnan Province, Kunming, 650000, Yunnan, China

    Dan Zhao

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  1. Sheng Zheng
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Contributions

SZ, JH, and JY contributed to the experiment design, manuscript draft, and data analysis. JH, YC, and DZ contributed to the experiment implementation and data analysis. YC and HY collected clinical samples. All authors read and approved the final manuscript.

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Correspondence to Juan Yang.

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Zheng, S., Hou, J., Chang, Y. et al. CircRNA Circ-CCND1 Aggravates Hepatocellular Carcinoma Tumorigenesis by Regulating the miR-497-5p/HMGA2 Axis. Mol Biotechnol 64, 178–186 (2022). https://doi.org/10.1007/s12033-021-00391-y

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  • DOI: https://doi.org/10.1007/s12033-021-00391-y

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