Hsa_circ_0008305 Facilitates the Malignant Progression of Hepatocellular Carcinoma by Regulating AKR1C3 Expression and Sponging MiR-379-5p

Overview

Journal Sci Rep

Date 2025 Jan 8

PMID 39779892

Authors

Shenglan Huang

Kan Liu

Yongkan Xu

Hua Wang

Shumin Fu

Jianbing Wu

Affiliations

Soon will be listed here.

Abstract

Circular RNAs (circRNAs) are widely involved in diverse biological processes of cancers. Nonetheless, the potential function of hsa_circ_0008305 in hepatocellular carcinoma (HCC) remains largely unknown. This study aims to elucidate the role and underlying mechanism of hsa_circ_0008305 in HCC. Our findings reveal that the novel circRNA hsa_circ_0008305 (circPTK2) is significantly upregulated in HCC tissues, with its elevated expression being positively correlated with advanced tumor T stage and vascular invasion. The circular characteristics and subcellular localization of hsa_circ_0008305 was determined by RNase R treatment and RNA nucleocytoplasmic separation. Further functional assays, including CCK8, EdU, colony formation assays, scratch-healing, transwell assays, and Xenograft tumor models were conducted to explore the biological functions of circPTK2. The regulatory mechanisms of circPTK2 were elucidated through RNA sequencing, enrichment analysis, and dual luciferase reporter assay. Our findings indicate that circPTK2 is stably localized in the cytoplasm. Functionally, circPKT2 promoted the HCC cells proliferation, migration, and invasion both in vitro and vivo. Mechanistically, circPTK2 was found to positively regulates the expression of AKR1C3 by acting as a sponge for miR-379-5p. Inhibition of miR-379-5p significantly mitigates the biological effects induced by circPTK2. AKR1C3 is identified as a direct target of miR-379-5p, and silencing AKR1C3 overturns the promotion progression effects of miR-379-5p inhibitor. In conclusion, our results revealed that circPTK2 facilitates the malignant progression of HCC via sponging miR-379-5p to up-regulate AKR1C3 expression.

References

Zhou Y, Mao X, Peng R, Bai D . CircRNAs in hepatocellular carcinoma: characteristic, functions and clinical significance. Int J Med Sci. 2022; 19(14):2033-2043. PMC: 9724243. DOI: 10.7150/ijms.74713. View

Liu C, Chen L . Circular RNAs: Characterization, cellular roles, and applications. Cell. 2022; 185(12):2016-2034. DOI: 10.1016/j.cell.2022.04.021. View

Zhang X, Li S, Gu Y, Xiao L, Ma X, Chen X . CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis. Mol Cancer. 2024; 23(1):113. PMC: 11131253. DOI: 10.1186/s12943-024-02030-x. View

Liu Z, Yang F, Xiao Z, Liu Y . Review of novel functions and implications of circular RNAs in hepatocellular carcinoma. Front Oncol. 2023; 13:1093063. PMC: 9986438. DOI: 10.3389/fonc.2023.1093063. View

Parikh N, Pillai A . Recent Advances in Hepatocellular Carcinoma Treatment. Clin Gastroenterol Hepatol. 2021; 19(10):2020-2024. DOI: 10.1016/j.cgh.2021.05.045. View

Liang M, Chen H, Min J . miR-379-5p inhibits proliferation and invasion of the endometrial cancer cells by inhibiting expression of ROR1. Acta Biochim Pol. 2021; 68(4):659-665. DOI: 10.18388/abp.2020_5538. View

Cheng D, Wang J, Dong Z, Li X . Cancer-related circular RNA: diverse biological functions. Cancer Cell Int. 2021; 21(1):11. PMC: 7789196. DOI: 10.1186/s12935-020-01703-z. View

Zhang Z, Xie Q, He D, Ling Y, Li Y, Li J . Circular RNA: new star, new hope in cancer. BMC Cancer. 2018; 18(1):834. PMC: 6102867. DOI: 10.1186/s12885-018-4689-7. View

Wang M, Chen D, Zhang H, Luo C . Circular RNA circPTK2 modulates migration and invasion via miR-136/NFIB signaling on triple-negative breast cancer cells in vitro. Inflamm Res. 2022; 71(4):409-421. DOI: 10.1007/s00011-022-01548-4. View

10.

Hu Z, Chen G, Zhao Y, Gao H, Li L, Yin Y . Exosome-derived circCCAR1 promotes CD8 + T-cell dysfunction and anti-PD1 resistance in hepatocellular carcinoma. Mol Cancer. 2023; 22(1):55. PMC: 10024440. DOI: 10.1186/s12943-023-01759-1. View

11.

Tian Y, Xiao H, Yang Y, Zhang P, Yuan J, Zhang W . Crosstalk between 5-methylcytosine and N-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma. Mol Cancer. 2023; 22(1):5. PMC: 9830866. DOI: 10.1186/s12943-022-01706-6. View

12.

Pan D, Yang W, Zeng Y, Qin H, Xu Y, Gui Y . AKR1C3 regulated by NRF2/MAFG complex promotes proliferation via stabilizing PARP1 in hepatocellular carcinoma. Oncogene. 2022; 41(31):3846-3858. DOI: 10.1038/s41388-022-02379-7. View

13.

Chen L . The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol. 2016; 17(4):205-11. DOI: 10.1038/nrm.2015.32. View

14.

Jansson A, Gunnarsson C, Cohen M, Sivik T, Stal O . 17beta-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer. Cancer Res. 2006; 66(23):11471-7. DOI: 10.1158/0008-5472.CAN-06-1448. View

15.

Conn V, Chinnaiyan A, Conn S . Circular RNA in cancer. Nat Rev Cancer. 2024; 24(9):597-613. DOI: 10.1038/s41568-024-00721-7. View

16.

Siegel R, Miller K, Fuchs H, Jemal A . Cancer statistics, 2022. CA Cancer J Clin. 2022; 72(1):7-33. DOI: 10.3322/caac.21708. View

17.

Zhong T, Xu F, Xu J, Liu L, Chen Y . Aldo-keto reductase 1C3 (AKR1C3) is associated with the doxorubicin resistance in human breast cancer via PTEN loss. Biomed Pharmacother. 2015; 69:317-25. DOI: 10.1016/j.biopha.2014.12.022. View

18.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

19.

Wang B, Gu Y, Hui K, Huang J, Xu S, Wu S . AKR1C3, a crucial androgenic enzyme in prostate cancer, promotes epithelial-mesenchymal transition and metastasis through activating ERK signaling. Urol Oncol. 2018; 36(10):472.e11-472.e20. DOI: 10.1016/j.urolonc.2018.07.005. View

20.

Zhou Q, Tian W, Jiang Z, Huang T, Ge C, Liu T . A Positive Feedback Loop of AKR1C3-Mediated Activation of NF-κB and STAT3 Facilitates Proliferation and Metastasis in Hepatocellular Carcinoma. Cancer Res. 2020; 81(5):1361-1374. DOI: 10.1158/0008-5472.CAN-20-2480. View