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BMC Cancer
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Hepatocellular Carcinoma | Research

A hsa_circ_001726 axis regulated by E2F6 contributes to metastasis of hepatocellular carcinoma

Authors: Jiaoyu Ai, Wanlin Zhang, Wensheng Deng, Likun Yan, Lidong Zhang, Zongjing Huang, Ziyi Wu, Junhua Ai, Hai Jiang

Published in: BMC Cancer | Issue 1/2024

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Abstract

Background

CircRNAs participate in the development of hepatocellular carcinoma (HCC). This work aims to explore the key tumor promoting circRNA as a gene therapy target.

Methods

The differentially expressed gene circRNAs in HCC tumor tissues was identified by mining GSE121714 dataset. EdU staining, wound healing, transwell invasion assay, TUNEL staining and western blotting examined proliferation, migration, invasion, apoptosis and epithelial mesenchymal transition (EMT). Xenograft mouse model and orthotopic transplantation tumor mouse model were constructed to verify the role of hsa_circ_001726 in growth and metastasis of HCC. The relationship among CCT2, E2F6, hsa_circ_001726, miR-671-5p and PRMT9 was identified by RNA-fluorescence in situ hybridization, luciferase reporter assay and RNA Immunoprecipitation.

Results

Eleven differentially expressed circRNAs were found in HCC tumors. Among them, hsa_circ_001726 was highly expressed in HCC tumors and cells, which was transcribed from CCT2. As a transcription factor of CCT2, E2F6 knockdown inactivated CCT2 promoter and reduced hsa_circ_001726 expression. Moreover, hsa_circ_001726 elevated PRMT9 expression by sponging miR-671-5p, and then activated Notch signaling pathway. Additionally, hsa_circ_001726 deficiency repressed malignant phenotypes of HCC cells, including proliferation, migration, invasion, EMT and apoptosis. In vivo, hsa_circ_001726 deficiency reduced tumor growth and lung metastasis of HCC in xenograft mouse models and orthotopic transplantation tumor mouse models.

Conclusion

Hsa_circ_001726 functioned as an oncogene in HCC, which was derived from CCT2 and regulated by E2F6. Hsa_circ_001726 elevated PRMT9 expression by sponging miR-671-5p, and then activated Notch signaling pathway, thereby accelerating malignant phenotypes of HCC. Therefore, targeting hsa_circ_001726 may be a new avenue for HCC treatment.
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Literature
1.
Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet (London, England). 2018;391(10127):1301–14.PubMedCrossRef
2.
Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol. 2017;14(4):203–17.PubMedCrossRef
3.
Kirstein MM, Wirth TC. Multimodal treatment of hepatocellular carcinoma. Der Internist. 2020;61(2):164–9.PubMedCrossRef
4.
Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Nikšić M, et al. Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet (London, England). 2018;391(10125):1023–75.PubMedPubMedCentralCrossRef
5.
Wu C, Ren X, Zhang Q. Incidence, risk factors, and prognosis in patients with primary hepatocellular carcinoma and lung metastasis: a population-based study. Cancer Manag Res. 2019;11:2759–68.PubMedPubMedCentralCrossRef
6.
Woo HY, Rhee H, Yoo JE, Kim SH, Choi GH, Kim DY, et al. Lung and lymph node metastases from hepatocellular carcinoma: Comparison of pathological aspects. Liver Int. 2022;42(1):199–209.PubMedCrossRef
7.
8.
Wang J, Zhao X, Wang Y, Ren F, Sun D, Yan Y, et al. circRNA-002178 act as a ceRNA to promote PDL1/PD1 expression in lung adenocarcinoma. Cell Death Dis. 2020;11(1):32.PubMedPubMedCentralCrossRef
9.
Chen L, Shan G. CircRNA in cancer: Fundamental mechanism and clinical potential. Cancer Lett. 2021;505:49–57.PubMedCrossRef
10.
Yuan G, Ding W, Sun B, Zhu L, Gao Y, Chen L. Upregulated circRNA_102231 promotes gastric cancer progression and its clinical significance. Bioengineered. 2021;12(1):4936–45.PubMedPubMedCentralCrossRef
11.
Xu J, Ji L, Liang Y, Wan Z, Zheng W, Song X, et al. CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1. Signal Transduct Target Ther. 2020;5(1):298.PubMedPubMedCentralCrossRef
12.
Ma X, Lu C, Chen Y, Li S, Ma N, Tao X, et al. CCT2 is an aggrephagy receptor for clearance of solid protein aggregates. Cell. 2022;185(8):1325-45.e22.PubMedCrossRef
13.
Ma X, Qiu S, Tang X, Song Q, Wang P, Wang J, et al. TSPAN31 regulates the proliferation, migration, and apoptosis of gastric cancer cells through the METTL1/CCT2 pathway. Transl Oncol. 2022;20:101423.PubMedPubMedCentralCrossRef
14.
Park SH, Jeong S, Kim BR, Jeong YA, Kim JL, Na YJ, et al. Activating CCT2 triggers Gli-1 activation during hypoxic condition in colorectal cancer. Oncogene. 2020;39(1):136–50.PubMedCrossRef
15.
Han L, Wang M, Yang Y, Xu H, Wei L, Huang X. Detection of Prognostic Biomarkers for Hepatocellular Carcinoma through CircRNA-associated CeRNA Analysis. J Clin Transl Hepatol. 2022;10(1):80–9.PubMedCrossRef
16.
Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol. 2019;234(5):5451–65.PubMedCrossRef
17.
Sell MC, Ramlogan-Steel CA, Steel JC, Dhungel BP. MicroRNAs in cancer metastasis: biological and therapeutic implications. Expert Rev Mol Med. 2023;25:e14.PubMedPubMedCentralCrossRef
18.
Diener C, Keller A, Meese E. Emerging concepts of miRNA therapeutics: from cells to clinic. Trends Genet. 2022;38(6):613–26.PubMedCrossRef
19.
Dou C, Zhou Z, Xu Q, Liu Z, Zeng Y, Wang Y, et al. Hypoxia-induced TUFT1 promotes the growth and metastasis of hepatocellular carcinoma by activating the Ca(2+)/PI3K/AKT pathway. Oncogene. 2019;38(8):1239–55.PubMedCrossRef
20.
Peng D, Wu T, Wang J, Huang J, Zheng L, Wang P, et al. microRNA-671-5p reduces tumorigenicity of ovarian cancer via suppressing HDAC5 and HIF-1α expression. Chem Biol Interact. 2022;355:109780.PubMedCrossRef
21.
Tan X, Li Z, Ren S, Rezaei K, Pan Q, Goldstein AT, et al. Dynamically decreased miR-671-5p expression is associated with oncogenic transformation and radiochemoresistance in breast cancer. Breast Cancer Res. 2019;21(1):89.PubMedPubMedCentralCrossRef
22.
Bai X, Sui C, Liu F, Chen T, Zhang L, Zheng Y, et al. The protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation. Nat Commun. 2022;13(1):5016.PubMedPubMedCentralCrossRef
23.
Jiang H, Zhou Z, Jin S, Xu K, Zhang H, Xu J, et al. PRMT9 promotes hepatocellular carcinoma invasion and metastasis via activating PI3K/Akt/GSK-3β/Snail signaling. Cancer Sci. 2018;109(5):1414–27.PubMedPubMedCentralCrossRef
24.
25.
26.
Deshmukh AP, Vasaikar SV, Tomczak K, Tripathi S, den Hollander P, Arslan E, et al. Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing. Proc Natl Acad Sci U S A. 2021;118(19):e2102050118.PubMedPubMedCentralCrossRef
27.
Ang HL, Mohan CD, Shanmugam MK, Leong HC, Makvandi P, Rangappa KS, et al. Mechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds. Med Res Rev. 2023;43(4):1141–200.PubMedCrossRef
28.
Xu ZT, Ding H, Fu TT, Zhu YL, Wang WP. A Nude Mouse Model of Orthotopic Liver Transplantation of Human Hepatocellular Carcinoma HCCLM3 Cell Xenografts and the Use of Imaging to Evaluate Tumor Progression. Med Sci Monit. 2019;25:8694–703.PubMedPubMedCentralCrossRef
29.
Huang Q, Wu D, Zhao J, Yan Z, Chen L, Guo S, et al. TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis. EMBO J. 2022;41(11):e110324.PubMedPubMedCentralCrossRef
30.
Iwakawa HO, Tomari Y. Life of RISC: Formation, action, and degradation of RNA-induced silencing complex. Mol Cell. 2022;82(1):30–43.PubMedCrossRef
31.
32.
Wang Y, Zhong Y, Hou T, Liao J, Zhang C, Sun C, et al. PM2.5 induces EMT and promotes CSC properties by activating Notch pathway in vivo and vitro. Ecotoxicol Environ Saf. 2019;178:159–67.PubMedCrossRef
33.
Gao Y, Shang S, Guo S, Li X, Zhou H, Liu H, et al. Lnc2Cancer 3.0: an updated resource for experimentally supported lncRNA/circRNA cancer associations and web tools based on RNA-seq and scRNA-seq data. Nucleic Acids Res. 2021;49(D1):D1251-d8.PubMedCrossRef
34.
Zhang L, Tao H, Li J, Zhang E, Liang H, Zhang B. Comprehensive analysis of the competing endogenous circRNA-lncRNA-miRNA-mRNA network and identification of a novel potential biomarker for hepatocellular carcinoma. Aging. 2021;13(12):15990–6008.PubMedPubMedCentralCrossRef
35.
Wang L, Long H, Zheng Q, Bo X, Xiao X, Li B. Circular RNA circRHOT1 promotes hepatocellular carcinoma progression by initiation of NR2F6 expression. Mol Cancer. 2019;18(1):119.PubMedPubMedCentralCrossRef
36.
37.
Liu J, Huang L, Zhu Y, He Y, Zhang W, Lei T, et al. Exploring the Expression and Prognostic Value of the TCP1 Ring Complex in Hepatocellular Carcinoma and Overexpressing Its Subunit 5 Promotes HCC Tumorigenesis. Front Oncol. 2021;11:739660.PubMedPubMedCentralCrossRef
38.
Liu Y, Yao Y, Liao B, Zhang H, Yang Z, Xia P, et al. A positive feedback loop of CENPU/E2F6/E2F1 facilitates proliferation and metastasis via ubiquitination of E2F6 in hepatocellular carcinoma. Int J Biol Sci. 2022;18(10):4071–87.PubMedPubMedCentralCrossRef
39.
Jing T, Wang B, Yang Z, Liu Y, Xu G, Xu X, et al. Deubiquitination of the repressor E2F6 by USP22 facilitates AKT activation and tumor growth in hepatocellular carcinoma. Cancer Lett. 2021;518:266–77.PubMedCrossRef
40.
Loh CY, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK, et al. The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges. Cells. 2019;8(10):1118.PubMedPubMedCentralCrossRef
41.
Pastushenko I, Blanpain C. EMT Transition States during Tumor Progression and Metastasis. Trends Cell Biol. 2019;29(3):212–26.PubMedCrossRef
42.
Chen X, Xiao W, Chen W, Liu X, Wu M, Bo Q, et al. MicroRNA-26a and -26b inhibit lens fibrosis and cataract by negatively regulating Jagged-1/Notch signaling pathway. Cell Death Differ. 2017;24(8):1431–42.PubMedPubMedCentralCrossRef
43.
Jin M, Wang J, Ji X, Cao H, Zhu J, Chen Y, et al. MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):136.PubMedPubMedCentralCrossRef
44.
Zhang X, Wang S, Wang H, Cao J, Huang X, Chen Z, et al. Circular RNA circNRIP1 acts as a microRNA-149-5p sponge to promote gastric cancer progression via the AKT1/mTOR pathway. Mol Cancer. 2019;18(1):20.PubMedPubMedCentralCrossRef
45.
Chen X, Mao R, Su W, Yang X, Geng Q, Guo C, et al. Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKα signaling in STK11 mutant lung cancer. Autophagy. 2020;16(4):659–71.PubMedCrossRef
46.
47.
Chen X, Luo J, Gao S, Jiang J, Yang B, Zhang Z. miR-671-5p Promotes Cell Proliferation, Invasion, and Migration in Hepatocellular Carcinoma through Targeting ALDH2. Crit Rev Eukaryot Gene Expr. 2022;32(4):73–82.PubMedCrossRef
48.
Zhang Q, Zhao Y, Song Z, Zhang Q, Tian C, Li R, et al. Identification of THSD7B and PRMT9 mutations as risk factors for familial lung adenocarcinoma: A case report. Medicine. 2023;102(6):e32872.PubMedPubMedCentralCrossRef
49.
Grypari IM, Pappa I, Papastergiou T, Zolota V, Bravou V, Melachrinou M, et al. Elucidating the role of PRMTs in prostate cancer using open access databases and a patient cohort dataset. Histol Histopathol. 2023;38(3):287–302.PubMed
Metadata
Title
A hsa_circ_001726 axis regulated by E2F6 contributes to metastasis of hepatocellular carcinoma
Authors
Jiaoyu Ai
Wanlin Zhang
Wensheng Deng
Likun Yan
Lidong Zhang
Zongjing Huang
Ziyi Wu
Junhua Ai
Hai Jiang
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11703-7

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