Skip to main content
Top
Published in: Journal of Experimental & Clinical Cancer Research 1/2020

Open Access 01-12-2020 | Hepatocellular Carcinoma | Research

Long noncoding RNA ZFPM2-AS1 acts as a miRNA sponge and promotes cell invasion through regulation of miR-139/GDF10 in hepatocellular carcinoma

Authors: Hui He, Yawei Wang, Peng Ye, Dehui Yi, Ying Cheng, Haibo Tang, Zhi Zhu, Xun Wang, Shi Jin

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

Login to get access

Abstract

Background

Emerging evidence has shown that dysregulated expression of long noncoding RNAs (lncRNAs) is implicated in liver hepatocellular carcinoma (HCC). However, the role and molecular mechanism of differentially expressed lncRNAs in HCC has not been fully explained.

Methods

The expression profiles of lncRNAs in HCC samples were derived from microarrays analysis or downloaded from The Cancer Genome Atlas (TCGA), and their correlation with prognosis and clinical characteristics were further analyzed. Silencing of lncRNA ZFPM2-AS1 was conducted to assess the effect of ZFPM2-AS1 in vitro. The miRcode and Target Scan databases were used to determine the lncRNA-miRNA-mRNA interactions. The biological functions were demonstrated by luciferase reporter assay, western blotting, PCR and rescue experiments.

Results

The expression level of lncRNA ZFPM2-AS1 was significantly higher in HCC tissues than in adjacent normal tissues, and higher ZFPM2-AS1 was remarkably related to poor survival. Functionally, silencing of lncRNA ZFPM2-AS1 inhibited cell proliferation, migration, invasion and promoted cell apoptosis in vitro. Bioinformatics analysis based on the miRcode and TargetScan databases showed that lncRNA ZFPM2-AS1 regulated GDF10 expression by competitively binding to miR-139. miR-139 and downregulated GDF10 reversed cell phenotypes caused by lncRNA ZFPM2-AS1 by rescue analysis.

Conclusions

ZFPM2-AS1, an upregulated lncRNA in HCC, was associated with malignant tumor phenotypes and worse patient survival. ZFPM2-AS1 regulated the progression of HCC by acting as a competing endogenous RNA (ceRNA) to competitively bind to miR-139 and regulate GDF10 expression. Our study provides new insight into the posttranscriptional regulation mechanism of lncRNA ZFPM2-AS1 and suggests that ZFPM2-AS1/miR-139/GDF10 may act as a potential therapeutic target and prognostic biomarker for HCC.
Appendix
Available only for authorised users
Literature
1.
go back to reference Petrizzo A, Mauriello A, Tornesello ML, Buonaguro FM, Tagliamonte M, Buonaguro L. Cellular prognostic markers in hepatitis-related hepatocellular carcinoma. Infect Agents Cancer. 2018;13:10.PubMedPubMedCentralCrossRef Petrizzo A, Mauriello A, Tornesello ML, Buonaguro FM, Tagliamonte M, Buonaguro L. Cellular prognostic markers in hepatitis-related hepatocellular carcinoma. Infect Agents Cancer. 2018;13:10.PubMedPubMedCentralCrossRef
2.
go back to reference Bertuccio P, Turati F, Carioli G, Rodriguez T, La Vecchia C, Malvezzi M, Negri E. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol. 2017;67(2):302–9.PubMedCrossRef Bertuccio P, Turati F, Carioli G, Rodriguez T, La Vecchia C, Malvezzi M, Negri E. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol. 2017;67(2):302–9.PubMedCrossRef
3.
go back to reference Lu TF, Hua XW, Cui XL, Xia Q. Liver transplantation for hepatocellular carcinoma: recent advances in China. J Dig Dis. 2014;15(2):51–3.PubMedCrossRef Lu TF, Hua XW, Cui XL, Xia Q. Liver transplantation for hepatocellular carcinoma: recent advances in China. J Dig Dis. 2014;15(2):51–3.PubMedCrossRef
4.
go back to reference Yin W, Zhao Y, Ji YJ, Tong LP, Liu Y, He SX, Wang AQ. Serum/plasma microRNAs as biomarkers for HBV-related hepatocellular carcinoma in China. Biomed Res Int. 2015;2015:965185.PubMedPubMedCentral Yin W, Zhao Y, Ji YJ, Tong LP, Liu Y, He SX, Wang AQ. Serum/plasma microRNAs as biomarkers for HBV-related hepatocellular carcinoma in China. Biomed Res Int. 2015;2015:965185.PubMedPubMedCentral
5.
go back to reference Xu X, Chen J, Wei Q, Liu ZK, Yang Z, Zhang M, Wang GY, Gao J, Yang ZX, Guo WY, et al. Clinical practice guidelines on liver transplantation for hepatocellular carcinoma in China (2018 edition). Hepatobiliary Pancreatic Dis Int. 2019;18(4):307–12.CrossRef Xu X, Chen J, Wei Q, Liu ZK, Yang Z, Zhang M, Wang GY, Gao J, Yang ZX, Guo WY, et al. Clinical practice guidelines on liver transplantation for hepatocellular carcinoma in China (2018 edition). Hepatobiliary Pancreatic Dis Int. 2019;18(4):307–12.CrossRef
6.
go back to reference Xu XF, Xing H, Han J, Li ZL, Lau WY, Zhou YH, Gu WM, Wang H, Chen TH, Zeng YY, et al. Risk factors, patterns, and outcomes of late recurrence after liver resection for hepatocellular carcinoma: a multicenter study from China. JAMA Surg. 2019;154(3):209–17.PubMedCrossRef Xu XF, Xing H, Han J, Li ZL, Lau WY, Zhou YH, Gu WM, Wang H, Chen TH, Zeng YY, et al. Risk factors, patterns, and outcomes of late recurrence after liver resection for hepatocellular carcinoma: a multicenter study from China. JAMA Surg. 2019;154(3):209–17.PubMedCrossRef
7.
go back to reference Zhu Q, Li N, Zeng X, Han Q, Li F, Yang C, Lv Y, Zhou Z, Liu Z. Hepatocellular carcinoma in a large medical center of China over a 10-year period: evolving therapeutic option and improving survival. Oncotarget. 2015;6(6):4440–50.PubMedPubMedCentralCrossRef Zhu Q, Li N, Zeng X, Han Q, Li F, Yang C, Lv Y, Zhou Z, Liu Z. Hepatocellular carcinoma in a large medical center of China over a 10-year period: evolving therapeutic option and improving survival. Oncotarget. 2015;6(6):4440–50.PubMedPubMedCentralCrossRef
8.
go back to reference Shang W, Adzika GK, Li Y, Huang Q, Ding N, Chinembiri B, Rashid MS, Machuki JO. Molecular mechanisms of circular RNAs, transforming growth factor-beta, and long noncoding RNAs in hepatocellular carcinoma. Cancer Med. 2019;8(15):6684–99.PubMedPubMedCentralCrossRef Shang W, Adzika GK, Li Y, Huang Q, Ding N, Chinembiri B, Rashid MS, Machuki JO. Molecular mechanisms of circular RNAs, transforming growth factor-beta, and long noncoding RNAs in hepatocellular carcinoma. Cancer Med. 2019;8(15):6684–99.PubMedPubMedCentralCrossRef
9.
go back to reference DiStefano JK. Long noncoding RNAs in the initiation, progression, and metastasis of hepatocellular carcinoma. Non-coding RNA Res. 2017;2(3–4):129–36.CrossRef DiStefano JK. Long noncoding RNAs in the initiation, progression, and metastasis of hepatocellular carcinoma. Non-coding RNA Res. 2017;2(3–4):129–36.CrossRef
10.
go back to reference Wang J, Pu J, Yao T, Lu X, Deng Y. Four long noncoding RNAs as potential prognostic biomarkers for hepatocellular carcinoma. J Cell Physiol. 2019;234(6):8709–16.PubMedCrossRef Wang J, Pu J, Yao T, Lu X, Deng Y. Four long noncoding RNAs as potential prognostic biomarkers for hepatocellular carcinoma. J Cell Physiol. 2019;234(6):8709–16.PubMedCrossRef
11.
go back to reference Yan H, Wang Q, Shen Q, Li Z, Tian J, Jiang Q, Gao L. Identification of potential transcription factors, long noncoding RNAs, and microRNAs associated with hepatocellular carcinoma. J Cancer Res Ther. 2018;14(Supplement):S622–7.PubMedCrossRef Yan H, Wang Q, Shen Q, Li Z, Tian J, Jiang Q, Gao L. Identification of potential transcription factors, long noncoding RNAs, and microRNAs associated with hepatocellular carcinoma. J Cancer Res Ther. 2018;14(Supplement):S622–7.PubMedCrossRef
12.
go back to reference Zhou H, Xu Q, Ni C, Ye S, Xu X, Hu X, Jiang J, Hong Y, Huang D, Yang L. Prospects of noncoding RNAs in hepatocellular carcinoma. Biomed Res Int. 2018;2018:6579436.PubMedPubMedCentral Zhou H, Xu Q, Ni C, Ye S, Xu X, Hu X, Jiang J, Hong Y, Huang D, Yang L. Prospects of noncoding RNAs in hepatocellular carcinoma. Biomed Res Int. 2018;2018:6579436.PubMedPubMedCentral
13.
go back to reference Lim LJ, Wong SYS, Huang F, Lim S, Chong SS, Ooi LL, Kon OL, Lee CG. Roles and regulation of long noncoding RNAs in hepatocellular carcinoma. Cancer Res. 2019;79(20):5131–9.PubMedCrossRef Lim LJ, Wong SYS, Huang F, Lim S, Chong SS, Ooi LL, Kon OL, Lee CG. Roles and regulation of long noncoding RNAs in hepatocellular carcinoma. Cancer Res. 2019;79(20):5131–9.PubMedCrossRef
14.
go back to reference Song M, Zhong A, Yang J, He J, Cheng S, Zeng J, Huang Y, Pan Q, Zhao J, Zhou Z, et al. Large-scale analyses identify a cluster of novel long noncoding RNAs as potential competitive endogenous RNAs in progression of hepatocellular carcinoma. Aging. 2019;11(22):10422–53.PubMedPubMedCentralCrossRef Song M, Zhong A, Yang J, He J, Cheng S, Zeng J, Huang Y, Pan Q, Zhao J, Zhou Z, et al. Large-scale analyses identify a cluster of novel long noncoding RNAs as potential competitive endogenous RNAs in progression of hepatocellular carcinoma. Aging. 2019;11(22):10422–53.PubMedPubMedCentralCrossRef
15.
go back to reference Yang J, Zhang Y, Song H. A disparate role of RP11-424C20.2/UHRF1 axis through control of tumor immune escape in liver hepatocellular carcinoma and thymoma. Aging. 2019;11(16):6422–39.PubMedPubMedCentralCrossRef Yang J, Zhang Y, Song H. A disparate role of RP11-424C20.2/UHRF1 axis through control of tumor immune escape in liver hepatocellular carcinoma and thymoma. Aging. 2019;11(16):6422–39.PubMedPubMedCentralCrossRef
16.
go back to reference Cai H, Yao J, An Y, Chen X, Chen W, Wu D, Luo B, Yang Y, Jiang Y, Sun D, et al. LncRNA HOTAIR acts a competing endogenous RNA to control the expression of notch3 via sponging miR-613 in pancreatic cancer. Oncotarget. 2017;8(20):32905–17.PubMedPubMedCentralCrossRef Cai H, Yao J, An Y, Chen X, Chen W, Wu D, Luo B, Yang Y, Jiang Y, Sun D, et al. LncRNA HOTAIR acts a competing endogenous RNA to control the expression of notch3 via sponging miR-613 in pancreatic cancer. Oncotarget. 2017;8(20):32905–17.PubMedPubMedCentralCrossRef
17.
go back to reference Jeggari A, Marks DS, Larsson E. miRcode: a map of putative microRNA target sites in the long non-coding transcriptome. Bioinformatics. 2012;28(15):2062–3.PubMedPubMedCentralCrossRef Jeggari A, Marks DS, Larsson E. miRcode: a map of putative microRNA target sites in the long non-coding transcriptome. Bioinformatics. 2012;28(15):2062–3.PubMedPubMedCentralCrossRef
18.
go back to reference Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40.CrossRef Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40.CrossRef
19.
go back to reference Li D, Zhang J, Li J. Role of miRNA sponges in hepatocellular carcinoma. Clin Chim Acta. 2020;500:10–9. Li D, Zhang J, Li J. Role of miRNA sponges in hepatocellular carcinoma. Clin Chim Acta. 2020;500:10–9.
20.
go back to reference Qadir MI, Rizvi SZ. miRNA in hepatocellular carcinoma: pathogenesis and therapeutic approaches. Crit Rev Eukaryot Gene Expr. 2017;27(4):355–61.PubMedCrossRef Qadir MI, Rizvi SZ. miRNA in hepatocellular carcinoma: pathogenesis and therapeutic approaches. Crit Rev Eukaryot Gene Expr. 2017;27(4):355–61.PubMedCrossRef
21.
go back to reference Tang X, Feng D, Li M, Zhou J, Li X, Zhao D, Hao B, Li D, Ding K. Transcriptomic analysis of mRNA-lncRNA-miRNA interactions in hepatocellular carcinoma. Sci Rep. 2019;9(1):16096.PubMedPubMedCentralCrossRef Tang X, Feng D, Li M, Zhou J, Li X, Zhao D, Hao B, Li D, Ding K. Transcriptomic analysis of mRNA-lncRNA-miRNA interactions in hepatocellular carcinoma. Sci Rep. 2019;9(1):16096.PubMedPubMedCentralCrossRef
22.
go back to reference Si H, Chen P, Li H, Wang X. Long non-coding RNA H19 regulates cell growth and metastasis via miR-138 in breast cancer. Am J Transl Res. 2019;11(5):3213–25.PubMedPubMedCentral Si H, Chen P, Li H, Wang X. Long non-coding RNA H19 regulates cell growth and metastasis via miR-138 in breast cancer. Am J Transl Res. 2019;11(5):3213–25.PubMedPubMedCentral
23.
go back to reference Quan D, Chen K, Zhang J, Guan Y, Yang D, Wu H, Wu S, Lv L. Identification of lncRNA NEAT1/miR-21/RRM2 axis as a novel biomarker in breast cancer. J Cell Physiol. 2020;235(4):3372–81. Quan D, Chen K, Zhang J, Guan Y, Yang D, Wu H, Wu S, Lv L. Identification of lncRNA NEAT1/miR-21/RRM2 axis as a novel biomarker in breast cancer. J Cell Physiol. 2020;235(4):3372–81.
24.
go back to reference Zheng L, Zhang Y, Fu Y, Gong H, Guo J, Wu K, Jia Q, Ding X. Long non-coding RNA MALAT1 regulates BLCAP mRNA expression through binding to miR-339-5p and promotes poor prognosis in breast cancer. Biosci Rep. 2019;39(2):BSR20181284. Zheng L, Zhang Y, Fu Y, Gong H, Guo J, Wu K, Jia Q, Ding X. Long non-coding RNA MALAT1 regulates BLCAP mRNA expression through binding to miR-339-5p and promotes poor prognosis in breast cancer. Biosci Rep. 2019;39(2):BSR20181284.
25.
go back to reference Zhao L, Zhang Y, Zhang Y. Long noncoding RNA CASC2 regulates hepatocellular carcinoma cell oncogenesis through miR-362-5p/Nf-kappaB axis. J Cell Physiol. 2018;233(10):6661–70.PubMedCrossRef Zhao L, Zhang Y, Zhang Y. Long noncoding RNA CASC2 regulates hepatocellular carcinoma cell oncogenesis through miR-362-5p/Nf-kappaB axis. J Cell Physiol. 2018;233(10):6661–70.PubMedCrossRef
26.
go back to reference Liu L, Cui S, Wan T, Li X, Tian W, Zhang R, Luo L, Shi Y. Long non-coding RNA HOTAIR acts as a competing endogenous RNA to promote glioma progression by sponging miR-126-5p. J Cell Physiol. 2018;233(9):6822–31.PubMedCrossRef Liu L, Cui S, Wan T, Li X, Tian W, Zhang R, Luo L, Shi Y. Long non-coding RNA HOTAIR acts as a competing endogenous RNA to promote glioma progression by sponging miR-126-5p. J Cell Physiol. 2018;233(9):6822–31.PubMedCrossRef
27.
go back to reference Li H, Chen S, Liu J, Guo X, Xiang X, Dong T, Ran P, Li Q, Zhu B, Zhang X, et al. Long non-coding RNA PVT1-5 promotes cell proliferation by regulating miR-126/SLC7A5 axis in lung cancer. Biochem Biophys Res Commun. 2018;495(3):2350–5.PubMedCrossRef Li H, Chen S, Liu J, Guo X, Xiang X, Dong T, Ran P, Li Q, Zhu B, Zhang X, et al. Long non-coding RNA PVT1-5 promotes cell proliferation by regulating miR-126/SLC7A5 axis in lung cancer. Biochem Biophys Res Commun. 2018;495(3):2350–5.PubMedCrossRef
28.
go back to reference Zhang Y, Xu Y, Feng L, Li F, Sun Z, Wu T, Shi X, Li J, Li X. Comprehensive characterization of lncRNA-mRNA related ceRNA network across 12 major cancers. Oncotarget. 2016;7(39):64148–67.PubMedPubMedCentralCrossRef Zhang Y, Xu Y, Feng L, Li F, Sun Z, Wu T, Shi X, Li J, Li X. Comprehensive characterization of lncRNA-mRNA related ceRNA network across 12 major cancers. Oncotarget. 2016;7(39):64148–67.PubMedPubMedCentralCrossRef
29.
go back to reference Yan J, Zhou C, Guo K, Li Q, Wang Z. A novel seven-lncRNA signature for prognosis prediction in hepatocellular carcinoma. J Cell Biochem. 2019;120(1):213–23.PubMedCrossRef Yan J, Zhou C, Guo K, Li Q, Wang Z. A novel seven-lncRNA signature for prognosis prediction in hepatocellular carcinoma. J Cell Biochem. 2019;120(1):213–23.PubMedCrossRef
30.
go back to reference Abbastabar M, Sarfi M, Golestani A, Khalili E. lncRNA involvement in hepatocellular carcinoma metastasis and prognosis. EXCLI J. 2018;17:900–13.PubMedPubMedCentral Abbastabar M, Sarfi M, Golestani A, Khalili E. lncRNA involvement in hepatocellular carcinoma metastasis and prognosis. EXCLI J. 2018;17:900–13.PubMedPubMedCentral
31.
go back to reference Dickson I. Hepatocellular carcinoma: A role for lncRNA in liver cancer. Nat Rev Gastroenterol Hepatol. 2016;13(3):122–3.PubMed Dickson I. Hepatocellular carcinoma: A role for lncRNA in liver cancer. Nat Rev Gastroenterol Hepatol. 2016;13(3):122–3.PubMed
32.
go back to reference Kong F, Deng X, Kong X, Du Y, Li L, Zhu H, Wang Y, Xie D, Guha S, Li Z, et al. ZFPM2-AS1, a novel lncRNA, attenuates the p53 pathway and promotes gastric carcinogenesis by stabilizing MIF. Oncogene. 2018;37(45):5982–96.PubMedPubMedCentralCrossRef Kong F, Deng X, Kong X, Du Y, Li L, Zhu H, Wang Y, Xie D, Guha S, Li Z, et al. ZFPM2-AS1, a novel lncRNA, attenuates the p53 pathway and promotes gastric carcinogenesis by stabilizing MIF. Oncogene. 2018;37(45):5982–96.PubMedPubMedCentralCrossRef
33.
go back to reference Liu JG, Wang HB, Wan G, Yang MZ, Jiang XJ, Yang JY. Long noncoding RNA ZFPM2-AS1 promotes the tumorigenesis of renal cell cancer via targeting miR-137. Eur Rev Med Pharmacol Sci. 2019;23(13):5675–81.PubMed Liu JG, Wang HB, Wan G, Yang MZ, Jiang XJ, Yang JY. Long noncoding RNA ZFPM2-AS1 promotes the tumorigenesis of renal cell cancer via targeting miR-137. Eur Rev Med Pharmacol Sci. 2019;23(13):5675–81.PubMed
34.
go back to reference Li J, Ge J, Yang Y, Liu B, Zheng M, Shi R. Long noncoding RNA ZFPM2-AS1 is involved in lung adenocarcinoma via miR-511-3p/AFF4 pathway. J Cell Biochem. 2020;121(3):2534–42.PubMedCrossRef Li J, Ge J, Yang Y, Liu B, Zheng M, Shi R. Long noncoding RNA ZFPM2-AS1 is involved in lung adenocarcinoma via miR-511-3p/AFF4 pathway. J Cell Biochem. 2020;121(3):2534–42.PubMedCrossRef
35.
go back to reference Miyoshi K, Okada TN, Siomi H, Siomi MC. Characterization of the miRNA-RISC loading complex and miRNA-RISC formed in the Drosophila miRNA pathway. Rna. 2009;15(7):1282–91.PubMedPubMedCentralCrossRef Miyoshi K, Okada TN, Siomi H, Siomi MC. Characterization of the miRNA-RISC loading complex and miRNA-RISC formed in the Drosophila miRNA pathway. Rna. 2009;15(7):1282–91.PubMedPubMedCentralCrossRef
36.
go back to reference Sibony M, Abdullah M, Greenfield L, Raju D, Wu T, Rodrigues DM, Galindo-Mata E, Mascarenhas H, Philpott DJ, Silverberg MS, et al. Microbial disruption of autophagy alters expression of the RISC component AGO2, a critical regulator of the miRNA silencing pathway. Inflamm Bowel Dis. 2015;21(12):2778–86.PubMedPubMedCentralCrossRef Sibony M, Abdullah M, Greenfield L, Raju D, Wu T, Rodrigues DM, Galindo-Mata E, Mascarenhas H, Philpott DJ, Silverberg MS, et al. Microbial disruption of autophagy alters expression of the RISC component AGO2, a critical regulator of the miRNA silencing pathway. Inflamm Bowel Dis. 2015;21(12):2778–86.PubMedPubMedCentralCrossRef
Metadata
Title
Long noncoding RNA ZFPM2-AS1 acts as a miRNA sponge and promotes cell invasion through regulation of miR-139/GDF10 in hepatocellular carcinoma
Authors
Hui He
Yawei Wang
Peng Ye
Dehui Yi
Ying Cheng
Haibo Tang
Zhi Zhu
Xun Wang
Shi Jin
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-01664-1

Other articles of this Issue 1/2020

Journal of Experimental & Clinical Cancer Research 1/2020 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine