Long non‑coding RNA ZSCAN16‑AS1 promotes the malignant properties of hepatocellular carcinoma by decoying microRNA‑451a and consequently increasing ATF2 expression

Lv,Chaohua; Wan,Qingsong; Shen,Chengxiang; Wu,Hongsheng; Zhou,Bin; Wang,Weiwei

doi:10.3892/mmr.2021.12420

Long non‑coding RNA ZSCAN16‑AS1 promotes the malignant properties of hepatocellular carcinoma by decoying microRNA‑451a and consequently increasing ATF2 expression

Authors:
- Chaohua Lv
- Qingsong Wan
- Chengxiang Shen
- Hongsheng Wu
- Bin Zhou
- Weiwei Wang
View Affiliations

Affiliations: Department of Hepatobiliary and Pancreatic Surgery, The People's Hospital of Tongliang, Chongqing 402575, P.R. China
Published online on: September 7, 2021 https://doi.org/10.3892/mmr.2021.12420
Article Number: 780
Copyright: © Lv et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The importance of long noncoding RNAs (lncRNAs) in the oncogenicity of hepatocellular carcinoma (HCC) has been widely studied. However, the detailed functions of ZSCAN16 antisense RNA 1 (ZSCAN16‑AS1) have seldom been explored in HCC until the present study. In the present study, experiments were performed to clarify whether ZSCAN16‑AS1 is implicated in the oncogenesis and progression of HCC and to explore the possible underlying mechanisms. ZSCAN16‑AS1 expression was analyzed using reverse transcription‑quantitative PCR. The effects of ZSCAN16‑AS1 on the biological behavior of HCC cells were demonstrated by functional experiments. The direct binding capacity of ZSCAN16‑AS1 with microRNA‑451a (miR‑451a) was indicated by the luciferase reporter assay and RNA immunoprecipitation. The high expression of ZSCAN16‑AS1 was confirmed in HCC by The Cancer Genome Atlas database and the cohort of the present study. Survival data revealed that patients with a high ZSCAN16‑AS1 level had worse prognosis compared with those with a low ZSCAN16‑AS1 level. Following ZSCAN16‑AS1 knockdown, HCC cell proliferation, migration and invasion were curbed, whereas cell apoptosis was promoted in vitro. The absence of ZSCAN16‑AS1 restricted tumor growth of HCC cells in vivo. Mechanistically, ZSCAN16‑AS1 acted as a competing endogenous RNA by decoying miR‑451a in HCC cells. Furthermore, activating transcription factor 2 (ATF2), a direct target of miR‑451a, was under the regulation of ZSCAN16‑AS1, which was exerted by sequestering miR‑451a. In addition, miR‑451a knockdown or ATF2 resumption reversed the proliferation suppression, apoptosis promotion and migration and invasion inhibition triggered by ZSCAN16‑AS1 silencing. In conclusion, ZSCAN16‑AS1, a pro‑oncogenic lncRNA, aggravated the malignancy of HCC by controlling the miR‑451a/ATF2 axis. An understanding of the competing endogenous RNA network of ZSCAN16‑AS1/miR‑451a/ATF2 in HCC might be instrumental in the development of attractive targets for molecular therapy.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
2	Helal Tel A, Radwan NA and Shaker M: Extrahepatic metastases as initial manifestations of hepatocellular carcinoma: An Egyptian experience. Diagn Pathol. 10:822015. View Article : Google Scholar : PubMed/NCBI
3	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
4	Inchingolo R, Posa A, Mariappan M and Spiliopoulos S: Locoregional treatments for hepatocellular carcinoma: Current evidence and future directions. World J Gastroenterol. 25:4614–4628. 2019. View Article : Google Scholar : PubMed/NCBI
5	Kulik L and El-Serag HB: Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 156:477–491.e1. 2019. View Article : Google Scholar : PubMed/NCBI
6	Gelli M, Sebagh M, Porcher R, Romanelli E, Vibert E, Sa Cunha A, Castaing D, Rosmorduc O, Samuel D, Adam R and Cherqui D: Liver resection for early hepatocellular carcinoma: Preoperative predictors of non transplantable recurrence and implications for treatment allocation. Ann Surg. 272:820–826. 2020. View Article : Google Scholar : PubMed/NCBI
7	Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, et al: Landscape of transcription in human cells. Nature. 489:101–108. 2012. View Article : Google Scholar : PubMed/NCBI
8	Karlsson O and Baccarelli AA: Environmental health and long non-coding RNAs. Curr Environ Health Rep. 3:178–187. 2016. View Article : Google Scholar : PubMed/NCBI
9	Peng WX, Koirala P and Mo YY: LncRNA-mediated regulation of cell signaling in cancer. Oncogene. 36:5661–5667. 2017. View Article : Google Scholar : PubMed/NCBI
10	Bhan A, Soleimani M and Mandal SS: Long noncoding RNA and cancer: A new paradigm. Cancer Res. 77:3965–3981. 2017. View Article : Google Scholar : PubMed/NCBI
11	Li J, Meng H, Bai Y and Wang K: Regulation of lncRNA and its role in cancer metastasis. Oncol Res. 23:205–217. 2016. View Article : Google Scholar : PubMed/NCBI
12	Bolha L, Ravnik-Glavac M and Glavac D: Long noncoding RNAs as biomarkers in cancer. Dis Markers. 2017:72439682017. View Article : Google Scholar : PubMed/NCBI
13	Botti G, Marra L, Malzone MG, Anniciello A, Botti C, Franco R and Cantile M: LncRNA HOTAIR as prognostic circulating marker and potential therapeutic target in patients with tumor diseases. Curr Drug Targets. 18:27–34. 2017. View Article : Google Scholar : PubMed/NCBI
14	Heo MJ, Yun J and Kim SG: Role of non-coding RNAs in liver disease progression to hepatocellular carcinoma. Arch Pharm Res. 42:48–62. 2019. View Article : Google Scholar : PubMed/NCBI
15	Abbastabar M, Sarfi M, Golestani A and Khalili E: lncRNA involvement in hepatocellular carcinoma metastasis and prognosis. EXCLI J. 17:900–913. 2018.PubMed/NCBI
16	Chen X, Fan S and Song E: Noncoding RNAs: New players in cancers. Adv Exp Med Biol. 927:1–47. 2016. View Article : Google Scholar : PubMed/NCBI
17	Abba M, Mudduluru G and Allgayer H: MicroRNAs in cancer: Small molecules, big chances. Anticancer Agents Med Chem. 12:733–743. 2012. View Article : Google Scholar : PubMed/NCBI
18	Yang C, Wang Y, Xue W, Xie Y, Dong Q and Zhu C: Competing endogenous RNA (ceRNA) network analysis of autophagy-related genes in hepatocellular carcinoma. Pharmgenomics Pers Med. 13:445–462. 2020.PubMed/NCBI
19	Niu ZS, Wang WH, Dong XN and Tian LM: Role of long noncoding RNA-mediated competing endogenous RNA regulatory network in hepatocellular carcinoma. World J Gastroenterol. 26:4240–4260. 2020. View Article : Google Scholar : PubMed/NCBI
20	Vaes E, Khan M and Mombaerts P: Statistical analysis of differential gene expression relative to a fold change threshold on NanoString data of mouse odorant receptor genes. BMC bioinformatics. 15:392014. View Article : Google Scholar : PubMed/NCBI
21	Ballester M, Cordon R and Folch JM: DAG expression: High-throughput gene expression analysis of real-time PCR data using standard curves for relative quantification. PLoS One. 8:e803852013. View Article : Google Scholar : PubMed/NCBI
22	van Iterson M, t Hoen PA, Pedotti P, Hooiveld GJ, den Dunnen JT, van Ommen GJ, Boer JM and Menezes RX: Relative power and sample size analysis on gene expression profiling data. BMC Genom. 10:4392009. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Peng L, Yuan XQ, Zhang CY, Peng JY, Zhang YQ, Pan X and Li GC: The emergence of long non-coding RNAs in hepatocellular carcinoma: An update. J Cancer. 9:2549–2558. 2018. View Article : Google Scholar : PubMed/NCBI
25	Mai H, Zhou B, Liu L, Yang F, Conran C, Ji Y, Hou J and Jiang D: Molecular pattern of lncRNAs in hepatocellular carcinoma. J Exp Clin Cancer Res. 38:1982019. View Article : Google Scholar : PubMed/NCBI
26	Lim LJ, Wong SYS, Huang F, Lim S, Chong SS, Ooi LL, Kon OL and Lee CG: Roles and regulation of long noncoding RNAs in hepatocellular carcinoma. Cancer Res. 79:5131–5139. 2019. View Article : Google Scholar : PubMed/NCBI
27	Wei L, Wang X, Lv L, Liu J, Xing H, Song Y, Xie M, Lei T, Zhang N and Yang M: The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma. Mol Cancer. 18:1472019. View Article : Google Scholar : PubMed/NCBI
28	Song XZ, Xu XJ, Ren XN, Ruan XX, Wang YL and Yao TT: LncRNA ANCR suppresses the progression of hepatocellular carcinoma through the inhibition of Wnt/β-catenin signaling pathway. OncoTargets Ther. 13:8907–8917. 2020. View Article : Google Scholar : PubMed/NCBI
29	Xu L, Wang Z, Yin C, Pan F, Shi T and Tian Y: Long noncoding RNA LINC02580 suppresses the invasion-metastasis cascade in hepatocellular carcinoma by targeting SRSF1. Biochem Biophys Res Commun. 533:685–691. 2020. View Article : Google Scholar : PubMed/NCBI
30	Mo W, Dai Y, Chen J, Liang L, Xu S and Xu X: Long Noncoding RNA (lncRNA) MT1JP Suppresses Hepatocellular Carcinoma (HCC) in vitro. Cancer Manag Res. 12:7949–7960. 2020. View Article : Google Scholar : PubMed/NCBI
31	Liu X and Shen Z: LncRNA TMPO-AS1 aggravates the development of hepatocellular carcinoma via miR-429/GOT1 axis. Am J Med Sci. 360:711–720. 2020. View Article : Google Scholar : PubMed/NCBI
32	Zhang X, Xu S, Hu C, Fang K, Zhou J, Guo Z, Zhu G and Li L: LncRNA ST8SIA6-AS1 promotes hepatocellular carcinoma progression by regulating MAGEA3 and DCAF4L2 expression. Biochem Biophys Res Commun. 533:1039–1047. 2020. View Article : Google Scholar : PubMed/NCBI
33	Zhang Z, Li H, Hu Y and Wang F: Long non-coding RNA ADAMTS9-AS1 exacerbates cell proliferation, migration, and invasion via triggering of the PI3K/AKT/mTOR pathway in hepatocellular carcinoma cells. Am J Transl Res. 12:5696–5707. 2020.PubMed/NCBI
34	Zhang XZ, Liu H and Chen SR: Mechanisms of long non-coding RNAs in cancers and their dynamic regulations. Cancers (Basel). 12:12452020. View Article : Google Scholar : PubMed/NCBI
35	Zhang H and Lu B: The roles of ceRNAs-mediated autophagy in cancer chemoresistance and metastasis. Cancers (Basel). 12:29262020. View Article : Google Scholar : PubMed/NCBI
36	Wei GY, Hu M, Zhao L and Guo WS: miR-451a suppresses cell proliferation, metastasis and EMT via targeting YWHAZ in hepatocellular carcinoma. Eur Rev Med Pharmacol Sci. 23:5158–5167. 2019.PubMed/NCBI
37	Zhao S, Li J, Zhang G, Wang Q, Wu C, Zhang Q, Wang H, Sun P, Xiang R and Yang S: Exosomal miR-451a functions as a tumor suppressor in hepatocellular carcinoma by targeting LPIN1. Cell Physiol Biochem. 53:19–35. 2019. View Article : Google Scholar : PubMed/NCBI
38	Huebner K, Procházka J, Monteiro AC, Mahadevan V and Schneider-Stock R: The activating transcription factor 2: An influencer of cancer progression. Mutagenesis. 34:375–389. 2019. View Article : Google Scholar : PubMed/NCBI
39	Watson G, Ronai ZA and Lau E: ATF2, a paradigm of the multifaceted regulation of transcription factors in biology and disease. Pharmacol Res. 119:347–357. 2017. View Article : Google Scholar : PubMed/NCBI