Long non‑coding RNA BCAR4 promotes liver cancer progression by regulating proliferation, migration and invasion

Wang,Aiyao; Meng,Jun; Liu,Hui; Li,Chen; Zhou,Zhiyong

doi:10.3892/ol.2020.11826

Long non‑coding RNA BCAR4 promotes liver cancer progression by regulating proliferation, migration and invasion

Authors:
- Aiyao Wang
- Jun Meng
- Hui Liu
- Chen Li
- Zhiyong Zhou
View Affiliations

Affiliations: Department of Gastroenterology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Orthopedics, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Oncology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: July 8, 2020 https://doi.org/10.3892/ol.2020.11826
Pages: 2779-2787
Copyright: © Wang 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

Liver cancer (LC) is one of the primary contributors of cancer‑associated death worldwide. Long non‑coding RNAs (lncRNAs) have been shown to participate in almost every aspect of cell biology and serve fundamental roles in carcinogenesis and cancer progression, including in LC. However, the clinical significance and functional role of the lncRNA breast cancer anti‑estrogen resistance 4 (BCAR4) in LC have not yet been identified. The present study measured the expression levels of BCAR4 in LC cells and tissues, and discovered that BCAR4 was upregulated in LC tissues compared with adjacent normal tissues. Furthermore, high BCAR4 expression was associated with the presence of multiple tumors and advanced Tumor‑Node‑Metastasis stages (III/IV). Survival analysis found that high BCAR4 expression indicated poor overall survival (OS) and progression‑free survival (PFS). By analyzing the risk factors of poor OS and PFS using univariate analysis and multivariate analysis, high BCAR4 expression was revealed to be an independent risk factor of poor prognosis. In addition, the role of BCAR4 was further investigated in vitro, which revealed overexpression of BCAR4 to markedly promote the proliferation, migration and invasion of LC cells. Conversely, the loss of BCAR4 expression repressed the proliferation, migration and invasion of LC cells. In conclusion, BCAR4 is overexpressed in LC and is associated with LC progression. Therefore, BCAR4 may be used as a potential prognostic marker in LC.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
2	Ayoub WS, Steggerda J, Yang JD, Kuo A, Sundaram V and Lu SC: Current status of hepatocellular carcinoma detection: Screening strategies and novel biomarkers. Ther Adv Med Oncol. 11:17588359198691202019. View Article : Google Scholar : PubMed/NCBI
3	Altekruse SF, McGlynn KA and Reichman ME: Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 27:1485–1491. 2009. View Article : Google Scholar : PubMed/NCBI
4	Alqahtani A, Khan Z, Alloghbi A, Said Ahmed TS, Ashraf M and Hammouda DM: Hepatocellular carcinoma: Molecular mechanisms and targeted therapies. Medicina (Kaunas). 55:E5262019. View Article : Google Scholar : PubMed/NCBI
5	Golabi P, Fazel S, Otgonsuren M, Sayiner M, Locklear CT and Younossi ZM: Mortality assessment of patients with hepatocellular carcinoma according to underlying disease and treatment modalities. Medicine (Baltimore). 96:e59042017. View Article : Google Scholar : PubMed/NCBI
6	Dhanasekaran R, Venkatesh SK, Torbenson MS and Roberts LR: Clinical implications of basic research in hepatocellular carcinoma. J Hepatol. 64:736–745. 2016. View Article : Google Scholar : PubMed/NCBI
7	Cheng H, Sun G, Chen H and Li Y, Han Z and Li Y, Zhang P, Yang L and Li Y: Trends in the treatment of advanced hepatocellular carcinoma: Immune checkpoint blockade immunotherapy and related combination therapies. Am J Cancer Res. 9:1536–1545. 2019.PubMed/NCBI
8	Kumari R, Sahu MK, Tripathy A, Uthansingh K and Behera M: Hepatocellular carcinoma treatment: Hurdles, advances and prospects. Hepat Oncol. 5:HEP082018. View Article : Google Scholar : PubMed/NCBI
9	Neureiter D, Stintzing S, Kiesslich T and Ocker M: Hepatocellular carcinoma: Therapeutic advances in signaling, epigenetic and immune targets. World J Gastroenterol. 25:3136–3150. 2019. View Article : Google Scholar : PubMed/NCBI
10	Villanueva A: Hepatocellular carcinoma. N Engl J Med. 380:1450–1462. 2019. View Article : Google Scholar : PubMed/NCBI
11	Sana J, Faltejskova P, Svoboda M and Slaby O: Novel classes of non-coding RNAs and cancer. J Transl Med. 10:1032012. View Article : Google Scholar : PubMed/NCBI
12	ENCODE Project Consortium, . An integrated encyclopedia of DNA elements in the human genome. Nature. 489:57–74. 2012. View Article : Google Scholar : PubMed/NCBI
13	Kopp F and Mendell JT: Functional classification and experimental dissection of long noncoding RNAs. Cell. 172:393–407. 2018. View Article : Google Scholar : PubMed/NCBI
14	Huang B and Zhang R: Regulatory non-coding RNAs: Revolutionizing the RNA world. Mol Biol Rep. 41:3915–3923. 2014. View Article : Google Scholar : PubMed/NCBI
15	Smekalova EM, Kotelevtsev YV, Leboeuf D, Shcherbinina EY, Fefilova AS, Zatsepin TS and Koteliansky V: lncRNA in the liver: Prospects for fundamental research and therapy by RNA interference. Biochimie. 131:159–172. 2016. View Article : Google Scholar : PubMed/NCBI
16	Bartonicek N, Maag JL and Dinger ME: Long noncoding RNAs in cancer: Mechanisms of action and technological advancements. Mol Cancer. 15:432016. View Article : Google Scholar : PubMed/NCBI
17	Niu ZS, Niu XJ and Wang WH: Long non-coding RNAs in hepatocellular carcinoma: Potential roles and clinical implications. World J Gastroenterol. 23:5860–5874. 2017. View Article : Google Scholar : PubMed/NCBI
18	Klingenberg M, Matsuda A, Diederichs S and Patel T: Non-coding RNA in hepatocellular carcinoma: Mechanisms, biomarkers and therapeutic targets. J Hepatol. 67:603–618. 2017. View Article : Google Scholar : PubMed/NCBI
19	Shibata C, Otsuka M, Kishikawa T, Ohno M, Yoshikawa T, Takata A and Koike K: Diagnostic and therapeutic application of noncoding RNAs for hepatocellular carcinoma. World J Hepatol. 7:1–6. 2015. View Article : Google Scholar : PubMed/NCBI
20	Sun J, Bie B, Zhang S, Yang J and Li Z: Long non-coding RNAs: Critical players in hepatocellular carcinoma. Int J Mol Sci. 15:20434–20448. 2014. View Article : Google Scholar : PubMed/NCBI
21	Shi L, Peng F, Tao Y, Fan X and Li N: Roles of long noncoding RNAs in hepatocellular carcinoma. Virus Res. 223:131–139. 2016. View Article : Google Scholar : PubMed/NCBI
22	Amin MB: American Joint Committee on Cancer Staging Manual. 8th. Springer; New York, NY: pp. 103–111. 2017, PubMed/NCBI
23	Schmittgen TD and Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 3:1101–1108. 2008. View Article : Google Scholar : PubMed/NCBI
24	Yuan SX, Wang J, Yang F, Tao QF, Zhang J, Wang LL, Yang Y, Liu H, Wang ZG, Xu QG, et al: Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1. Hepatology. 63:499–511. 2016. View Article : Google Scholar : PubMed/NCBI
25	Zhu P, Wang Y, Huang G, Ye B, Liu B, Wu J, Du Y, He L and Fan Z: lnc-β-Catm elicits EZH2-dependent β-catenin stabilization and sustains liver CSC self-renewal. Nat Struct Mol Biol. 23:631–639. 2016. View Article : Google Scholar : PubMed/NCBI
26	Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, Liu F, Pan W, Wang TT, Zhou CC, et al: A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 25:666–681. 2014. View Article : Google Scholar : PubMed/NCBI
27	Zheng Q, Lin Z, Li X, Xin X, Wu M, An J, Gui X, Li T, Pu H, Li H and Lu D: Inflammatory cytokine IL6 cooperates with CUDR to aggravate hepatocyte-like stem cells malignant transformation through NF-kB signaling. Sci Rep. 6:368432016. View Article : Google Scholar : PubMed/NCBI
28	Wang X, Sun W, Shen W, Xia M, Chen C, Xiang D, Ning B, Cui X, Li H, Li X, et al: Long non-coding RNA DILC regulates liver cancer stem cells via IL-6/STAT3 axis. J Hepatol. 64:1283–1294. 2016. View Article : Google Scholar : PubMed/NCBI
29	Lv L, Chen G, Zhou J, Li J and Gong J: WT1-AS promotes cell apoptosis in hepatocellular carcinoma through down-regulating of WT1. J Exp Clin Cancer Res. 34:1192015. View Article : Google Scholar : PubMed/NCBI
30	Wang F, Yuan JH, Wang SB, Yang F, Yuan SX, Ye C, Yang N, Zhou WP, Li WL, Li W and Sun SH: Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2. Hepatology. 60:1278–1290. 2014. View Article : Google Scholar : PubMed/NCBI
31	Guo W and Liu S, Cheng Y, Lu L, Shi J, Xu G, Li N, Cheng K, Wu M, Cheng S and Liu S: ICAM-1-related noncoding RNA in cancer stem cells maintains ICAM-1 expression in hepatocellular carcinoma. Clin Cancer Res. 22:2041–2050. 2016. View Article : Google Scholar : PubMed/NCBI
32	Yang F, Huo XS, Yuan SX, Zhang L, Zhou WP, Wang F and Sun SH: Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis. Mol Cell. 49:1083–1096. 2013. View Article : Google Scholar : PubMed/NCBI
33	Wang TH, Yu CC, Lin YS, Chen TC, Yeh CT, Liang KH, Shieh TM, Chen CY and Hsueh C: Long noncoding RNA CPS1-IT1 suppresses the metastasis of hepatocellular carcinoma by regulating HIF-1α activity and inhibiting epithelial-mesenchymal transition. Oncotarget. 7:43588–43603. 2016. View Article : Google Scholar : PubMed/NCBI
34	Panzitt K, Tschernatsch MM, Guelly C, Moustafa T, Stradner M, Strohmaier HM, Buck CR, Denk H, Schroeder R, Trauner M and Zatloukal K: Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology. 132:330–342. 2007. View Article : Google Scholar : PubMed/NCBI
35	Bao H and Su H: Long Noncoding RNAs Act as novel biomarkers for hepatocellular carcinoma: Progress and prospects. Biomed Res Int. 2017:60494802017. View Article : Google Scholar : PubMed/NCBI
36	Zheng C, Hao H, Chen L and Shao J: Long noncoding RNAs as novel serum biomarkers for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis. Clin Transl Oncol. 19:961–968. 2017. View Article : Google Scholar : PubMed/NCBI
37	George J and Patel T: Noncoding RNA as therapeutic targets for hepatocellular carcinoma. Semin Liver Dis. 35:63–74. 2015. View Article : Google Scholar : PubMed/NCBI
38	Ma L, Chua MS, Andrisani O and So S: Epigenetics in hepatocellular carcinoma: An update and future therapy perspectives. World J Gastroenterol. 20:333–345. 2014. View Article : Google Scholar : PubMed/NCBI
39	Parasramka MA, Maji S, Matsuda A, Yan IK and Patel T: Long non-coding RNAs as novel targets for therapy in hepatocellular carcinoma. Pharmacol Ther. 161:67–78. 2016. View Article : Google Scholar : PubMed/NCBI
40	Meijer D, van Agthoven T, Bosma PT, Nooter K and Dorssers LC: Functional screen for genes responsible for tamoxifen resistance in human breast cancer cells. Mol Cancer Res. 4:379–386. 2006. View Article : Google Scholar : PubMed/NCBI
41	van Agthoven T, Godinho MF, Wulfkuhle JD, Petricoin EF 3rd and Dorssers LC: Protein pathway activation mapping reveals molecular networks associated with antiestrogen resistance in breast cancer cell lines. Int J Cancer. 131:1998–2007. 2012. View Article : Google Scholar : PubMed/NCBI
42	Godinho MF, Wulfkuhle JD, Look MP, Sieuwerts AM, Sleijfer S, Foekens JA, Petricoin EF 3rd, Dorssers LC and van Agthoven T: BCAR4 induces antioestrogen resistance but sensitises breast cancer to lapatinib. Br J Cancer. 107:947–955. 2012. View Article : Google Scholar : PubMed/NCBI
43	Godinho M, Meijer D, Setyono-Han B, Dorssers LC and van Agthoven T: Characterization of BCAR4, a novel oncogene causing endocrine resistance in human breast cancer cells. J Cell Physiol. 226:1741–1749. 2011. View Article : Google Scholar : PubMed/NCBI
44	Godinho MF, Sieuwerts AM, Look MP, Meijer D, Foekens JA, Dorssers LC and van Agthoven T: Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer. Br J Cancer. 103:1284–1291. 2010. View Article : Google Scholar : PubMed/NCBI
45	Ju L, Zhou YM and Yang GS: Up-regulation of long non-coding RNA BCAR4 predicts a poor prognosis in patients with osteosarcoma, and promotes cell invasion and metastasis. Eur Rev Med Pharmacol Sci. 20:4445–4451. 2016.PubMed/NCBI
46	Li Q, Dai Y, Wang F and Hou S: Differentially expressed long non-coding RNAs and the prognostic potential in colorectal cancer. Neoplasma. 63:977–983. 2016. View Article : Google Scholar : PubMed/NCBI
47	Li N, Gao WJ and Liu NS: LncRNA BCAR4 promotes proliferation, invasion and metastasis of non-small cell lung cancer cells by affecting epithelial-mesenchymal transition. Eur Rev Med Pharmacol Sci. 21:2075–2086. 2017.PubMed/NCBI
48	Shui X, Zhou C, Lin W, Yu Y, Feng Y and Kong J: Long non-coding RNA BCAR4 promotes chondrosarcoma cell proliferation and migration through activation of mTOR signaling pathway. Exp Biol Med (Maywood). 242:1044–1050. 2017. View Article : Google Scholar : PubMed/NCBI
49	Wang L, Chunyan Q, Zhou Y, He Q, Ma Y, Ga Y and Wang X: BCAR4 increase cisplatin resistance and predicted poor survival in gastric cancer patients. Eur Rev Med Pharmacol Sci. 21:4064–4070. 2017.PubMed/NCBI
50	Yang H, Yan L, Sun K, Sun X, Zhang X, Cai K and Song T: LncRNA BCAR4 increases viability, invasion and migration non-small cell lung cancer cells by targeting glioma-associated oncogene 2(GLI2). Oncol Res. 27:359–369. 2019. View Article : Google Scholar : PubMed/NCBI
51	Ouyang S, Zheng X, Zhou X, Chen Z, Yang X and Xie M: LncRNA BCAR4 promotes colon cancer progression via activating Wnt/betaβ-catenin signaling. Oncotarget. 8:92815–92826. 2017. View Article : Google Scholar : PubMed/NCBI