MicroRNA‑486‑5p functions as a tumor suppressor of proliferation and cancer stem‑like cell properties by targeting Sirt1 in liver cancer

Yan,Xinlong; Liu,Xinhui; Wang,Zhaohai; Cheng,Qian; Ji,Guanghong; Yang,Hui; Wan,Lingfei; Ge,Chen; Zeng,Quan; Huang,Hua; Xi,Jiafei; He,Lijuan; Nan,Xue; Yue,Wen; Pei,Xuetao

doi:10.3892/or.2018.6930

MicroRNA‑486‑5p functions as a tumor suppressor of proliferation and cancer stem‑like cell properties by targeting Sirt1 in liver cancer

Authors:
- Xinlong Yan
- Xinhui Liu
- Zhaohai Wang
- Qian Cheng
- Guanghong Ji
- Hui Yang
- Lingfei Wan
- Chen Ge
- Quan Zeng
- Hua Huang
- Jiafei Xi
- Lijuan He
- Xue Nan
- Wen Yue
- Xuetao Pei
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Affiliations: College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, P.R. China, Department of Gastroenterology and Hepatology, Beijing 302 Hospital, Beijing 100039, P.R. China, Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, P.R. China, Stem Cell and Regenerative Medicine Laboratory, Institute of Health Service and Transfusion Medicine, Beijing 100850, P.R. China
Published online on: December 13, 2018 https://doi.org/10.3892/or.2018.6930
Pages: 1938-1948

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Abstract

Cancer stem‑like cells (CSCs) are critical for the initiation, progression, chemoresistance and postsurgical recurrence of liver cancer. They are thought to be novel targets for the treatment of liver cancer, however, efficient agents that target liver cancer stem cells (CSCs) have not been identified. MicroRNAs (miRNAs) are small non‑coding RNAs that target the 3'untranslated region (3'UTR) of mRNAs. Their dysregulation has been implicated in several types of cancer including liver cancer, but it still remains unknown if they play a role in targeting liver CSCs. We compared the miRNA profiles between liver cancer samples and adjacent non‑tumor tissues using The Cancer Genome Atlas (TCGA) datasets. Several miRNAs including miR‑486‑5p (miR‑486) were found to be significantly downregulated in liver cancer tissues. These differentially expressed miRNAs were screened between CSC‑enriched tumor spheres and adherent cells. miR‑486 was significantly downregulated in tumor spheres and liver cancer samples. Ectopic expression of miR‑486 significantly repressed the self‑renewal and invasion of CSCs in vitro and tumorigenesis in vivo. Notably, we found that sirtuin 1 (Sirt1) served as a direct target of miR‑486. The high expression of Sirt1 was involved in maintaining the self‑renewal and tumorigenic potential of liver CSCs. The results of the present study indicated that the miR‑486‑Sirt1 axis was involved in suppressing CSC traits and tumor progression.

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1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Visvader JE: Cells of origin in cancer. Nature. 469:314–322. 2011. View Article : Google Scholar : PubMed/NCBI
3	Easwaran H, Tsai HC and Baylin SB: Cancer epigenetics: Tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 54:716–727. 2014. View Article : Google Scholar : PubMed/NCBI
4	Kreso A and Dick JE: Evolution of the cancer stem cell model. Cell Stem Cell. 14:275–291. 2014. View Article : Google Scholar : PubMed/NCBI
5	Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C, Honorio S, et al: The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 17:211–215. 2011. View Article : Google Scholar : PubMed/NCBI
6	Muthukrishnan SD, Alvarado AG and Kornblum HI: Building bonds: Cancer stem cells depend on their progeny to drive tumor progression. Cell Stem Cell. 22:473–474. 2018. View Article : Google Scholar : PubMed/NCBI
7	Liu C, Liu L, Chen X, Cheng J, Zhang H, Shen J, Shan J, Xu Y, Yang Z, Lai M and Qian C: Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma. Hepatology. 64:117–129. 2016. View Article : Google Scholar : PubMed/NCBI
8	Zhang L, Sun H, Zhao F, Lu P, Ge C, Li H, Hou H, Yan M, Chen T, Jiang G, et al: BMP4 administration induces differentiation of CD133⁺ hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma. Cancer Res. 72:4276–4285. 2012. View Article : Google Scholar : PubMed/NCBI
9	Tang KH, Ma S, Lee TK, Chan YP, Kwan PS, Tong CM, Ng IO, Man K, To KF, Lai PB, et al: CD133⁺ liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology. 55:807–820. 2012. View Article : Google Scholar : PubMed/NCBI
10	Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, Chu PW, Lam CT, Poon RT and Fan ST: Significance of CD90⁺ cancer stem cells in human liver cancer. Cancer Cell. 13:153–166. 2008. View Article : Google Scholar : PubMed/NCBI
11	Mani SK, Zhang H, Diab A, Pascuzzi PE, Lefrançois L, Fares N, Bancel B, Merle P and Andrisani O: EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis B virus-infected hepatocytes. J Hepatol. 65:888–898. 2016. View Article : Google Scholar : PubMed/NCBI
12	Haraguchi N, Ishii H, Mimori K, Tanaka F, Ohkuma M, Kim HM, Akita H, Takiuchi D, Hatano H, Nagano H, Barnard GF, et al: CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest. 120:3326–3339. 2010. View Article : Google Scholar : PubMed/NCBI
13	Christ B, Stock P and Dollinger MM: CD13: Waving the flag for a novel cancer stem cell target. Hepatology. 53:1388–1390. 2011. View Article : Google Scholar : PubMed/NCBI
14	Kawai T, Yasuchika K, Ishii T, Katayama H, Yoshitoshi EY, Ogiso S, Kita S, Yasuda K, Fukumitsu K, Mizumoto M, et al: Keratin 19, a cancer stem cell marker in human hepatocellular carcinoma. Clin Cancer Res. 21:3081–3091. 2015. View Article : Google Scholar : PubMed/NCBI
15	Yang W, Wang C, Lin Y, Liu Q, Yu LX, Tang L, Yan HX, Fu J, Chen Y, Zhang HL, et al: OV6⁺ tumor-initiating cells contribute to tumor progression and invasion in human hepatocellular carcinoma. J Hepatol. 57:613–620. 2012. View Article : Google Scholar : PubMed/NCBI
16	Yamashita T and Wang XW: Cancer stem cells in the development of liver cancer. J Clin Invest. 123:1911–1918. 2013. View Article : Google Scholar : PubMed/NCBI
17	Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H and Taniguchi H: Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology. 44:240–251. 2006. View Article : Google Scholar : PubMed/NCBI
18	Visvader JE and Lindeman GJ: Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nat Rev Cancer. 8:755–768. 2008. View Article : Google Scholar : PubMed/NCBI
19	Di Leva G, Garofalo M and Croce CM: MicroRNAs in cancer. Annu Rev Pathol. 9:287–314. 2014. View Article : Google Scholar : PubMed/NCBI
20	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
21	Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S and Zucman-Rossi J: MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 47:1955–1963. 2008. View Article : Google Scholar : PubMed/NCBI
22	Borel F, Konstantinova P and Jansen PL: Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma. J Hepatol. 56:1371–1383. 2012. View Article : Google Scholar : PubMed/NCBI
23	Yan XL, Jia YL, Chen L, Zeng Q, Zhou JN, Fu CJ, Chen HX, Yuan HF, Li ZW, Shi L, et al: Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: Role of the S100A4-miR155-SOCS1-MMP9 axis. Hepatology. 57:2274–2286. 2013. View Article : Google Scholar : PubMed/NCBI
24	Chai S, Ng KY, Tong M, Lau EY, Lee TK, Chan KW, Yuan YF, Cheung TT, Cheung ST, Wang XQ, et al: Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells. Hepatology. 64:2062–2076. 2016. View Article : Google Scholar : PubMed/NCBI
25	Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, Chen J, Gao DM and Bao WH: Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol. 7:630–636. 2001. View Article : Google Scholar : PubMed/NCBI
26	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
27	Yan XL, Fu CJ, Chen L, Qin JH, Zeng Q, Yuan HF, Nan X, Chen HX, Zhou JN, Lin YL, et al: Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway. Breast Cancer Res Treat. 132:153–164. 2012. View Article : Google Scholar : PubMed/NCBI
28	Miao X, Yan X, Qu D, Li D, Tao FF and Sun Z: Red emissive sulfur, nitrogen codoped carbon dots and their application in ion detection and theraonostics. ACS Appl Mater Interfaces. 9:18549–18556. 2017. View Article : Google Scholar : PubMed/NCBI
29	Zhou JN, Zeng Q, Wang HY, Zhang B, Li ST, Nan X, Cao N, Fu CJ, Yan X, Jia YL, et al: MicroRNA-125b attenuates epithelial-mesenchymal transitions and targets stem-like liver cancer cells through small mothers against decapentaplegic 2 and 4. Hepatology. 62:801–815. 2015. View Article : Google Scholar : PubMed/NCBI
30	Yan X, Zhang D, Wu W, Wu S, Qian J, Hao Y, Yan F, Zhu P, Wu J, Huang G, et al: Mesenchymal stem cells promote hepatocarcinogenesis via lncRNA-MUF interaction with ANXA2 and miR-34a. Cancer Res. 77:6704–6716. 2017. View Article : Google Scholar : PubMed/NCBI
31	Li Y, Tian B, Yang J, Zhao L, Wu X, Ye SL, Liu YK and Tang ZY: Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics. J Cancer Res Clin Oncol. 130:460–468. 2004. View Article : Google Scholar : PubMed/NCBI
32	Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, et al: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 103:2257–2261. 2006. View Article : Google Scholar : PubMed/NCBI
33	Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG, Calin GA, Giovannini C, Ferrazzi E, Grazi GL, et al: Cyclin G1 is a target of miR-122a, a microRNA frequently down- regulated in human hepatocellular carcinoma. Cancer Res. 67:6092–6099. 2007. View Article : Google Scholar : PubMed/NCBI
34	Wang J, Tian X, Han R, Zhang X, Wang X, Shen H, Xue L, Liu Y, Yan X, Shen J, et al: Downregulation of miR-486-5p contributes to tumor progression and metastasis by targeting protumorigenic ARHGAP5 in lung cancer. Oncogene. 33:1181–1189. 2014. View Article : Google Scholar : PubMed/NCBI
35	Oh HK, Tan AL, Das K, Ooi CH, Deng NT, Tan IB, Beillard E, Lee J, Ramnarayanan K, Rha SY, et al: Genomic loss of miR-486 regulates tumor progression and the OLFM4 antiapoptotic factor in gastric cancer. Clin Cancer Res. 17:2657–2667. 2011. View Article : Google Scholar : PubMed/NCBI
36	Liu L, Liu C, Zhang Q, Shen J, Zhang H, Shan J, Duan G, Guo D, Chen X, Cheng J, et al: SIRT1-mediated transcriptional regulation of SOX2 is important for self-renewal of liver cancer stem cells. Hepatology. 64:814–827. 2016. View Article : Google Scholar : PubMed/NCBI