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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

MicroRNA-302a/d inhibits the self-renewal capability and cell cycle entry of liver cancer stem cells by targeting the E2F7/AKT axis

Authors: Yu-Shui Ma, Zhong-Wei Lv, Fei Yu, Zheng-Yan Chang, Xian-Ling Cong, Xiao-Ming Zhong, Gai-Xia Lu, Jian Zhu, Da Fu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

There is increasing evidence that liver cancer stem cells (LCSCs) contribute to hepatocellular carcinoma (HCC) initiation and progression. MicroRNA (miRNA) plays a significant functional role by directly regulating respective targets in LCSCs-triggered HCC, however, little is known about the function of the miRNA-302 family in LCSCs.

Methods

MiRNAs microarray was used to detect the miRNAs involved in LCSCs maintenance and differentiation. Biological roles and the molecular mechanism of miRNA-302a/d and its target gene E2F7 were detected in HCC in vitro. The expression and correlation of miRNA-302a/d and E2F7 in HCC patients was evaluated by quantitative PCR and Kaplan–Meier survival analysis.

Results

We found that the miRNA-302 family was downregulated during the spheroid formation of HCC cells and patients with lower miRNA-302a/d expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, E2F7 was confirmed to be directly targeted and inhibited by miRNA-302a/d. Furthermore, concomitant low expression of miRNA-302a/d and high expression of E2F7 correlated with a shorter median OS and PFS in HCC patients. Cellular functional analysis demonstrated that miRNA-302a/d negatively regulates self-renewal capability and cell cycle entry of liver cancer stem cells via suppression of its target gene E2F7 and its downstream AKT/β-catenin/CCND1 signaling pathway.

Conclusions

Our data provide the first evidence that E2F7 is a direct target of miRNA-302a/d and miRNA-302a/d inhibits the stemness of LCSCs and proliferation of HCC cells by targeting the E2F7/AKT/β-catenin/CCND1 signaling pathway.
Appendix
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Literature
1.
Lee D, Xu IM, Chiu DK, Lai RK, Tse AP, Lan Li L, Law CT, Tsang FH, Wei LL, Chan CY, Wong CM, Ng IO, Wong CC. Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma. J Clin Invest. 2017;127(5):1856–72.CrossRef
2.
Ma Y, Zhang H, Xiong C, Liu Z, Xu Q, Feng J, Zhang J, Wang Z, Yan X. CD146 mediates an E-cadherin-to-N-cadherin switch during TGF-β signaling-induced epithelial-mesenchymal transition. Cancer Lett. 2018;430:201–14.CrossRef
3.
Wang Y, Ma YS, Fang Y, Wu SD, Liu LL, Fu D, Shen XZ. Regulatory T cell: a protection for tumor cells. J Cell Mol Med. 2012;16(3):425–36.CrossRef
4.
Wu SD, Ma YS, Fu D, Shen XZ. Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treat Rev. 2012;38(3):218–25.CrossRef
5.
Liu LL, Fu D, Ma YS, Shen X. The power and the promise of liver cancer stem cell markers. Stem Cells Dev. 2011;20(12):2023–30.CrossRef
6.
Lv H, Lv G, Han Q, Yang W, Wang H. Noncoding RNAs in liver cancer stem cells: the big impact of little things. Cancer Lett. 2018;418:51–63.CrossRef
7.
Liang Z, Kong R, He Z, Lin LY, Qin SS, Chen CY, Xie ZQ, Yu F, Sun GQ, Li CG, Fu D, Jiang GX, Chen J, Ma YS. High expression of miR-493-5p positively correlates with clinical prognosis of non small cell lung cancer by targeting oncogene ITGB1. Oncotarget. 2017;8(29):47389–99.PubMedPubMedCentral
8.
Hou LK, Ma YS, Han Y, Lu GX, Luo P, Chang ZY, Xie RT, Yang HQ, Chai L, Cai MX, Wu TM, Yu F, Qin SS, Lv ZW, Wu CY, Fu D. Association of microRNA-33a molecular signature with non-small cell lung cancer diagnosis and prognosis after chemotherapy. PLoS One. 2017;12:e0170431.CrossRef
9.
Yang H, Li Y, Zhong X, Luo P, Luo P, Sun R, Xie R, Fu D, Ma Y, Cong X, Li W. Upregulation of microRNA-32 is associated with tumorigenesis and poor prognosis in patients with hepatocellular carcinoma. Oncol Lett. 2018;15(4):4097–104.PubMedPubMedCentral
10.
Ma YS, Wu TM, Lv ZW, Lu GX, Cong XL, Xie RT, Yang HQ, Chang ZY, Sun R, Chai L, Cai MX, Zhong XJ, Zhu J, Fu D. High expression of miR-105-1 positively correlates with clinical prognosis of hepatocellular carcinoma by targeting oncogene NCOA1. Oncotarget. 2017;8(7):11896–905.PubMedPubMedCentral
11.
Wang XF, Zhu YZ, Ma YS, Wang J, Zhang F, Xia Q, Fu D. The role of cancer stem cells in cancer metastasis: new perspective and progress. Cancer Epidemiol. 2013;37(1):60–3.CrossRef
12.
Xie RT, Cong XL, Zhong XM, Luo P, Yang HQ, Lu GX, Luo P, Chang ZY, Sun R, Wu TM, Lv ZW, Fu D, Ma YS. MicroRNA-33a downregulation is associated with tumorigenesis and poor prognosis in patients with hepatocellular carcinoma. Oncol Lett. 2018;15(4):4571–7.PubMedPubMedCentral
13.
Nwosu ZC, Battello N, Rothley M, Piorońska W, Sitek B, Ebert MP, Hofmann U, Sleeman J, Wölfl S, Meyer C, Megger DA, Dooley S. Liver cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumours. J Exp Clin Cancer Res. 2018;37(1):211.CrossRef
14.
Huang Q, Zhang XW, Ma YS, Lu GX, Xie RT, Yang HQ, Lv ZW, Zhong XM, Liu T, Huang SX, Fu D, Xie C. Up-regulated microRNA-299 corrected with poor prognosis of glioblastoma multiforme patients by targeting ELL2. Jpn J Clin Oncol. 2017;47(7):590–6.CrossRef
15.
Shah R, Tanriverdi K, Levy D, Larson M, Gerstein M, Mick E, Rozowsky J, Kitchen R, Murthy V, Mikalev E, Freedman JE. Discordant expression of circulating microrna from cellular and extracellular sources. PLoS One. 2016;11:e0153691.CrossRef
16.
Chen X, Zhang S, Wang Z, Wang F, Cao X, Wu Q, Zhao C, Ma H, Ye F, Wang H, Fang Z. Supervillin promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma in hypoxia via activation of the RhoA/ROCK-ERK/p38 pathway. J Exp Clin Cancer Res. 2018;37(1):128.CrossRef
17.
Yang Y, Zhu J, Zhang T, Liu J, Li Y, Zhu Y, Xu L, Wang R, Su F, Ou Y, Wu Q. PHD-finger domain protein 5A functions as a novel oncoprotein in lung adenocarcinoma. J Exp Clin Cancer Res. 2018;37(1):65.CrossRef
18.
Fu D, Ma YS, Wu W, Zhu XC, Jia CY, Zhao QL, Zhang CY, Wu XZ. Cell-cycle-dependent PC-PLC regulation by APC/CCdc20-mediated ubiquitin-proteasome pathway. J Cell Biochem. 2009;107(4):686–96.CrossRef
19.
Lv D, Ma QH, Duan JJ, Wu HB, Zhao XL, Yu SC, Bian XW. Optimized dissociation protocol for isolating human glioma stem cells from tumorspheres via fluorescence-activated cell sorting. Cancer Lett. 2016;377(1):105–15.CrossRef
20.
Yu J, Lei R, Zhuang X, Li X, Li G, Lev S, Segura MF, Zhang X, Hu G. MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells. Nat Commun. 2016;7:13884.CrossRef
21.
Paladini L, Fabris L, Bottai G, Raschioni C, Calin GA, Santarpia L. Targeting microRNAs as key modulators of tumor immune response. J Exp Clin Cancer Res. 2016;35:103.CrossRef
22.
Ma YS, Huang T, Zhong XM, Zhang HW, Cong XL, Xu H, Lu GX, Yu F, Xue SB, Lv ZW, Fu D. Proteogenomic characterization and comprehensive integrative genomic analysis of human colorectal cancer liver metastasis. Mol Cancer. 2018;17(1):139.CrossRef
23.
Yuan H, Li N, Fu D, Ren J, Hui J, Peng J, Liu Y, Qiu T, Jiang M, Pan Q, Han Y, Wang X, Li Q, Qin J. Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis. J Clin Invest. 2017;127(9):3375–91.CrossRef
24.
Zhang B, Fu D, Xu Q, Cong X, Wu C, Zhong X, Ma Y, Lv Z, Chen F, Han L, Qian M, Chin YE, Lam EW, Chiao P, Sun Y. The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nat Commun. 2018;9(1):1723.CrossRef
25.
Chi Y, Zhou D. MicroRNAs in colorectal carcinoma--from pathogenesis to therapy. J Exp Clin Cancer Res. 2016;35:43.CrossRef
26.
Kim W, Khan SK, Gvozdenovic-Jeremic J, Kim Y, Dahlman J, Kim H, Park O, Ishitani T, Jho EH, Gao B, Yang Y. Hippo signaling interactions with Wnt/β-catenin and notch signaling repress liver tumorigenesis. J Clin Invest. 2017;127(1):137–52.CrossRef
27.
Luo P, Yang Q, Cong LL, Wang XF, Li YS, Zhong XM, Xie RT, Jia CY, Yang HQ, Li WP, Cong XL, Xia Q, Fu D, Zeng QH, Ma YS. Identification of miR-124a as a novel diagnostic and prognostic biomarker in non-small cell lung cancer for chemotherapy. Mol Med Rep. 2017;16(1):238–46.CrossRef
28.
Zhao L, Wang Y, Jiang L, He M, Bai X, Yu L, Wei M. MiR-302a/b/c/d cooperatively sensitizes breast cancer cells to adriamycin via suppressing P-glycoprotein(P-gp) by targeting MAP/ERK kinase kinase 1 (MEKK1). J Exp Clin Cancer Res. 2016;35:25.CrossRef
29.
Yan GJ, Yu F, Wang B, Zhou HJ, Ge QY, Su J, Hu YL, Sun HX, Ding LJ. MicroRNA miR-302 inhibits the tumorigenicity of endometrial cancer cells by suppression of cyclin D1 and CDK1. Cancer Lett. 2014;345:39–47.CrossRef
30.
Sun J, Shi R, Zhao S, Li X, Lu S, Bu H, Ma X, Su C. E2F8, a direct target of miR-144, promotes papillary thyroid cancer progression via regulating cell cycle. J Exp Clin Cancer Res. 2017;36(1):40.CrossRef
31.
Ozturk M, Arslan-Ergul A, Bagislar S, Senturk S, Yuzugullu H. Senescence and immortality in hepatocellular carcinoma. Cancer Lett. 2009;286(1):103–13.CrossRef
32.
Chen B, Lee JB, Kang H, Minden MD, Zhang L. Targeting chemotherapy-resistant leukemia by combining DNT cellular therapy with conventional chemotherapy. J Exp Clin Cancer Res. 2018;37:88.CrossRef
33.
Du L, Li YJ, Fakih M, Wiatrek RL, Duldulao M, Chen Z, Chu P, Garcia-Aguilar J, Chen Y. Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal. Nat Commun. 2016;7:12326.CrossRef
34.
DeWaal D, Nogueira V, Terry AR, Patra KC, Jeon SM, Guzman G, Au J, Long CP, Antoniewicz MR, Hay N. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 2018;9(1):446.CrossRef
35.
Jing W, Gao S, Zhu M, Luo P, Jing X, Chai H, Tu J. Potential diagnostic value of lncRNA SPRY4-IT1 in hepatocellular carcinoma. Oncol Rep. 2016;36(2):1085–92.CrossRef
36.
Zhu P, Wang Y, Wu J, Huang G, Liu B, Ye B, Du Y, Gao G, Tian Y, He L, Fan Z. LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells. Nat Commun. 2016;7:13608.CrossRef
37.
Solé C, Larrea E, Di Pinto G, Tellaetxe M, Lawrie CH. miRNAs in B-cell lymphoma: molecular mechanisms and biomarker potential. Cancer Lett. 2017;405:79–89.CrossRef
38.
Wilson R, Espinosa-Diez C, Kanner N, Chatterjee N, Ruhl R, Hipfinger C, Advani SJ, Li J, Khan OF, Franovic A, Weis SM, Kumar S, Coussens LM, Anderson DG, Chen CC, Cheresh DA, Anand S. MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment. Nat Commun. 2016;7:13597.CrossRef
39.
Fu XT, Shi YH, Zhou J, Peng YF, Liu WR, Shi GM, Gao Q, Wang XY, Song K, Fan J, Ding ZB. MicroRNA-30a suppresses autophagy-mediated anoikis resistance and metastasis in hepatocellular carcinoma. Cancer Lett. 2018;412:108–17.CrossRef
40.
Chen J, Jin R, Zhao J, Liu J, Ying H, Yan H, Zhou S, Liang Y, Huang D, Liang X, Yu H, Lin H, Cai X. Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma. Cancer Lett. 2015;367:1–11.CrossRef
41.
Piao LS, Hur W, Kim TK, Hong SW, Kim SW, Choi JE, Sung PS, Song MJ, Lee BC, Hwang D, Yoon SK. CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Lett. 2012;315(2):129–37.CrossRef
42.
Shaw KL, Garabedian E, Mishra S, Barman P, Davila A, Carbonaro D, Shupien S, Silvin C, Geiger S, Nowicki B, Smogorzewska EM, Brown B, Wang X, de Oliveira S, Choi Y, Ikeda A, Terrazas D, Fu PY, Yu A, Fernandez BC, Cooper AR, Engel B, Podsakoff G, Balamurugan A, Anderson S, Muul L, Jagadeesh GJ, Kapoor N, Tse J, Moore TB, Purdy K, Rishi R, Mohan K, Skoda-Smith S, Buchbinder D, Abraham RS, Scharenberg A, Yang OO, Cornetta K, Gjertson D, Hershfield M, Sokolic R, Candotti F, Kohn DB. Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency. J Clin Invest. 2017;127(5):1689–899.CrossRef
43.
Liu N, Li J, Zhao Z, Han J, Jiang T, Chen Y, Hou N, Huang C. MicroRNA-302a enhances 5-fluorouracil-induced cell death in human colon cancer cells. Oncol Rep. 2017;37(1):631–9.CrossRef
44.
Yang X, Cui Y, Yang F, Sun C, Gao X. MicroRNA-302a suppresses cell proliferation, migration and invasion in osteosarcoma by targeting ADAM9. Mol Med Rep. 2017;16(3):3565–72.CrossRef
45.
Ma J, Yu J, Liu J, Yang X, Lou M, Liu J, Feng F, Ji P, Wang L. MicroRNA-302a targets GAB2 to suppress cell proliferation, migration and invasion of glioma. Oncol Rep. 2017;37(2):1159–67.CrossRef
46.
Lee CC, Chen PH, Ho KH, Shih CM, Cheng CH, Lin CW, Cheng KT, Liu AJ, Chen KC. The microRNA-302b-inhibited insulin-like growth factor-binding protein 2 signaling pathway induces glioma cell apoptosis by targeting nuclear factor IA. PLoS One. 2017;12:e0173890.CrossRef
47.
Cai N, Wang YD, Zheng PS. The microRNA-302-367 cluster suppresses the proliferation of cervical carcinoma cells through the novel target AKT1. RNA. 2013;19(1):85–95.CrossRef
48.
Zhang GM, Bao CY, Wan FN, Cao DL, Qin XJ, Zhang HL, Zhu Y, Dai B, Shi GH, Ye DW. MicroRNA-302a suppresses tumor cell proliferation by inhibiting AKT in prostate Cancer. PLoS One. 2014;10:e0124410.CrossRef
49.
Mantel PY, Hjelmqvist D, Walch M, Kharoubi-Hess S, Nilsson S, Ravel D, Ribeiro M, Grüring C, Ma S, Padmanabhan P, Trachtenberg A, Ankarklev J, Brancucci NM, Huttenhower C, Duraisingh MT, Ghiran I, Kuo WP, Filgueira L, Martinelli R, Marti M. Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria. Nat Commun. 2016;7:12727.CrossRef
50.
Morgunova E, Yin Y, Jolma A, Dave K, Schmierer B, Popov A, Eremina N, Nilsson L, Taipale J. Structural insights into the DNA-binding specificity of E2F family transcription factors. Nat Commun. 2015;6:10050.CrossRef
51.
Kent LN, Rakijas JB, Pandit SK, Westendorp B, Chen HZ, Huntington JT, Tang X, Bae S, Srivastava A, Senapati S, Koivisto C, Martin CK, Cuitino MC, Perez M, Clouse JM, Chokshi V, Shinde N, Kladney R, Sun D, Perez-Castro A, Matondo RB, Nantasanti S, Mokry M, Huang K, Machiraju R, Fernandez S, Rosol TJ, Coppola V, Pohar KS, Pipas JM, Schmidt CR, de Bruin A, Leone G. E2f8 mediates tumor suppression in postnatal liver development. J Clin Invest. 2016;126(8):2955–69.CrossRef
52.
Aksoy O, Chicas A, Zeng T, Zhao Z, McCurrach M, Wang X, Lowe SW. The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence. Genes Dev. 2012;26(14):1546–57.CrossRef
53.
McNair C, Xu K, Mandigo AC, Benelli M, Leiby B, Rodrigues D, Lindberg J, Gronberg H, Crespo M, De Laere B, Dirix L, Visakorpi T, Li F, Feng FY, de Bono J, Demichelis F, Rubin MA, Brown M, Knudsen KE. Differential impact of RB status on E2F1 reprogramming in human cancer. J Clin Invest. 2018;128(1):341–58.CrossRef
54.
Qin X, Livingston D, Kaelin WK Jr, Adams P. Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc Natl Acad Sci U S A. 1994;91(23):10918–22.CrossRef
55.
Wu X, Levine A. p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci U S A. 1994;91(9):3602–6.CrossRef
56.
Yuzugullu H, Benhaj K, Ozturk N, Senturk S, Celik E, Toylu A, Tasdemir N, Yilmaz M, Erdal E, Akcali KC, Atabey N, Ozturk M. Canonical Wnt signaling is antagonized by noncanonical Wnt5a in hepatocellular carcinoma cells. Mol Cancer. 2009;8:90.CrossRef
Metadata
Title
MicroRNA-302a/d inhibits the self-renewal capability and cell cycle entry of liver cancer stem cells by targeting the E2F7/AKT axis
Authors
Yu-Shui Ma
Zhong-Wei Lv
Fei Yu
Zheng-Yan Chang
Xian-Ling Cong
Xiao-Ming Zhong
Gai-Xia Lu
Jian Zhu
Da Fu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0927-8

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