Upregulation of microRNA‑300 induces the proliferation of liver cancer by downregulating transcription factor FOXO1

Chang,Yuanhong; Zhou,Cancan; Fan,Lin; Qiu,Guanglin; Wang,Guanghui; Wei,Guangbing; Chang,Xinming; Li,Xuqi

doi:10.3892/or.2018.6727

Upregulation of microRNA‑300 induces the proliferation of liver cancer by downregulating transcription factor FOXO1

Authors:
- Yuanhong Chang
- Cancan Zhou
- Lin Fan
- Guanglin Qiu
- Guanghui Wang
- Guangbing Wei
- Xinming Chang
- Xuqi Li
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Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Departments of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Departments of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: September 21, 2018 https://doi.org/10.3892/or.2018.6727
Pages: 3561-3572

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Abstract

In the present study, we investigated whether miRNA‑300 (miR‑300) is an oncogene in human liver cancer and sought to determine the mechanism underlying its activity. We also investigated the effect of miRNA‑300 on the growth in liver cancer. To identify its target molecule, we performed luciferase assays. The downstream signaling pathway was detected by immunohistochemical (IHC) analysis in human HCC tissues, and the protein levels of AKT, 4E‑BP1, S6K1, SNAIL and MMP2 were determined using western blotting. miR‑300 levels were higher in patients with high‑stage HCC, and miR‑300 promoted cell growth both in vitro and in vivo. miRNA‑300 inhibited the luciferase activity of FOXO1 by targeting its 3'‑untranslated region (UTR), and overexpression of miR‑300 upregulated the protein levels of phospho‑AKT, phospho‑4E‑BP1, phospho‑S6K1, SNAIL and MMP2. These data revealed that miRNA‑300 functions as an oncogene in liver cancer by inhibiting FOXO1 and interacting with the AKT/mTOR signaling pathway.

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1	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
2	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
3	Maluccio M and Covey A: Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin. 62:394–399. 2012. View Article : Google Scholar : PubMed/NCBI
4	Altomare DA and Testa JR: Perturbations of the AKT signaling pathway in human cancer. Oncogene. 24:7455–7464. 2005. View Article : Google Scholar : PubMed/NCBI
5	Cui SX, Shi WN, Song ZY, Wang SQ, Yu XF, Gao ZH and Qu XJ: Des-gamma-carboxy prothrombin antagonizes the effects of Sorafenib on human hepatocellular carcinoma through activation of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways. Oncotarget. 7:36767–36782. 2016. View Article : Google Scholar : PubMed/NCBI
6	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
7	He L and Hannon GJ: MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI
8	Liu Z, Dou C, Yao B, Xu M, Ding L, Wang Y, Jia Y, Li Q, Zhang H, Tu K, et al: Methylation-mediated repression of microRNA-129-2 suppresses cell aggressiveness by inhibiting high mobility group box 1 in human hepatocellular carcinoma. Oncotarget. 7:36909–36923. 2016.PubMed/NCBI
9	Yang W, Dou C, Wang Y, Jia Y, Li C, Zheng X and Tu K: MicroRNA-92a contributes to tumor growth of human hepatocellular carcinoma by targeting FBXW7. Oncol Rep. 34:2576–2584. 2015. View Article : Google Scholar : PubMed/NCBI
10	Lu CY, Lin KY, Tien MT, Wu CT, Uen YH and Tseng TL: Frequent DNA methylation of MiR-129-2 and its potential clinical implication in hepatocellular carcinoma. Genes Chromosomes Cancer. 52:636–643. 2013.PubMed/NCBI
11	Furuta M, Kozaki KI, Tanaka S, Arii S, Imoto I and Inazawa J: miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. Carcinogenesis. 31:766–776. 2010. View Article : Google Scholar : PubMed/NCBI
12	Liu Y, Ren F, Rong M, Luo Y, Dang Y and Chen G: Association between underexpression of microrna-203 and clinicopathological significance in hepatocellular carcinoma tissues. Cancer Cell Int. 15:622015. View Article : Google Scholar : PubMed/NCBI
13	Alpini G, Glaser SS, Zhang JP, Francis H, Han Y, Gong J, Stokes A, Francis T, Hughart N, Hubble L, et al: Regulation of placenta growth factor by microRNA-125b in hepatocellular cancer. J Hepatol. 55:1339–1345. 2011. View Article : Google Scholar : PubMed/NCBI
14	Coulouarn C, Factor VM, Andersen JB, Durkin ME and Thorgeirsson SS: Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene. 28:3526–3536. 2009. View Article : Google Scholar : PubMed/NCBI
15	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
16	Lin CJ, Gong HY, Tseng HC, Wang WL and Wu JL: miR-122 targets an anti-apoptotic gene, Bcl-w, in human hepatocellular carcinoma cell lines. Biochem Biophys Res Commun. 375:315–320. 2008. View Article : Google Scholar : PubMed/NCBI
17	Greer EL and Brunet A: FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 24:7410–7425. 2005. View Article : Google Scholar : PubMed/NCBI
18	Hartmann W, Küchler J, Koch A, Friedrichs N, Waha A, Endl E, Czerwitzki J, Metzger D, Steiner S, Wurst P, et al: Activation of phosphatidylinositol-3′-kinase/AKT signaling is essential in hepatoblastoma survival. Clin Cancer Res. 15:4538–4545. 2009. View Article : Google Scholar : PubMed/NCBI
19	Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, Unterman T and Hay N: Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell. 14:458–470. 2008. View Article : Google Scholar : PubMed/NCBI
20	Gospodarowicz MK, Brierley JD and Wittekind C: TNM classifcation of malignant tumours. 8th edition. John Wiley & Sons; Oxford, UK: 2017
21	Sinicrope FA, Ruan SB, Cleary KR, Stephens LC, Lee JJ and Levin B: Bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res. 55:237–241. 1995.PubMed/NCBI
22	Miyoshi A, Kitajima Y, Sumi K, Sato K, Hagiwara A, Koga Y and Miyazaki K: Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer. 90:1265–1273. 2004. View Article : Google Scholar : PubMed/NCBI
23	Xiang ZL, Zhao XM, Zhang L, Yang P, Fan J, Tang ZY and Zeng ZC: MicroRNA-34a expression levels in serum and intratumoral tissue can predict bone metastasis in patients with hepatocellular carcinoma. Oncotarget. 7:87246–87256. 2016. View Article : Google Scholar : PubMed/NCBI
24	Dou C, Wang Y, Li C, Liu Z, Jia Y, Li Q, Yang W, Yao Y, Liu Q and Tu K: MicroRNA-212 suppresses tumor growth of human hepatocellular carcinoma by targeting FOXA1. Oncotarget. 6:13216–13228. 2015. View Article : Google Scholar : PubMed/NCBI
25	Calin GA and Croce CM: MicroRNA-cancer connection: The beginning of a new tale. Cancer Res. 66:7390–7394. 2006. View Article : Google Scholar : PubMed/NCBI
26	Machida S, Spangenburg EE and Booth FW: Forkhead transcription factor FoxO1 transduces insulin-like growth factor's signal to p27Kip1 in primary skeletal muscle satellite cells. J Cell Physiol. 196:523–531. 2003. View Article : Google Scholar : PubMed/NCBI
27	Kim SJ, Winter K, Nian C, Tsuneoka M, Koda Y and McIntosh CH: Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression. J Biol Chem. 280:22297–22307. 2005. View Article : Google Scholar : PubMed/NCBI
28	Grinius L, Kessler C, Schroeder J and Handwerger S: Forkhead transcription factor FOXO1A is critical for induction of human decidualization. J Endocrinol. 189:179–187. 2006. View Article : Google Scholar : PubMed/NCBI
29	Xie L, Ushmorov A, Leithäuser F, Guan H, Steidl C, Färbinger J, Pelzer C, Vogel MJ, Maier HJ, Gascoyne RD, et al: FOXO1 is a tumor suppressor in classical Hodgkin lymphoma. Blood. 119:3503–3511. 2012. View Article : Google Scholar : PubMed/NCBI
30	Wu Y, Elshimali Y, Sarkissyan M, Mohamed H, Clayton S and Vadgama JV: Expression of FOXO1 is associated with GATA3 and Annexin-1 and predicts disease-free survival in breast cancer. Am J Cancer Res. 2:104–115. 2012.PubMed/NCBI
31	Rena G, Guo S, Cichy SC, Unterman TG and Cohen P: Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem. 274:17179–17183. 1999. View Article : Google Scholar : PubMed/NCBI
32	Morgan TM, Koreckij TD and Corey E: Targeted therapy for advanced prostate cancer: Inhibition of the PI3K/Akt/mTOR pathway. Curr Cancer Drug Targets. 9:237–249. 2009. View Article : Google Scholar : PubMed/NCBI
33	Dong XY, Chen C, Sun X, Guo P, Vessella RL, Wang RX, Chung LW, Zhou W and Dong JT: FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Cancer Res. 66:6998–7006. 2006. View Article : Google Scholar : PubMed/NCBI
34	Calnan DR and Brunet A: The FoxO code. Oncogene. 27:2276–2288. 2008. View Article : Google Scholar : PubMed/NCBI
35	Huang H and Tindall DJ: FOXO factors: A matter of life and death. Future Oncol. 2:83–89. 2006. View Article : Google Scholar : PubMed/NCBI
36	Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K and Motoyama N: FOXO forkhead transcription factors induce G₂-M checkpoint in response to oxidative stress. J Biol Chem. 277:26729–26732. 2002. View Article : Google Scholar : PubMed/NCBI
37	Arden KC: FoxOs in tumor suppression and stem cell maintenance. Cell. 128:235–237. 2007. View Article : Google Scholar : PubMed/NCBI
38	Ichiyama K, Gonzalez-Martin A, Kim BS, Jin HY, Jin W, Xu W, Sabouri-Ghomi M, Xu S, Zheng P, Xiao C and Dong C: The MicroRNA-183-96-182 cluster promotes T helper 17 cell pathogenicity by negatively regulating transcription factor Foxo1 expression. Immunity. 44:1284–1298. 2016. View Article : Google Scholar : PubMed/NCBI
39	Haflidadóttir BS, Larne O, Martin M, Persson M, Edsjö A, Bjartell A and Ceder Y: Upregulation of miR-96 enhances cellular proliferation of prostate cancer cells through FOXO1. PLoS One. 8:e724002013. View Article : Google Scholar : PubMed/NCBI
40	Wu Z, Sun H, Zeng W, He J and Mao X: Upregulation of MircoRNA-370 induces proliferation in human prostate cancer cells by downregulating the transcription factor FOXO1. PLoS One. 7:e458252012. View Article : Google Scholar : PubMed/NCBI
41	López-Terrada D, Cheung SW, Finegold MJ and Knowles BB: Hep G2 is a hepatoblastoma-derived cell line. Hum Pathol. 40:1512–1515. 2009. View Article : Google Scholar