Gastric cancer is the third dominating cause of cancer-associated death. MiroRNAs are potential clinical tools for cancer diagnosis and therapy. In this project, we demonstrated significant overexpression of ONECUT2 and down-regulation of hsa-miR-15a-5p in gastric cancer via bioinformatics analysis and in vitro assays. Meanwhile, ONECUT2 expression is related to clinical prognosis in gastric cancer and inversely proportional to the differentiation degree of gastric adenocarcinoma according to immunohistochemistry results. Then, we separated CD133+/CD44+ MKN45 by flow cytometry and found that, compared with parental MKN45, CD133+/CD44+ MKN45 gastric cancer stem cells (GCSCs) had higher levels of ONECUT2 and lower levels of hsa-miR-15a-5p. In addition, we applied both in vivo and ex vivo assays to demonstrate hsa-miR-15a-5p regulates the stemness maintenance, epithelial–mesenchymal transition, and chemosensitivity of GCSCs through targeting ONECUT2. Also, hsa-miR-15a-5p inhibits G0 phase block of GCSCs by regulating ONECUT2/β-catenin signaling pathway. However, this study has provided novel perspective into the dynamic control of cancer stem cells for advanced gastric cancer treatment.
SiegelRLMillerKDJemalA.Cancer statistics, 2020. CA – Cancer J Clin2020;
70:7–30
2.
BrayFFerlayJSoerjomataramISiegelRLTorreLAJemalA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA – Cancer J Clin2018;
68:394–424
3.
DewiDLIshiiHKanoYNishikawaSHaraguchiNSakaiDSatohTDokiYMoriM.Cancer stem cell theory in gastrointestinal malignancies: recent progress and upcoming challenges. J Gastroenterol2011;
46:1145–57
4.
ZhangNLiRTaoKSCaoDYTiZYDingRCaiLZhangFQDouKF.Characterization of a stem-like population in hepatocellular carcinoma MHCC97 cells. Oncol Rep2010;
23:827–31
5.
LiuTXuFDuXLaiDLiuTZhaoYHuangQJiangLHuangWChengWLiuZ.Establishment and characterization of multi-drug resistant, prostate carcinoma-initiating stem-like cells from human prostate cancer cell lines 22RV1. Mol Cell Biochem2010;
340:265–73
6.
SapkotaDChintalaHWuFFlieslerSJHuZMuX.Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development. Proc Natl Acad Sci U S A2014;
111:E4086–95
7.
KlimovaLAntosovaBKuzelovaAStrnadHKozmikZ.Onecut1 and Onecut2 transcription factors operate downstream of Pax6 to regulate horizontal cell development. Dev Biol2015;
402:48–60
8.
WuYJiangGZhangNLiuSLinXPerschonCZhengSLDingQWangXNaRSunJXuJ.HOXA9, PCDH17, POU4F2, and ONECUT2 as a urinary biomarker combination for the detection of bladder cancer in Chinese patients with hematuria. Eur Urol Focus2020;
6:284–91
9.
LuTWuBYuYZhuWZhangSZhangYGuoJDengN.Blockade of ONECUT2 expression in ovarian cancer inhibited tumor cell proliferation, migration, invasion and angiogenesis. Cancer Sci2018;
109:2221–34
10.
GuoHCiXAhmedMHuaJTSoaresFLinDPucaLVosoughiAXueHLiESuPChenSNguyenTLiangYZhangYXuXXuJSheahanAVBa-AlawiWZhangSMahamudOVellankiRNGleaveMBristowRGHaibe-KainsBPoirierJTRudinCMTsaoMSWoutersBGFazliLFengFYEllisLvan der KwastTBerlinAKoritzinskyMBoutrosPCZoubeidiABeltranHWangYHeHH.ONECUT2 is a driver of neuroendocrine prostate cancer. Nat Commun2019;
10:278
11.
RotinenMYouSYangJCoetzeeSGReis-SobreiroMHuangWCHuangFPanXYáñezAHazelettDJChuCYSteadmanKMorrisseyCMNelsonPSCoreyEChungLWKFreedlandSJDi VizioDGarrawayIPMuraliRKnudsenBSFreemanMR.ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat Med2018;
24:1887–98
12.
SunYShenSLiuXTangHWangZYuZLiXWuM.MiR-429 inhibits cells growth and invasion and regulates EMT-related marker genes by targeting Onecut2 in colorectal carcinoma. Mol Cell Biochem2014;
390:19–30
13.
ZhangJChengJZengZWangYLiXXieQJiaJYanYGuoZGaoJYaoMChenXLuF.Comprehensive profiling of novel microRNA-9 targets and a tumor suppressor role of microRNA-9 via targeting IGF2BP1 in hepatocellular carcinoma. Oncotarget2015;
6:42040–52
14.
JungSYPappJCSobelEMPellegriniMYuHZhangZF.Pro-inflammatory cytokine polymorphisms in ONECUT2 and HNF4A and primary colorectal carcinoma: a post genome-wide gene-lifestyle interaction study. Am J Cancer Res2020;
10:2955–76
15.
HuJChenYLiXMiaoHLiRChenDWenZ.THUMPD3-AS1 is correlated with non-small cell lung cancer and regulates self-renewal through miR-543 and ONECUT2. Onco Targets Ther2019;
12:9849–60
16.
ShenMDongCRuanXYanWCaoMPizzoDWuXYangLLiuLRenXWangSE.Chemotherapy-induced extracellular vesicle miRNAs promote breast cancer stemness by targeting ONECUT2. Cancer Res2019;
79:3608–21
17.
LiuJValencia-SanchezMAHannonGJParkerR.MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat Cell Biol2005;
7:719–23
18.
TangZLiCKangBGaoGLiCZhangZ.GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res2017;
45:W98–102
19.
ChandrashekarDSBashelBBalasubramanyaSAHCreightonCJPonce-RodriguezIChakravarthiBVaramballyS.UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia (New York, NY)2017;
19:649–58
20.
ChenEYTanCMKouYDuanQWangZMeirellesGVClarkNRMa'ayanA.Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics2013;
14:128
21.
MaXLiuJLiJLiYLeVMLiSLiangXLiuLLiuJ.miR-139-5p reverses stemness maintenance and metastasis of colon cancer stem-like cells by targeting E2-2. J Cell Physiol2019;
234:22703–18
22.
TakaishiSOkumuraTTuSWangSSShibataWVigneshwaranRGordonSAShimadaYWangTC.Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells (Dayton, Ohio)2009;
27:1006–20
23.
ZhangXHuaRWangXHuangMGanLWuZZhangJWangHChengYLiJGuoW.Identification of stem-like cells and clinical significance of candidate stem cell markers in gastric cancer. Oncotarget2016;
7:9815–31
24.
QiaoXTGumucioDL.Current molecular markers for gastric progenitor cells and gastric cancer stem cells. J Gastroenterol2011;
46:855–65
25.
ShapiraALivneyYDBroxtermanHJAssarafYG.Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance. Drug Resist Updat2011;
14:150–63
26.
WangGHZhouYMYuZDengJPLiuSFWeiCZFengYMaoMWangZ.Up-regulated ONECUT2 and down-regulated SST promote gastric cell migration, invasion, epithelial–mesenchymal transition and tumor growth in gastric cancer. Eur Rev Med Pharmaco2020;
24:9378–90
27.
SeoEHKimHJKimJHLimBParkJLKimSYLeeSIJeongHYSongKSKimYS.ONECUT2 upregulation is associated with CpG hypomethylation at promoter-proximal DNA in gastric cancer and triggers ACSL5. Int J Cancer2020;
146:3354–68
28.
YangYPChienYChiouGYCherngJYWangMLLoWLChangYLHuangPIChenYWShihYHChenMTChiouSH.Inhibition of cancer stem cell-like properties and reduced chemoradioresistance of glioblastoma using microRNA145 with cationic polyurethane-short branch PEI. Biomaterials2012;
33:1462–76
29.
ClementsWMWangJSarnaikAKimOJMacDonaldJFenoglio-PreiserCGrodenJLowyAM.Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res2002;
62:3503–6
