Musashi-1 (MSI1), a neural RNA-binding protein, is considered a gastric and intestinal stem cell marker. Although the function of MSI1 in gastric cancer has attracted increasing interest, it is not known whether MSI1 can be used as a biomarker to monitor gastric cancer development and response to treatment. Here, the role of MSI1 in the chemotherapeutic sensitivity of gastric cancer was investigated. Patients with high MSI1 levels had poor outcomes, implicating the gene in the development and progression of the disease. We overexpressed and silenced MSI1 in the human gastric cancer cell lines MKN45 and HGC27, finding that knockdown reduced proliferation, invasion, and migration, while promoting apoptosis. A patient-derived xenograft gastric cancer model was constructed in which mice received chemical drugs, si-MSI1, or a drug-si-MSI1 combination. It was found that blocking MSI1 expression reduced gastric cancer drug tolerance. The combination treatment with si-MSI1 was superior to 5F-dUMP and cisplatin, either separately or in combination, indicating that including si-MSI1 was better than drug therapy alone. Transcriptome sequencing analysis showed that MSI1 altered cell cycle regulation and growth signal transduction, including that of blood vessel epicardial substance (BVES). These results suggest that MSI1 reduces the tolerance of gastric cancer to chemical drugs through modulation of MSI1/BVES signaling.
YinXWuQMongaJXieEWangHWangSZhangHWangZYZhouTShiYRogersJLinHMinJWangF. HDAC1 governs iron homeostasis independent of histone deacetylation in iron-overload Murine models.Antioxid Redox Signal2018;28:1224–37
2.
DesiderioJChaoJMelstromLWarnerSTozziFFongYParisiAWooY. The 30-year experience: a meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer.Eur J Cancer2017;79:1–14
3.
DigkliaAWagnerAD. Advanced gastric cancer: current treatment landscape and future perspectives.World J Gastroenterol2016;22:2403–14
4.
HuangSGuoYLiZZhangYZhouTYouWPanKLiW. A systematic review of metabolomic profiling of gastric cancer and esophageal cancer.Cancer Biol Med2020;17:181–98
5.
GleesonFCKippBRKerrSEVossJSGrahamRPCampionMBMinotDMTuZJKleeEWLazaridisKNHenryMRLevyMJ. Kinase genotype analysis of gastric gastrointestinal stromal tumor cytology samples using targeted next-generation sequencing.Clin Gastroenterol Hepatol2015;13:202–6
6.
KanadaMKimBDHardyJWRonaldJABachmannMHBernardMPPerezGIZareaAAGeTJWithrowAIbrahimSAToomajianVGambhirSSPaulmuruganRContagCH. Microvesicle-mediated delivery of minicircle DNA results in effective gene-directed enzyme prodrug cancer therapy.Mol Cancer Ther2019;18:2331–42
7.
MalikYSSheikhMAXingZGuoZZhuXTianHChenX. Polylysine-modified polyethylenimine polymer can generate genetically engineered mesenchymal stem cells for combinational suicidal gene therapy in glioblastoma.Acta Biomaterialia2018;80:144–53
8.
OkabeMSawamotoKImaiTSakakibaraSYoshikawaSOkanoH. Intrinsic and extrinsic determinants regulating cell fate decision in developing nervous system.Dev Neurosci1997;19:9–16
9.
KudinovAEKaranicolasJGolemisEABoumberY. Musashi RNA-binding proteins as cancer drivers and novel therapeutic targets.Clin Cancer Res2017;23:2143–53
10.
OkanoHKawaharaHToriyaMNakaoKShibataSImaiT. Function of RNA-binding protein Musashi-1 in stem cells.Exp Cell Res2005;306:349–56
11.
KuangRGKuangYLuoQFZhouCJJiRWangJW. Expression and significance of Musashi-1 in gastric cancer and precancerous lesions.World J Gastroenterol2013;19:6637–44
12.
XiaoRYuYShenSLiuFKuangR. Musashi1 promotes tumor metastasis and is a prognostic marker for renal carcinoma.Int J Clin Exp Pathol2019;12:313–9
13.
GuanAWangHLiXXieHWangRZhuYLiR. MiR-330-3p inhibits gastric cancer progression through targeting MSI1.Am J Transl Res2016;8:4802–11
14.
WangTOngCWShiJSrivastavaSYanBChengCLYongWPChanSLYeohKGIacopettaBSalto-TellezM. Sequential expression of putative stem cell markers in gastric carcinogenesis.Br J Cancer2011;105:658–65
15.
ShouZJinXHeXZhaoZChenYYeMYaoJ. Overexpression of Musashi-1 protein is associated with progression and poor prognosis of gastric cancer.Oncol Lett2017;13:3556–66
16.
LangYKongXHeCWangFLiuBZhangSNingJZhuKXuS. Musashi1 promotes non-small cell lung carcinoma malignancy and chemoresistance via activating the Akt signaling pathway.Cell Physiol Biochem2017;44:455–66
17.
BrungsDAghmeshehMVineKLBeckerTMCarolanMGRansonM. Gastric cancer stem cells: evidence, potential markers, and clinical implications.J Gastroenterol2016;51:313–26
18.
WuHLiJChenJYinYDaPChenQZhangZWangJWangGQiuX. Efficacy of radiation exposure in laryngeal squamous cell carcinoma is mediated by the LAMP3/LAMC2/tenascin-C pathway.Exp Biol Med2019;244:1070–80
19.
GaoHKornJMFerrettiSMonahanJEWangYSinghMZhangCSchnellCYangGZhangYBalbinOABarbeSCaiHCaseyFChatterjeeSChiangDYChuaiSCoganSMCollinsSDDammassaEEbelNEmbryMGreenJKauffmannAKowalCLearyRJLeharJLiangYLooALorenzanaERobert McDonaldE3rdMcLaughlinMEMerkinJMeyerRNaylorTLPatawaranMReddyARöelliCRuddyDASalangsangFSantacroceFSinghAPTangYTinettoWToblerSVelazquezRVenkatesanKVon ArxFWangHQWangZWiesmannMWyssDXuFBitterHAtadjaPLeesEHofmannFLiEKeenNCozensRJensenMRPryerNKWilliamsJASellersWR. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response.Nat Med2015;21:1318–25
20.
GaoCYuanXJiangZGanDDingLSunYZhouJXuLLiuYWangG. Regulation of AKT phosphorylation by GSK3β and PTEN to control chemoresistance in breast cancer.Breast Cancer Res Treat2019;176:291–301
21.
LinSWangHYangWWangAGengC. Silencing of long non-coding RNA colon cancer-associated transcript 2 inhibits the growth and metastasis of gastric cancer through blocking mTOR signaling.Onco Targets Ther2020;13:337–49
22.
SakuraiYUraguchiTImazuHHasegawaSMatsubaraTOchiaiMFunabikiT. Changes in thymidylate synthase and its inhibition rate and changes in dihydropyrimidine dehydrogenase after the administration of 5-fluorouracil with cisplatin to nude mice with gastric cancer xenograft SC-1-NU.Gastric Cancer2004;7:110–6
23.
GuoXFLiuJPMaSQZhangPSunWD. Avicularin reversed multidrug-resistance in human gastric cancer through enhancing Bax and BOK expressions.Biomed Pharmacother2018;103:67–74
24.
ItoTKwonHYZimdahlBCongdonKLBlumJLentoWEZhaoCLagooAGerrardGForoniLGoldmanJGohHKimSHKimDWChuahCOehlerVGRadichJPJordanCTReyaT. Regulation of myeloid leukaemia by the cell-fate determinant Musashi.Nature2010;466:765–8
25.
BobryshevYVFreemanAKBotelhoNKTranDLevert-MignonAJLordRV. Expression of the putative stem cell marker Musashi-1 in Barrett’s esophagus and esophageal adenocarcinoma.Dis Esophagus2010;23:580–9
26.
PötschkeRGielenGPietschTKrammCKlusmannJHHüttelmaierSKühnölCD. Musashi1 enhances chemotherapy resistance of pediatric glioblastoma cells in vitro.Pediatr Res2020;87:669–76
27.
ChenLLanBChenXHLiJFQuYYuBQYuYYGuQLZhuZGLiuBY. Cell cycle dependent genes from the gastric cancer cell MKN45 can affect tumorigenesis.Hepatogastroenterology2011;58:674–81
28.
JungJSeolHSChangS. The generation and application of patient-derived xenograft model for cancer research.Cancer Res Treat2018;50:1–10
29.
WeeberFOoftSNDijkstraKKVoestEE. Tumor organoids as a pre-clinical cancer model for drug discovery.Cell Chem Biol2017;24: 1092–100
InoueTTeradaNKobayashiTOgawaO. Patient-derived xenografts as in vivo models for research in urological malignancies.Nat Rev Urol2017;14:267–83
32.
VoDTSubramaniamDRemkeMBurtonTLUrenPJGelfondJAde Sousa AbreuRBurnsSCQiaoMSureshUKorshunovADubucAMNorthcottPASmithADPfisterSMTaylorMDJangaSCAnantSVogelCPenalvaLO. The RNA-binding protein Musashi1 affects medulloblastoma growth via a network of cancer-related genes and is an indicator of poor prognosis.Am J Pathol2012;181:1762–72
33.
BishRVogelC. RNA binding protein-mediated post-transcriptional gene regulation in medulloblastoma.Mol Cells2014;37:357–64
34.
GlazerRIVoDTPenalvaLOF. Musashi1: an RBP with versatile functions in normal and cancer stem cells.Front Biosci-Landmrk2012;17:54–64
35.
VelascoMXKostiAGuardiaGDASantosMCTeggeAQiaoMCorreaBRSHernandezGKokovayEGalantePAFPenalvaLOF. Antagonism between the RNA-binding protein Musashi1 and miR-137 and its potential impact on neurogenesis and glioblastoma development.RNA2019;25:768–82
36.
ParangBThompsonJJWilliamsCS. Blood Vessel Epicardial Substance (BVES) in junctional signaling and cancer.Tissue Barr2018;6:1–12
37.
PageKASeoDBelfort-DeAguiarRLacadieCDzuiraJNaikSAmarnathSConstableRTSherwinRSSinhaR. Circulating glucose levels modulate neural control of desire for high-calorie foods in humans.J Clin Invest2011;121:4161–9
38.
KimMJangHRHaamKKangTWKimJHKimSYNohSMSongKSChoJSJeongHYKimJCYooHSKimYS. Frequent silencing of popeye domain-containing genes, BVES and POPDC3, is associated with promoter hypermethylation in gastric cancer.Carcinogenesis2010;31:1685–93
39.
HagerHABaderDM. Bves: ten years after.Histol Histopathol2009;24:777–87
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
