Role of MAML1 in targeted therapy against the esophageal cancer stem cells.
Aged, 80 and over
Animals
Biomarkers, Tumor
/ metabolism
Cell Cycle
Cell Movement
DNA-Binding Proteins
/ metabolism
Drug Resistance, Neoplasm
Esophageal Neoplasms
/ genetics
Gene Expression Regulation, Neoplastic
Humans
Hyaluronan Receptors
/ metabolism
Male
Mice, Nude
Molecular Targeted Therapy
Neoplastic Stem Cells
/ metabolism
RNA, Messenger
/ genetics
Receptors, Notch
/ metabolism
Spheroids, Cellular
/ metabolism
Transcription Factors
/ metabolism
ABC transporter
CD44
Cancer stem cell
ESCC
MAML1
NOTCH pathway
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
16 04 2019
16 04 2019
Historique:
received:
27
02
2019
accepted:
06
04
2019
entrez:
18
4
2019
pubmed:
18
4
2019
medline:
11
4
2020
Statut:
epublish
Résumé
Esophageal cancer is the sixth-leading cause of cancer-related deaths worldwide. Cancer stem cells (CSCs) are the main reason for tumor relapse in esophageal squamous cell carcinoma (ESCC). The NOTCH pathway is important in preservation of CSCs, therefore it is possible to target such cells by targeting MAML1 as the main component of the NOTCH transcription machinery. In present study we isolated the CD44+ ESCC CSCs and designed a MAML1-targeted therapy to inhibit the NOTCH signaling pathway. CSCs were isolated using magnetic cell sorting utilizing the CD44 cell surface marker. Several stem cell markers were analyzed in the levels of protein and mRNA expression. The isolated CSCs were characterized in vivo in NUDE mice. Biological role of MAML1 was assessed in isolated CD44+ CSCs. A drug resistance assay was also performed to assess the role of MAML1 in CD44+ CSCs with 5FU resistance. The CD44+ CSCs had ability to form tumors in NUDE mice. MAML1 silencing caused a significant decrease (p = 0.019) and ectopic expression caused a significant increase in migration of CD44+ CSCs (p = 0.012). Moreover, MAML1 silencing and ectopic expression significantly increased and decreased 5FU resistance, respectively (p < 0.05). MAML1 silencing significantly increased the number of cells in G1 phase (p = 0.008), and its ectopic expression significantly increased the number of CD44+ CSCS in S phase (p = 0.037). MAML1 may be utilized for targeted therapy with a low side effect to eliminate the CD44+ CSCs through inhibition of canonical NOTCH pathway in ESCC patients.
Sections du résumé
BACKGROUND
Esophageal cancer is the sixth-leading cause of cancer-related deaths worldwide. Cancer stem cells (CSCs) are the main reason for tumor relapse in esophageal squamous cell carcinoma (ESCC). The NOTCH pathway is important in preservation of CSCs, therefore it is possible to target such cells by targeting MAML1 as the main component of the NOTCH transcription machinery.
METHODS
In present study we isolated the CD44+ ESCC CSCs and designed a MAML1-targeted therapy to inhibit the NOTCH signaling pathway. CSCs were isolated using magnetic cell sorting utilizing the CD44 cell surface marker. Several stem cell markers were analyzed in the levels of protein and mRNA expression. The isolated CSCs were characterized in vivo in NUDE mice. Biological role of MAML1 was assessed in isolated CD44+ CSCs. A drug resistance assay was also performed to assess the role of MAML1 in CD44+ CSCs with 5FU resistance.
RESULTS
The CD44+ CSCs had ability to form tumors in NUDE mice. MAML1 silencing caused a significant decrease (p = 0.019) and ectopic expression caused a significant increase in migration of CD44+ CSCs (p = 0.012). Moreover, MAML1 silencing and ectopic expression significantly increased and decreased 5FU resistance, respectively (p < 0.05). MAML1 silencing significantly increased the number of cells in G1 phase (p = 0.008), and its ectopic expression significantly increased the number of CD44+ CSCS in S phase (p = 0.037).
CONCLUSIONS
MAML1 may be utilized for targeted therapy with a low side effect to eliminate the CD44+ CSCs through inhibition of canonical NOTCH pathway in ESCC patients.
Identifiants
pubmed: 30992079
doi: 10.1186/s12967-019-1876-5
pii: 10.1186/s12967-019-1876-5
pmc: PMC6469193
doi:
Substances chimiques
Biomarkers, Tumor
0
CD44 protein, human
0
DNA-Binding Proteins
0
Hyaluronan Receptors
0
MAML1 protein, human
0
RNA, Messenger
0
Receptors, Notch
0
Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
126Références
Cancer Cell. 2012 Aug 14;22(2):222-34
pubmed: 22897852
Mol Cell Biol. 2002 Nov;22(21):7688-700
pubmed: 12370315
Nat Commun. 2012 Jun 06;3:883
pubmed: 22673910
J Gastrointest Cancer. 2016 Sep;47(3):273-7
pubmed: 27142513
J Gastrointest Cancer. 2014 Dec;45(4):466-71
pubmed: 25139105
Gut. 2000 Jan;46(1):14-9
pubmed: 10601048
Oncogene. 2016 Sep 8;35(36):4787-97
pubmed: 26876203
Nature. 2012 Aug 23;488(7412):522-6
pubmed: 22854781
Radiother Oncol. 2011 Dec;101(3):438-42
pubmed: 21908064
Genes Dev. 1998 Aug 1;12(15):2269-77
pubmed: 9694793
J Biol Chem. 2004 Mar 26;279(13):12876-82
pubmed: 14709552
Iran J Basic Med Sci. 2015 Apr;18(4):380-4
pubmed: 26019801
Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10158-63
pubmed: 17548814
Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18261-6
pubmed: 17114293
Middle East J Dig Dis. 2011 Mar;3(1):28-34
pubmed: 25197529
J Cell Biol. 2008 Jul 28;182(2):315-25
pubmed: 18663143
Gastroenterology. 2009 Mar;136(3):1012-24
pubmed: 19150350
Int J Cancer. 1996 Aug 22;69(4):254-8
pubmed: 8797863
Pathol Oncol Res. 2014 Apr;20(2):427-33
pubmed: 24163304
Methods. 2012 Sep;58(1):69-78
pubmed: 22842086
Cell. 1991 Mar 22;64(6):1083-92
pubmed: 2004417
Mol Cell Biol. 1998 Jan;18(1):644-54
pubmed: 9418910
Mol Cell Biol. 2002 Jun;22(11):3927-41
pubmed: 11997524
N Engl J Med. 1991 May 16;324(20):1385-93
pubmed: 1850498
J Clin Invest. 2010 Jan;120(1):41-50
pubmed: 20051635
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):4014-9
pubmed: 11891288
Am J Surg. 2010 Oct;200(4):446-53
pubmed: 20409512
Nat Rev Cancer. 2011 Apr;11(4):254-67
pubmed: 21390059
Cancer Res. 2005 Dec 1;65(23):10946-51
pubmed: 16322242
J Clin Oncol. 2006 May 10;24(14):2137-50
pubmed: 16682732
Mol Cancer Ther. 2012 Sep;11(9):1999-2009
pubmed: 22752426
Nat Med. 2007 Jan;13(1):70-7
pubmed: 17173050
J Cell Commun Signal. 2016 Mar;10(1):49-53
pubmed: 26643817
PLoS One. 2011;6(6):e21419
pubmed: 21731740
Mol Cell Biol. 2001 Nov;21(22):7761-74
pubmed: 11604511
EMBO J. 2001 Jul 2;20(13):3427-36
pubmed: 11432830
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
pubmed: 15761078
Dig Dis Sci. 2008 Nov;53(11):2851-7
pubmed: 18368492
Immunity. 2010 Jan 29;32(1):14-27
pubmed: 20152168
Cancer Cell. 2011 Mar 8;19(3):387-400
pubmed: 21397861
J Gastrointest Cancer. 2015 Dec;46(4):365-9
pubmed: 26294058
Clin Cancer Res. 2004 Feb 1;10(3):1130-40
pubmed: 14871993
Cancer Lett. 2011 Aug 1;307(1):26-36
pubmed: 21463919
Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):23-8
pubmed: 9874765
Ann Surg Oncol. 2012 Mar;19(3):743-9
pubmed: 22006371
Nature. 2005 Jun 16;435(7044):964-8
pubmed: 15959516
Nature. 2010 Apr 15;464(7291):1052-7
pubmed: 20393564
Med Oncol. 2014 Sep;31(9):69
pubmed: 25064729
Mol Cell Biol. 2001 Sep;21(17):5925-34
pubmed: 11486031
N Engl J Med. 2012 May 31;366(22):2074-84
pubmed: 22646630
PLoS One. 2011 Jan 27;6(1):e16466
pubmed: 21304586