RPL22L1 induction in colorectal cancer is associated with poor prognosis and 5-FU resistance.
Animals
Cell Proliferation
Colorectal Neoplasms
/ drug therapy
DNA Modification Methylases
/ metabolism
DNA Repair Enzymes
/ metabolism
Drug Resistance, Neoplasm
Fluorouracil
/ therapeutic use
Humans
Mice
MutL Protein Homolog 1
/ metabolism
Prognosis
Proto-Oncogene Proteins
/ metabolism
RNA-Binding Proteins
/ metabolism
Ribosomal Proteins
/ metabolism
Tumor Suppressor Proteins
/ metabolism
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
07
08
2019
accepted:
19
08
2019
entrez:
4
10
2019
pubmed:
4
10
2019
medline:
12
3
2020
Statut:
epublish
Résumé
We have previously demonstrated that loss of the tumor suppressive activity of ribosomal protein (RP) RPL22 predisposes to development of leukemia in mouse models and aggressive disease in human patients; however, the role of RPL22 in solid tumors, specifically colorectal cancer (CRC), had not been explored. We report here that RPL22 is either deleted or mutated in 36% of CRC and provide new insights into its mechanism of action. Indeed, Rpl22 inactivation causes the induction of its highly homologous paralog, RPL22L1, which serves as a driver of cell proliferation and anchorage-independent growth in CRC cells. Moreover, RPL22L1 protein is highly expressed in patient CRC samples and correlates with poor survival. Interestingly, the association of high RPL22L1 expression with poor prognosis appears to be linked to resistance to 5-Fluorouracil, which is a core component of most CRC therapeutic regimens. Indeed, in an avatar trial, we found that human CRC samples that were unresponsive to 5-Fluorouracil in patient-derived xenografts exhibited elevated expression levels of RPL22L1. This link between RPL22L1 induction and 5-Fluorouracil resistance appears to be causal, because ectopic expression or knockdown of RPL22L1 in cell lines increases and decreases 5-Fluorouracil resistance, respectively, and this is associated with changes in expression of the DNA-repair genes, MGMT and MLH1. In summary, our data suggest that RPL22L1 might be a prognostic marker in CRC and predict 5-FU responsiveness.
Identifiants
pubmed: 31581233
doi: 10.1371/journal.pone.0222392
pii: PONE-D-19-20209
pmc: PMC6776433
doi:
Substances chimiques
MLH1 protein, human
0
Proto-Oncogene Proteins
0
RNA-Binding Proteins
0
RPL22L1 protein, human
0
RPL22L1 protein, mouse
0
Ribosomal Proteins
0
Tumor Suppressor Proteins
0
RPL22 protein, human
135844-68-7
DNA Modification Methylases
EC 2.1.1.-
MGMT protein, human
EC 2.1.1.63
MutL Protein Homolog 1
EC 3.6.1.3
DNA Repair Enzymes
EC 6.5.1.-
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0222392Subventions
Organisme : NCI NIH HHS
ID : P30 CA006927
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI110985
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA077429
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA216825
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared no competing interests exist.
Références
Int J Mol Sci. 2017 Jan 06;18(1):
pubmed: 28067827
Hum Mutat. 2014 Dec;35(12):1442-5
pubmed: 25196364
Int J Cancer. 2008 Jun 1;122(11):2429-36
pubmed: 18240147
Dev Cell. 2013 Feb 25;24(4):411-25
pubmed: 23449473
Nat Clin Pract Gastroenterol Hepatol. 2009 Feb;6(2):108-20
pubmed: 19153564
Cancer Res. 2016 Jun 1;76(11):3387-96
pubmed: 27197189
Eur J Cancer. 2004 Jan;40(2):298-307
pubmed: 14728946
Immunity. 2007 Jun;26(6):759-72
pubmed: 17555992
Curr Treat Options Oncol. 2017 Feb;18(2):9
pubmed: 28214977
Cancer Res. 2001 Jul 1;61(13):5193-201
pubmed: 11431359
Clin Cancer Res. 2013 Apr 15;19(8):2265-72
pubmed: 23422094
Biomed Rep. 2015 Jan;3(1):33-37
pubmed: 25469243
Ann Oncol. 2016 Nov;27(11):2074-2081
pubmed: 27573560
Clin Colorectal Cancer. 2015 Mar;14(1):1-10
pubmed: 25579803
Lancet Oncol. 2015 Oct;16(13):1306-15
pubmed: 26338525
Clin Cancer Res. 2003 Oct 1;9(12):4368-75
pubmed: 14555508
Ann Oncol. 2017 Jan 1;28(1):96-102
pubmed: 27742654
Blood. 2012 Nov 1;120(18):3764-73
pubmed: 22976955
Oncogene. 2016 Apr 28;35(17):2178-85
pubmed: 26257058
Cell Rep. 2017 Jan 10;18(2):545-556
pubmed: 28076796
Cancer Cell. 2016 Aug 8;30(2):363
pubmed: 27505681
N Engl J Med. 2004 Jun 3;350(23):2343-51
pubmed: 15175436
Neuro Oncol. 2009 Jun;11(3):281-91
pubmed: 18952979
Nat Rev Cancer. 2013 Oct;13(10):714-26
pubmed: 24060863
Cancer Causes Control. 2011 Feb;22(2):301-9
pubmed: 21140203
N Engl J Med. 2003 Jul 17;349(3):247-57
pubmed: 12867608
Clin Cancer Res. 2009 Oct 1;15(19):6087-95
pubmed: 19789303
J Natl Cancer Inst. 2011 Jun 8;103(11):863-75
pubmed: 21597022
Gynecol Oncol. 2013 Mar;128(3):470-4
pubmed: 23127973
PLoS Genet. 2013;9(8):e1003708
pubmed: 23990801
Eur J Cancer. 2009 Feb;45(3):365-73
pubmed: 18722765
Nature. 2012 Jul 18;487(7407):330-7
pubmed: 22810696
Front Oncol. 2013 Oct 18;3:266
pubmed: 24151575
Gastroenterology. 2007 Dec;133(6):1858-68
pubmed: 18054558
Cell Rep. 2016 Apr 26;15(4):857-865
pubmed: 27149842
Clin Cancer Res. 2013 Sep 15;19(18):5053-67
pubmed: 23900136
CA Cancer J Clin. 2017 Jan;67(1):7-30
pubmed: 28055103
Seikagaku. 2013 Oct;85(10):909-15
pubmed: 24392590
Oncol Rep. 2007 Jun;17(6):1461-7
pubmed: 17487405
Ann Oncol. 2015 Jan;26(1):126-32
pubmed: 25361982
Clin Cancer Res. 2013 Dec 1;19(23):6633-43
pubmed: 24088734