Prognostic impact of mRNA levels of LGR5 transcript variants in OSCC patients.
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor
/ genetics
Carcinoma, Squamous Cell
/ diagnosis
Epithelial-Mesenchymal Transition
/ physiology
Female
Gene Expression
Humans
Lymph Nodes
/ pathology
Male
Middle Aged
Mouth Neoplasms
/ diagnosis
Neoplasm Metastasis
Prognosis
Protein Isoforms
/ genetics
RNA, Messenger
/ genetics
Receptors, G-Protein-Coupled
/ genetics
Survival Analysis
Transcription, Genetic
Wnt Signaling Pathway
/ physiology
EMT
Head and neck squamous cell carcinoma, overall survival, stem cell-associated gene
LGR5
Splice variants
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
15 Feb 2019
15 Feb 2019
Historique:
received:
28
02
2018
accepted:
28
01
2019
entrez:
17
2
2019
pubmed:
17
2
2019
medline:
14
6
2019
Statut:
epublish
Résumé
The human leucine-rich, repeat-containing G protein-coupled receptor 5 (LGR5) is a stem cell marker in numerous adult tissues and is overexpressed in a large number of human carcinoma including colon cancer, breast cancer and oral squamous cell carcinomas (OSCC). The role of the full length transcript (LGR5FL) in progression and prognosis of several cancers was reported. However, the biological function of three splice variants of LGR5 (LGR5Δ5, LGR5Δ8 and LGR5Δ5-8) has yet to be thoroughly investigated. Seventy-eight frozen tumor samples from adult OSCC patients were studied using quantitative real-time TaqMan™ PCR analysis. The mRNA levels of full length LGR5, the splice variant of LGR5 lacking exon 5 (LGR5Δ5), the splice variant of LGR5 lacking exon 8 (LGR5Δ8) and the mRNA level of all known transcript variants together (LGR5all) were quantified and correlated to overall and disease-specific survival of OSCC patients, clinical parameters and the mRNA level of different tumor-associated markers. An elevated level of tumoral LGR5Δ5 mRNA, but not LGR5FL, LGR5Δ8 or LGR5all mRNA was significantly associated with a poor prognosis for the overall and disease-specific survival of OSCC patients (hazard ratio (HR) = 2.0; p = 0.02; 95% CI: 1.1-3.7; HR = 3.2; p = 0.01; 95% CI: 1.3-8.0; multivariable Cox regression), respectively. Additionally, a higher tumoral level of LGR5Δ5 mRNA in primary tumors was associated with the occurrence of regional lymph node metastases in OSCC patients (odds ratio (OR) = 3.1; p = 0.022; 95% CI: 1.2-7.9; binary logistic regression). Furthermore, the mRNA levels of all investigated LGR5 transcript variants were significantly correlated with the mRNA expression of Wnt-target genes and markers of epithelial-to-mesenchymal transition (EMT). The mRNA level of the LGR5 splice variant LGR5Δ5 is an independent negative prognostic marker for overall and disease-specific survival and metastasis in OSCC patients. Additionally, we suggest, all LGR5 transcript variants are involved in the EMT process mainly through activating the Wnt-signalling pathway.
Sections du résumé
BACKGROUND
BACKGROUND
The human leucine-rich, repeat-containing G protein-coupled receptor 5 (LGR5) is a stem cell marker in numerous adult tissues and is overexpressed in a large number of human carcinoma including colon cancer, breast cancer and oral squamous cell carcinomas (OSCC). The role of the full length transcript (LGR5FL) in progression and prognosis of several cancers was reported. However, the biological function of three splice variants of LGR5 (LGR5Δ5, LGR5Δ8 and LGR5Δ5-8) has yet to be thoroughly investigated.
METHODS
METHODS
Seventy-eight frozen tumor samples from adult OSCC patients were studied using quantitative real-time TaqMan™ PCR analysis. The mRNA levels of full length LGR5, the splice variant of LGR5 lacking exon 5 (LGR5Δ5), the splice variant of LGR5 lacking exon 8 (LGR5Δ8) and the mRNA level of all known transcript variants together (LGR5all) were quantified and correlated to overall and disease-specific survival of OSCC patients, clinical parameters and the mRNA level of different tumor-associated markers.
RESULTS
RESULTS
An elevated level of tumoral LGR5Δ5 mRNA, but not LGR5FL, LGR5Δ8 or LGR5all mRNA was significantly associated with a poor prognosis for the overall and disease-specific survival of OSCC patients (hazard ratio (HR) = 2.0; p = 0.02; 95% CI: 1.1-3.7; HR = 3.2; p = 0.01; 95% CI: 1.3-8.0; multivariable Cox regression), respectively. Additionally, a higher tumoral level of LGR5Δ5 mRNA in primary tumors was associated with the occurrence of regional lymph node metastases in OSCC patients (odds ratio (OR) = 3.1; p = 0.022; 95% CI: 1.2-7.9; binary logistic regression). Furthermore, the mRNA levels of all investigated LGR5 transcript variants were significantly correlated with the mRNA expression of Wnt-target genes and markers of epithelial-to-mesenchymal transition (EMT).
CONCLUSION
CONCLUSIONS
The mRNA level of the LGR5 splice variant LGR5Δ5 is an independent negative prognostic marker for overall and disease-specific survival and metastasis in OSCC patients. Additionally, we suggest, all LGR5 transcript variants are involved in the EMT process mainly through activating the Wnt-signalling pathway.
Identifiants
pubmed: 30770730
doi: 10.1186/s12885-019-5327-8
pii: 10.1186/s12885-019-5327-8
pmc: PMC6377725
doi:
Substances chimiques
Biomarkers, Tumor
0
LGR5 protein, human
0
Protein Isoforms
0
RNA, Messenger
0
Receptors, G-Protein-Coupled
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
155Subventions
Organisme : Wilhelm-Roux-Program of BMBF/NBL3
ID : FKZ: 16/18, 21/25
Références
Cancer Control. 2002 Sep-Oct;9(5):387-99
pubmed: 12410178
Cancer Biol Ther. 2006 Apr;5(4):419-26
pubmed: 16575208
Nature. 2007 Oct 25;449(7165):1003-7
pubmed: 17934449
Nat Protoc. 2008;3(6):1101-8
pubmed: 18546601
Oral Oncol. 2009 Mar;45(3):201-11
pubmed: 18674959
Am J Pathol. 2008 Sep;173(3):835-43
pubmed: 18688030
Blood. 2008 Dec 15;112(13):4793-807
pubmed: 19064739
Nature. 2009 Jan 29;457(7229):608-11
pubmed: 19092804
J Clin Invest. 2009 Jun;119(6):1420-8
pubmed: 19487818
Head Neck. 2010 Mar;32(3):357-67
pubmed: 19644932
Int J Colorectal Dis. 2010 May;25(5):583-90
pubmed: 20195621
BMC Cancer. 2010 Apr 08;10:132
pubmed: 20377868
Cancer Sci. 2010 Jul;101(7):1731-7
pubmed: 20384634
Oncologist. 2010;15(9):994-1001
pubmed: 20798198
Ann Surg Oncol. 2011 Apr;18(4):1166-74
pubmed: 21125339
Anticancer Res. 2011 Jan;31(1):263-70
pubmed: 21273608
Nat Med. 2011 Mar;17(3):313-9
pubmed: 21386835
Cell Stem Cell. 2011 May 6;8(5):511-24
pubmed: 21419747
Nature. 2011 Jul 04;476(7360):293-7
pubmed: 21727895
PLoS One. 2011;6(7):e22733
pubmed: 21829496
BMC Cancer. 2011 Oct 06;11:429
pubmed: 21978106
Nature. 2012 Jan 18;481(7381):306-13
pubmed: 22258609
Brain Pathol. 2013 Jan;23(1):60-72
pubmed: 22805276
World J Surg Oncol. 2012 Nov 15;10:244
pubmed: 23153436
Pathol Int. 2013 Jan;63(1):13-9
pubmed: 23356221
Development. 2013 Jun;140(12):2484-94
pubmed: 23715542
Cell Rep. 2013 Jun 27;3(6):1885-92
pubmed: 23809763
Lung Cancer. 2013 Oct;82(1):143-8
pubmed: 23915911
Carcinogenesis. 2014 Apr;35(4):849-58
pubmed: 24282287
Cell Stem Cell. 2014 Mar 6;14(3):275-91
pubmed: 24607403
Oral Surg Oral Med Oral Pathol Oral Radiol. 2015 Apr;119(4):436-40.e1
pubmed: 25592865
Oncotarget. 2015 Nov 24;6(37):40053-67
pubmed: 26517508
J Transl Med. 2016 Apr 05;14:85
pubmed: 27044404
Br J Cancer. 2016 May 24;114(11):1251-60
pubmed: 27140312
JAMA Oncol. 2017 Apr 1;3(4):524-548
pubmed: 27918777
Immunol Lett. 2017 Oct;190:7-14
pubmed: 28690187
Oncotarget. 2017 Feb 7;8(31):50896-50903
pubmed: 28881613
Clin Transl Radiat Oncol. 2017 Jun 27;5:6-11
pubmed: 29594211
Cancer Res. 1996 Jun 1;56(11):2488-92
pubmed: 8653682