G protein-coupled receptor LGR6 is an independent risk factor for colon adenocarcinoma

Wenjing Wang, Shigang Ding, Hejun Zhang, Jun Li, Jun Zhan, Hongquan Zhang

PDF(1146 KB)
PDF(1146 KB)
Front. Med. ›› 2019, Vol. 13 ›› Issue (4) : 482-491. DOI: 10.1007/s11684-018-0633-0
RESEARCH ARTICLE
RESEARCH ARTICLE

G protein-coupled receptor LGR6 is an independent risk factor for colon adenocarcinoma

Author information +
History +

Abstract

LGR6 is a member of the G protein-coupled receptor family that plays a tumor-suppressive role in colon cancer. However, the relationship between LGR6 expression in patients and clinicopathological factors remains unclear. This study aimed to clarify whether the expression level of LGR6 is correlated with colon adenocarcinoma progression. Immunohistochemistry was used to detect LGR6 expression in colon adenoma tissues (n = 21), colon adenocarcinoma tissues (n = 156), and adjacent normal tissues (n = 124). The expression levels of LGR6 in colon adenoma and adenocarcinoma were significantly higher than those in normal colon epithelial tissues (P<0.001). Low LGR6 expression predicted a short overall survival in patients with colon adenocarcinoma (log-rank test, P = 0.016). Univariate and multivariate survival analyses showed that, in addition to N and M classification, LGR6 expression served as an independent prognostic factor. Thus, low expression of LGR6 can be used as an independent prognostic parameter in patients with colon adenocarcinoma.

Keywords

LGR6 / colon adenocarcinoma / immunohistochemistry / prognosis

Cite this article

Download citation ▾
Wenjing Wang, Shigang Ding, Hejun Zhang, Jun Li, Jun Zhan, Hongquan Zhang. G protein-coupled receptor LGR6 is an independent risk factor for colon adenocarcinoma. Front. Med., 2019, 13(4): 482‒491 https://doi.org/10.1007/s11684-018-0633-0

References

[1]
Chen W, Zheng R, Zeng H, Zhang S. The incidence and mortality of major cancers in China, 2012. Chin J Cancer 2016; 35(1): 73
CrossRef Pubmed Google scholar
[2]
Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet 2014; 383(9927): 1490–1502
CrossRef Pubmed Google scholar
[3]
Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007; 50(1): 113–130
CrossRef Pubmed Google scholar
[4]
Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 2009; 361(25): 2449–2460
CrossRef Pubmed Google scholar
[5]
Sinicrope FA, Sargent DJ. Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications. Clin Cancer Res 2012; 18(6): 1506–1512
CrossRef Pubmed Google scholar
[6]
De Sousa E Melo F, Wang X, Jansen M, Fessler E, Trinh A, de Rooij LP, de Jong JH, de Boer OJ, van Leersum R, Bijlsma MF, Rodermond H, van der Heijden M, van Noesel CJ, Tuynman JB, Dekker E, Markowetz F, Medema JP, Vermeulen L. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med 2013; 19(5): 614–618
CrossRef Pubmed Google scholar
[7]
Carmona FJ, Azuara D, Berenguer-Llergo A, Fernández AF, Biondo S, de Oca J, Rodriguez-Moranta F, Salazar R, Villanueva A, Fraga MF, Guardiola J, Capellá G, Esteller M, Moreno V. DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer. Cancer Prev Res (Phila) 2013; 6(7): 656–665
CrossRef Pubmed Google scholar
[8]
Vatandoost N, Ghanbari J, Mojaver M, Avan A, Ghayour-Mobarhan M, Nedaeinia R, Salehi R. Early detection of colorectal cancer: from conventional methods to novel biomarkers. J Cancer Res Clin Oncol 2016; 142(2): 341–351
CrossRef Pubmed Google scholar
[9]
Böhme I, Beck-Sickinger AG. Illuminating the life of GPCRs. Cell Commun Signal 2009; 7(1): 16
CrossRef Pubmed Google scholar
[10]
Hsu SY, Kudo M, Chen T, Nakabayashi K, Bhalla A, van der Spek PJ, van Duin M, Hsueh AJ. The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol 2000; 14(8): 1257–1271
CrossRef Pubmed Google scholar
[11]
de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M, Stange DE, van Es JE, Guardavaccaro D, Schasfoort RB, Mohri Y, Nishimori K, Mohammed S, Heck AJ, Clevers H. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 2011; 476(7360): 293–297
CrossRef Pubmed Google scholar
[12]
Leushacke M, Barker N. Lgr5 and Lgr6 as markers to study adult stem cell roles in self-renewal and cancer. Oncogene 2012; 31(25): 3009–3022
CrossRef Pubmed Google scholar
[13]
Lehoczky JA, Tabin CJ. Lgr6 marks nail stem cells and is required for digit tip regeneration. Proc Natl Acad Sci USA 2015; 112(43): 13249–13254
CrossRef Pubmed Google scholar
[14]
Gao Y, Kitagawa K, Hiramatsu Y, Kikuchi H, Isobe T, Shimada M, Uchida C, Hattori T, Oda T, Nakayama K, Nakayama KI, Tanaka T, Konno H, Kitagawa M. Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res 2006; 66(24): 11623–11631
CrossRef Pubmed Google scholar
[15]
Steffen JS, Simon E, Warneke V, Balschun K, Ebert M, Röcken C. LGR4 and LGR6 are differentially expressed and of putative tumor biological significance in gastric carcinoma. Virchows Arch 2012; 461(4): 355–365
CrossRef Pubmed Google scholar
[16]
Ryuge S, Sato Y, Jiang SX, Wang G, Kobayashi M, Nagashio R, Katono K, Iyoda A, Satoh Y, Masuda N. The clinicopathological significance of Lgr5 expression in lung adenocarcinoma. Lung Cancer 2013; 82(1): 143–148
CrossRef Pubmed Google scholar
[17]
Simon E, Petke D, Böger C, Behrens HM, Warneke V, Ebert M, Röcken C. The spatial distribution of LGR5+ cells correlates with gastric cancer progression. PLoS One 2012; 7(4): e35486
CrossRef Pubmed Google scholar
[18]
Gregorieff A, Liu Y, Inanlou MR, Khomchuk Y, Wrana JL. Yap-dependent reprogramming of Lgr5+ stem cells drives intestinal regeneration and cancer. Nature 2015; 526(7575): 715–718
CrossRef Pubmed Google scholar
[19]
Takahashi H, Ishii H, Nishida N, Takemasa I, Mizushima T, Ikeda M, Yokobori T, Mimori K, Yamamoto H, Sekimoto M, Doki Y, Mori M. Significance of Lgr5+ve cancer stem cells in the colon and rectum. Ann Surg Oncol 2011; 18(4): 1166–1174
CrossRef Pubmed Google scholar
[20]
Walker FZhang HH, Odorizzi A, Burgess AW. LGR5 is a negative regulator of tumourigenicity, antagonizes Wnt signalling and regulates cell adhesion in colorectal cancer cell lines. PLoS One 2011; 6(7): e22733
CrossRef Pubmed Google scholar
[21]
de Sousa E Melo F, Colak S, Buikhuisen J, Koster J, Cameron K, de Jong JH, Tuynman JB, Prasetyanti PR, Fessler E, van den Bergh SP, Rodermond H, Dekker E, van der Loos CM, Pals ST, van de Vijver MJ, Versteeg R, Richel DJ, Vermeulen L, Medema JP. Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell 2011; 9(5): 476–485
CrossRef Pubmed Google scholar
[22]
Guinot A, Oeztuerk-Winder F, Ventura JJ. miR-17–92/p38a dysregulation enhances Wnt signaling and selects Lgr6+ cancer stem-like cells during lung adenocarcinoma progression. Cancer Res 2016; 76(13): 4012–4022
CrossRef Pubmed Google scholar
[23]
Blaas L, Pucci F, Messal HA, Andersson AB, Josue Ruiz E, Gerling M, Douagi I, Spencer-Dene B, Musch A, Mitter R, Bhaw L, Stone R, Bornhorst D, Sesay AK, Jonkers J, Stamp G, Malanchi I, Toftgård R, Behrens A. Lgr6 labels a rare population of mammary gland progenitor cells that are able to originate luminal mammary tumours. Nat Cell Biol 2016; 18(12): 1346–1356
CrossRef Pubmed Google scholar
[24]
Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science 2006; 314(5797): 268–274
CrossRef Pubmed Google scholar
[25]
Chan TA, Glockner S, Yi JM, Chen W, Van Neste L, Cope L, Herman JG, Velculescu V, Schuebel KE, Ahuja N, Baylin SB. Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis. PLoS Med 2008; 5(5): e114
CrossRef Pubmed Google scholar
[26]
Gong X, Carmon KS, Lin Q, Thomas A, Yi J, Liu Q. LGR6 is a high affinity receptor of R-spondins and potentially functions as a tumor suppressor. PLoS One 2012; 7(5): e37137
CrossRef Pubmed Google scholar
[27]
Wang X, Sun Q. TP53 mutations, expression and interaction networks in human cancers. Oncotarget 2017; 8(1): 624–643
CrossRef Pubmed Google scholar
[28]
Zhan J, Niu M, Wang P, Zhu X, Li S, Song J, He H, Wang Y, Xue L, Fang W, Zhang H. Elevated HOXB9 expression promotes differentiation and predicts a favourable outcome in colon adenocarcinoma patients. Br J Cancer 2014; 111(5): 883–893
CrossRef Pubmed Google scholar
[29]
Clevers H, Nusse R. Wnt/b-catenin signaling and disease. Cell 2012; 149(6): 1192–1205
CrossRef Pubmed Google scholar
[30]
Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/b-catenin signaling. Proc Natl Acad Sci USA 2011; 108(28): 11452–11457
CrossRef Pubmed Google scholar
[31]
Lappano R, Maggiolini M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov 2011; 10(1): 47–60
CrossRef Pubmed Google scholar

Acknowledgements

This study was supported by grants from the Ministry of Science and Technology of China (Nos. 2016YFC1302103, 2015CB553906, and 2013CB910501); the National Natural Science Foundation of China (Nos. 81230051, 81472734, 31170711, 81321003, and 30830048); the Beijing Natural Science Foundation (No. 7120002); the 111 Project of the Ministry of Education, Peking University (Nos. BMU20120314 and BMU20130364); and the Leading Academic Discipline Project of Beijing Education Bureau to Hongquan Zhang.

Compliance with ethics guidelines

Wenjing Wang, Shigang Ding, Hejun Zhang, Jun Li, Jun Zhan, and Hongquan Zhang declare no conflicts of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (the ethical committee of Peking University Health Science Center, China) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients enrolled in the study.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-018-0633-0 and is accessible for authorized users.

RIGHTS & PERMISSIONS

2018 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature
AI Summary AI Mindmap
PDF(1146 KB)

Accesses

Citations

Detail

Sections
Recommended

/