The Clinical Prognostic Value of LRG1 in Esophageal Squamous Cell Carcinoma

Author(s): Yuanyuan Wang, Qian Xing, Xue Chen, Jianbo Wang, Shanghui Guan, Xuan Chen, Peng Sun, Mingxia Wang, Yufeng Cheng*

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 9 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Leucine-rich-alpha-2-glycoprotein1 (LRG1) is a new oncogene-related gene, which has been proven important for the development and poor prognosis of human cancers. However, whether it participates in esophageal squamous cell carcinoma (ESCC) progression remains unclear.

Objective: To investigate the expression level and functional influence of LRG1 in ESCC.

Methods: The expression of LRG1 was evaluated on the mRNA and protein level in ESCC patients. Then, correlation of LRG1 expression with clinicpathological variables was analyzed in ESCC. Besides, to clarify the biological function of LRG1, Eca109 and KYSE150 cells were transfected with LRG1 shRNA, the cell viability, clonal efficiency, apoptosis and invasion assays in vitro were performed.

Results: LRG1 was significantly over-expressed in ESCC and related to deeper invasion depth (T stage) and distal metastasis (M stage). Kaplan-Meier analysis indicated that LRG1 up-regulation in ESCC was closely correlated to worse clinical survival (overall survival and progression-free survival), all P<0.001. LRG1 was confirmed to be an independent poor premonitory indicator for clinical outcomes in ESCC through the univariate and multivariate analyses. Down-regulation of LRG1 in ESCC cells markedly suppressed cell proliferation and invasion, stimulated apoptosis (all p <0.01).

Conclusion: LRG1 might play a significant role in the progression of ESCC, and could be served as a promising prognostic prediction for ESCC patients.

Keywords: LRG1, esophageal carcinoma, squamous cell carcinoma, prognosis, proliferation, invasion.

[1]
Wang, Y.; Guan, S.; Bi, Y.; Lin, S.; Ma, J.; Xing, Q.; Liu, C.; Zhang, R.; Qu, Z.; Jiang, P.; Chen, X. Survival impact of delaying postoperative radiotherapy in patients with esophageal cancer. Transl. Oncol., 2018, 11, 1358-1363.
[2]
Holmes, R.S.; Vaughan, T.L. Epidemiology and pathogenesis of esophageal cancer. Semin. Radiat. Oncol., 2007, 17, 2-9.
[3]
Wang, X.; Fan, J.C.; Wang, A.R.; Leng, Y.; Li, J.; Bao, Y.; Wang, Y.; Yang, Q.F.; Ren, Y. Epidemiology of esophageal cancer in Yanting - regional report of a national screening programme in China. Asian Pac. J. Cancer Prev., 2013, 14, 2429-2432.
[4]
Pennathur, A.; Gibson, M.K.; Jobe, B.A.; Luketich, J.D. Oesophageal carcinoma. Lancet, 2013, 381, 400-412.
[5]
Jemal, A.; Siegel, R.; Xu, J.; Ward, E. Cancer statistics, 2010. CA Cancer J. Clin., 2010, 60, 277-300.
[6]
Haupt, H.; Baudner, S. Isolation and characterization of an unknown, leucine-rich 3.1-S-alpha2-glycoprotein from human serum. Hoppe Seylers Z. Physiol. Chem., 1977, 358, 639-646.
[7]
Hoogland, C.; Mostaguir, K.; Sanchez, J.C.; Hochstrasser, D.F.; Appel, R.D. SWISS-2DPAGE, ten years later. Proteomics, 2004, 4, 2352-2356.
[8]
Donnell, L.C.; Druhan, L.J.; Avalos, B.R. Molecular characterization and expression analysis of leucine-rich alpha2-glycoprotein, a novel marker of granulocytic differentiation. J. Leukoc. Biol., 2002, 72, 478-485.
[9]
Serada, S.; Fujimoto, M.; Terabe, F.; Iijima, H.; Shinzaki, S.; Matsuzaki, S.; Ohkawara, T.; Nezu, R.; Nakajima, S.; Kobayashi, T. Serum leucine- rich alpha-2 glycoprotein is a disease activity biomarker in ulcerative colitis. Inflamm. Bowel Dis., 2012, 18, 2169-2179.
[10]
Kobe, B.; Kajava, A.V. The leucine-rich repeat as a protein recognition motif. Curr. Opin. Struct. Biol., 2001, 11, 725-732.
[11]
Saito, K.; Tanaka, T.; Kanda, H.; Ebisuno, Y.; Izawa, D.; Kawamoto, S.; Okubo, K.; Miyasaka, M. Gene expression profiling of mucosal addressin cell adhesion molecule-1+ high endothelial venule cells (HEV) and identification of a leucine-rich HEV glycoprotein as a HEV marker. J. Immunol., 2002, 168, 1050-1059.
[12]
Weivoda, S.; Andersen, J.D.; Skogen, A.; Schlievert, P.M.; Fontana, D.; Schacker, T.; Tuite, P.; Dubinsky, J.M.; Jemmerson, R. ELISA for human serum leucine-rich alpha-2-glycoprotein-1 employing cytochrome c as the capturing ligand. J. Immunol. Method., 2008, 336, 22-29.
[13]
Thompson, F.C. The Vietnam War added a motive to go on studying. Nature, 2007, 449, 13.
[14]
Lynch, J.; Meehan, M.H.; Crean, J.; Copeland, J.; Stallings, R.L.; Bray, I.M. Metastasis suppressor microrna-335 targets the formin family of actin nucleators. PLoS One, 2013, 8e78428
[15]
Wang, X.; Abraham, S.; McKenzie, J.A.G.; Jeffs, N.; Swire, M.; Tripathi, V.B.; Luhmann, U.F.O.; Lange, C.A.K.; Zhai, Z.; Arthur, H.M. LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling. Nature, 2013, 499, 306-311.
[16]
Lynch, J.; Fay, J.; Meehan, M.; Bryan, K.; Watters, K.M.; Murphy, D.M.; Stallings, R.L. Mirna-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical tgf- signalling pathway. Carcinogenesis, 2012, 33, 976-985.
[17]
Zhong, D.; Zhao, S.; He, G.; Li, J.; Lang, Y.; Ye, W.; Li, Y.; Jiang, C.; Li, X. Stable knockdown of LRG1 by RNA interference inhibits growth and promotes apoptosis of glioblastoma cells in vitro and in vivo. Tumour Biol., 2015, 36, 4271-4278.
[18]
Liu, Y.; Luo, X.; Hu, H.; Wang, R.; Sun, Y.; Zeng, R.; Chen, H. Integrative proteomics and tissue microarray profiling indicate the association between overexpressed serum proteins and non-small cell lung cancer. PLoS One, 2012, 7 e51748
[19]
Li, Y.; Zhang, Y.; Qiu, F.; Qiu, Z. Proteomic identification of exosomal LRG1: a potential urinary biomarker for detecting NSCLC. Electrophoresis, 2011, 32, 1976-1983.
[20]
Wang, C.H.; Li, M.; Liu, L.L.; Zhou, R.Y.; Fu, J.; Zhang, C.Z.; Yun, J.P. LRG1 expression indicates unfavorable clinical outcome in hepatocellular carcinoma. Oncotarget, 2015, 6, 42118-42129.
[21]
Andersen, J.D.; Boylan, K.L.; Jemmerson, R.; Geller, M.A.; Misemer, B.; Harrington, K.M.; Weivoda, S.; Witthuhn, B.A.; Argenta, P.; Vogel, R.I. Leucine-rich alpha-2-glycoprotein-1 is upregulated in sera and tumors of ovarian cancer patients. J. Ovarian Res., 2010, 3, 21.
[22]
Yamamoto, M.; Takahashi, T.; Serada, S.; Sugase, T.; Tanaka, K.; Miyazaki, Y.; Makino, T.; Kurokawa, Y.; Yamasaki, M.; Nakajima, K. Overexpression of leucine-rich α2-glycoprotein-1 is a prognostic marker and enhances tumor migration in gastric cancer. Cancer Sci., 2017, 108, 2052-2060.
[23]
Donohoe, C.L.; Phillips, A.W. Cancer of the Esophagus and Esophagogastric Junction: An 8th Edition Staging Primer. J. Thorac. Oncol., 2017, 12, 36-42.
[24]
Chen, X.; Xu, W.; Wang, C.; Liu, F.; Guan, S.; Sun, Y.; Wang, X.; An, D.; Wen, Z.; Chen, P.; Cheng, Y. The clinical significance of isocitrate dehydrogenase 2 in esophageal squamous cell carcinoma. Am. J. Cancer Res., 2017, 7, 700-714.
[25]
Sun, D.C.; Shi, Y.; Wang, L.X.; Lv, Y.; Han, Q.L.; Wang, Z.K.; Dai, G.H. Leucine-rich alpha-2-glycoprotein-1, relevant with microvessel density, is an independent survival prognostic factor for stage III colorectal cancer patients: a retrospective analysis. Oncotarget, 2017, 8, 66550-66558.
[26]
Wen, S.Y.; Zhang, L.N.; Yang, X.M.; Zhang, Y.L.; Ma, L.; Ge, Q.L.; Jiang, S.H.; Zhu, X.L.; Xu, W.; Ding, W.J. LRG1 is an independent prognostic factor for endometrial carcinoma. Tumour Biol., 2014, 35, 7125-7133.
[27]
Wang, Y.; Chen, C.; Hua, Q.; Wang, L.; Li, F.; Li, M.; Mei, Z.; Zhou, T.; Xiao, B.; Tao, Z. Downregulation of leucine-rich-α-2-glycoprotein 1 expression is associated with the tumorigenesis of head and neck squamous cell carcinoma. Oncol. Rep., 2017, 37, 1503-1510.
[28]
Song, W.; Wang, X. The role of TGF-β and LRG1 in cardiac remodeling and heart failure. Biophys. Rev., 2015, 7, 91-104.
[29]
Lynch, J.; Fay, J.; Meehan, M.; Bryan, K.; Watters, K.M.; Murphy, D.M.; Stallings, R.L. MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-beta signalling pathway. Carcinogenesis, 2012, 33, 976-985.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 9
Year: 2019
Published on: 20 December, 2019
Page: [756 - 763]
Pages: 8
DOI: 10.2174/1568009619666190204095942
Price: $65

Article Metrics

PDF: 31
HTML: 4