Abstract
Background
Leucine-rich alpha-2-glycoprotein-1 (LRG1) is widely involved in proliferation, migration, and invasion of various tumor cells. Recent studies have evaluated the potential of LRG1 as both an early tumor and a prognostic biomarker.
Method
The relevant literature from PubMed is reviewed in this article.
Results
It has been found that LRG1 mainly acts on the regulatory mechanisms of angiogenesis, epithelial-mesenchymal transition (EMT), and apoptosis by transforming growth factor (TGF-β) signaling pathway as well as affecting the occurrence and development of the tumors. Moreover, with advancement of research, LRG1 regulation pathways which are independent of TGF-β signaling pathway have been gradually revealed in different tumor cells; There are several studies on the biological effects of LRG1 as an inflammatory factor, vascular growth regulator, cell adhesion, and a cell viability influencing factor. In addition, various tumor suppression methods which are based on regulation of LRG1 levels have also shown high potential clinical value.
Conclusions
LRG1 are critical for the processes of tumorigenesis, development, and metastasis in various tumors. The present study reviewed the latest research on the achievements of LRG1 in tumor genesis and development. Further, this study also discussed the related molecular mechanisms of various biological functions of LRG1.
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References
Ahmadi A, Najafi M, Farhood B, Mortezaee K (2019) Transforming growth factor-beta signaling: tumorigenesis and targeting for cancer therapy. J Cell Physiol 234:12173–12187. https://doi.org/10.1002/jcp.27955
Amer R, Tiosano L, Pe’er J (2018) Leucine-rich alpha-2-glycoprotein-1 (LRG-1) expression in retinoblastoma. Invest Ophthalmol vis Sci 59:685–692. https://doi.org/10.1167/iovs.17-22785
Andersen JD et al (2010) Leucine-rich alpha-2-glycoprotein-1 is upregulated in sera and tumors of ovarian cancer patients. J Ovarian Res 3:21. https://doi.org/10.1186/1757-2215-3-21
Ban Z, He J, Tang Z, Zhang L, Xu Z (2019) LRG1 enhances the migration of thyroid carcinoma cells through promotion of the epithelialmesenchymal transition by activating MAPK/p38 signaling. Oncol Rep 41:3270–3280. https://doi.org/10.3892/or.2019.7123
Boudreau HE, Casterline BW, Rada B, Korzeniowska A, Leto TL (2012) Nox4 involvement in TGF-beta and SMAD3-driven induction of the epithelial-to-mesenchymal transition and migration of breast epithelial cells. Free Radic Biol Med 53:1489–1499. https://doi.org/10.1016/j.freeradbiomed.2012.06.016
Buchanan SG, Gay NJ (1996) Structural and functional diversity in the leucine-rich repeat family of proteins. Prog Biophys Mol Biol 65:1–44. https://doi.org/10.1016/s0079-6107(96)00003-x
Capello M et al (2017) Sequential validation of blood-based protein biomarker candidates for early-stage pancreatic cancer. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djw266
Chang SC et al (2019) Glycoproteomic identification of novel plasma biomarkers for oral cancer. J Food Drug Anal 27:483–493. https://doi.org/10.1016/j.jfda.2018.12.008
Choi YJ et al (2021) Diagnostic model for pancreatic cancer using a multi-biomarker panel. Ann Surg Treat Res 100:144–153. https://doi.org/10.4174/astr.2021.100.3.144
Chokchaichamnankit D et al (2019) Urinary biomarkers for the diagnosis of cervical cancer by quantitative label-free mass spectrometry analysis. Oncol Lett 17:5453–5468. https://doi.org/10.3892/ol.2019.10227
Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584. https://doi.org/10.1038/nature02006
Derynck R, Budi EH (2019) Specificity, versatility, and control of TGF-beta family signaling. Sci Signal. https://doi.org/10.1126/scisignal.aav5183
Druhan LJ et al (2017) Leucine rich alpha-2 glycoprotein: a novel neutrophil granule protein and modulator of myelopoiesis. PLoS ONE 12:e0170261. https://doi.org/10.1371/journal.pone.0170261
Fan M et al (2019) Knockdown of long noncoding RNA-taurine-upregulated gene 1 inhibits tumor angiogenesis in ovarian cancer by regulating leucine-rich alpha-2-glycoprotein-1. Anticancer Drugs 30:562–570. https://doi.org/10.1097/CAD.0000000000000734
Feng J, Zhan J, Ma S (2021) LRG1 promotes hypoxia-induced cardiomyocyte apoptosis and autophagy by regulating hypoxia-inducible factor-1α. Bioengineered 12:8897–8907. https://doi.org/10.1080/21655979.2021.1988368
Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186. https://doi.org/10.1056/NEJM197111182852108
Fouda MS, Aljarwani RM, Aboul-Enein K, Omran MM (2021) Diagnostic performances of leucine-rich alpha-2-glycoprotein 1 and stem cell factor for diagnosis and follow-up of colorectal cancer. J Genet Eng Biotechnol 19:17. https://doi.org/10.1186/s43141-021-00116-3
Fujimoto M et al (2020) Leucine-rich alpha 2 glycoprotein is a new marker for active disease of tuberculosis. Sci Rep 10:3384. https://doi.org/10.1038/s41598-020-60450-3
Furuta T et al (2020) The multipotential of leucine-rich alpha-2 glycoprotein 1 as a clinicopathological biomarker of glioblastoma. J Neuropathol Exp Neurol 79:873–879. https://doi.org/10.1093/jnen/nlaa058
Goumans MJ, Liu Z, ten Dijke P (2009) TGF-beta signaling in vascular biology and dysfunction. Cell Res 19:116–127. https://doi.org/10.1038/cr.2008.326
Gu Z et al (2020) MicroRNA-497 elevation or LRG1 knockdown promotes osteoblast proliferation and collagen synthesis in osteoporosis via TGF-beta1/Smads signalling pathway. J Cell Mol Med 24:12619–12632. https://doi.org/10.1111/jcmm.15826
Guo YJ et al (2020) ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med 19:1997–2007. https://doi.org/10.3892/etm.2020.8454
Haupt H, Baudner S (1977) Isolation and characterization of an unknown, leucine-rich 3.1-S-alpha2-glycoprotein from human serum (author’s transl). Hoppe Seylers Z Physiol Chem 358:639–646
Heldin CH, Moustakas A (2016) Signaling Receptors for TGF-beta Family Members. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a022053
Hiraga R, Kato M, Miyagawa S, Kamata T (2013) Nox4-derived ROS signaling contributes to TGF-beta-induced epithelial-mesenchymal transition in pancreatic cancer cells. Anticancer Res 33:4431–4438
Hong Q et al (2019) LRG1 promotes diabetic kidney disease progression by enhancing TGF-beta-Induced angiogenesis. J Am Soc Nephrol 30:546–562. https://doi.org/10.1681/ASN.2018060599
Hong Q, Wang S, Liu S, Chen X, Cai G (2020) LRG1 may accelerate the progression of ccRCC via the TGF-beta pathway. Biomed Res Int. https://doi.org/10.1155/2020/1285068
Ishida T et al (2020) Correlation of increased serum leucine-rich alpha2-glycoprotein levels with disease prognosis, progression, and activity of interstitial pneumonia in patients with dermatomyositis: a retrospective study. PLoS ONE 15:e0234090. https://doi.org/10.1371/journal.pone.0234090
Ivancic MM et al (2019) Conserved serum protein biomarkers associated with growing early colorectal adenomas. Proc Natl Acad Sci USA 116:8471–8480. https://doi.org/10.1073/pnas.1813212116
Jang CW et al (2002) TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nat Cell Biol 4:51–58. https://doi.org/10.1038/ncb731
Javaid F et al (2021) Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel ADC target. RSC Chem Biol 2:1206–1220. https://doi.org/10.1039/d1cb00104c
Jemmerson R, Staskus K, Higgins L, Conklin K, Kelekar A (2021) Intracellular leucine-rich alpha-2-glycoprotein-1 competes with Apaf-1 for binding cytochrome c in protecting MCF-7 breast cancer cells from apoptosis. Apoptosis 26:71–82. https://doi.org/10.1007/s10495-020-01647-9
Jiang W et al (2020) Identification of urinary candidate biomarkers of cisplatin-induced nephrotoxicity in patients with carcinoma. J Proteomics 210:103533. https://doi.org/10.1016/j.jprot.2019.103533
Jin J et al (2019) LRG1 promotes apoptosis and autophagy through the TGFbeta-smad1/5 signaling pathway to exacerbate ischemia/reperfusion injury. Neuroscience 413:123–134. https://doi.org/10.1016/j.neuroscience.2019.06.008
Jin Z et al (2020) The prognostic impact of leucine-rich alpha-2-glycoprotein-1 in cholangiocarcinoma and its association with the IL-6/TGF-beta1 axis. J Surg Res 252:147–155. https://doi.org/10.1016/j.jss.2020.03.018
Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428. https://doi.org/10.1172/JCI39104
Keshet Y, Seger R (2010) The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions. Methods Mol Biol 661:3–38. https://doi.org/10.1007/978-1-60761-795-2_1
Kim SK, Henen MA, Hinck AP (2019) Structural biology of betaglycan and endoglin, membrane-bound co-receptors of the TGF-beta family. Exp Biol Med (maywood) 244:1547–1558. https://doi.org/10.1177/1535370219881160
Kobe B, Kajava AV (2001) The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol 11:725–732. https://doi.org/10.1016/s0959-440x(01)00266-4
Ladd JJ et al (2012) Increased plasma levels of the APC-interacting protein MAPRE1, LRG1, and IGFBP2 preceding a diagnosis of colorectal cancer in women. Cancer Prev Res (phila) 5:655–664. https://doi.org/10.1158/1940-6207.CAPR-11-0412
Lee HG et al (2019) Effect of responsiveness of lymph nodes to preoperative chemoradiotherapy in patients with rectal cancer on prognosis after radical resection. Clin Colorectal Cancer 18:e191–e199. https://doi.org/10.1016/j.clcc.2019.03.001
Li Y, Zhang Y, Qiu F, Qiu Z (2011) Proteomic identification of exosomal LRG1: a potential urinary biomarker for detecting NSCLC. Electrophoresis 32:1976–1983. https://doi.org/10.1002/elps.201000598
Li Z et al (2019) Exosomal leucine-rich-alpha2-glycoprotein 1 derived from non-small-cell lung cancer cells promotes angiogenesis via TGF-beta signal pathway. Mol Ther Oncolytics 14:313–322. https://doi.org/10.1016/j.omto.2019.08.001
Linden M et al (2012) Proteomic analysis of urinary biomarker candidates for nonmuscle invasive bladder cancer. Proteomics 12:135–144. https://doi.org/10.1002/pmic.201000810
Liu TT et al (2021) LRG1 mitigates renal interstitial fibrosis through alleviating capillary rarefaction and inhibiting inflammatory and pro-fibrotic cytokines. Am J Nephrol 52:228–238. https://doi.org/10.1159/000514167
Lou T, Ke K, Zhang L, Miao C, Liu Y (2020) LncRNA PART1 facilitates the malignant progression of colorectal cancer via miR-150-5p/LRG1 axis. J Cell Biochem 121:4271–4281. https://doi.org/10.1002/jcb.29635
Luan L, Hu Q, Wang Y, Lu L, Ling J (2021) Knockdown of lncRNA NEAT1 expression inhibits cell migration, invasion and EMT by regulating the miR-24-3p/LRG1 axis in retinoblastoma cells. Exp Ther Med 21:367. https://doi.org/10.3892/etm.2021.9798
Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791. https://doi.org/10.1146/annurev.biochem.67.1.753
Massague J (2000) How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1:169–178. https://doi.org/10.1038/35043051
Massague J (2012) TGFbeta signalling in context. Nat Rev Mol Cell Biol 13:616–630. https://doi.org/10.1038/nrm3434
Massague J, Seoane J, Wotton D (2005) Smad transcription factors. Genes Dev 19:2783–2810. https://doi.org/10.1101/gad.1350705
Miyauchi E et al (2018) Identification of blood biomarkers in glioblastoma by SWATH mass spectrometry and quantitative targeted absolute proteomics. PLoS ONE 13:e0193799. https://doi.org/10.1371/journal.pone.0193799
Mohamad Hanif EA (2019) Dysregulation of non-histone molecule miR205 and LRG1 post-transcriptional de-regulation by SETD1A in triple negative breast cancer. Mol Biol Rep 46:6617–6624. https://doi.org/10.1007/s11033-019-05079-w
Mu AK, Lim BK, Hashim OH, Shuib AS (2013) Identification of O-glycosylated proteins that are aberrantly excreted in the urine of patients with early stage ovarian cancer. Int J Mol Sci 14:7923–7931. https://doi.org/10.3390/ijms14047923
Mundo L et al (2021) LRG1 expression is elevated in the eyes of patients with neovascular age-related macular degeneration. Int J Mol Sci. https://doi.org/10.3390/ijms22168879
Nambu M et al (2019) Leucine-rich alpha-2-glycoprotein 1 in serum is a possible biomarker to predict response to preoperative chemoradiotherapy for esophageal cancer. Biol Pharm Bull 42:1766–1771. https://doi.org/10.1248/bpb.b19-00395
Nickel J, Ten Dijke P, Mueller TD (2018) TGF-beta family co-receptor function and signaling. Acta Biochim Biophys Sin (shanghai) 50:12–36. https://doi.org/10.1093/abbs/gmx126
Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700. https://doi.org/10.1016/s0092-8674(03)00432-x
Shimizu M, Inoue N, Mizuta M, Nakagishi Y, Yachie A (2019) Serum leucine-rich alpha2-glycoprotein as a biomarker for monitoring disease activity in patients with systemic juvenile idiopathic arthritis. J Immunol Res. https://doi.org/10.1155/2019/3140204
Shinozaki E et al (2018) Serum leucine-rich alpha-2-glycoprotein-1 with fucosylated triantennary N-glycan: a novel colorectal cancer marker. BMC Cancer 18:406. https://doi.org/10.1186/s12885-018-4252-6
Singhal M et al (2021) Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis. Sci Transl Med 13:eabe6805. https://doi.org/10.1126/scitranslmed.abe6805
Takahashi N, Takahashi Y, Putnam FW (1985) Periodicity of leucine and tandem repetition of a 24-amino acid segment in the primary structure of leucine-rich alpha 2-glycoprotein of human serum. Proc Natl Acad Sci USA 82:1906–1910. https://doi.org/10.1073/pnas.82.7.1906
Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890. https://doi.org/10.1016/j.cell.2009.11.007
Thomas SJ, Snowden JA, Zeidler MP, Danson SJ (2015) The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer 113:365–371. https://doi.org/10.1038/bjc.2015.233
Vander Ark A, Cao J, Li X (2018) TGF-beta receptors: In and beyond TGF-beta signaling. Cell Signal 52:112–120. https://doi.org/10.1016/j.cellsig.2018.09.002
Viloria-Petit AM et al (2009) A role for the TGFbeta-Par6 polarity pathway in breast cancer progression. Proc Natl Acad Sci USA 106:14028–14033. https://doi.org/10.1073/pnas.0906796106
Wang X et al (2013) LRG1 promotes angiogenesis by modulating endothelial TGF-beta signalling. Nature 499:306–311. https://doi.org/10.1038/nature12345
Wang CH et al (2015) LRG1 expression indicates unfavorable clinical outcome in hepatocellular carcinoma. Oncotarget 6:42118–42129. https://doi.org/10.18632/oncotarget.5967
Wang Y et al (2019) The clinical prognostic value of LRG1 in esophageal squamous cell carcinoma. Curr Cancer Drug Targets 19:756–763. https://doi.org/10.2174/1568009619666190204095942
Wu J, Xie X, Nie S, Buckanovich RJ, Lubman DM (2013) Altered expression of sialylated glycoproteins in ovarian cancer sera using lectin-based ELISA assay and quantitative glycoproteomics analysis. J Proteome Res 12:3342–3352. https://doi.org/10.1021/pr400169n
Wu J et al (2015) Validation of LRG1 as a potential biomarker for detection of epithelial ovarian cancer by a blinded study. PLoS ONE 10:e0121112. https://doi.org/10.1371/journal.pone.0121112
Xiao S, Zhu H (2018) Leucine-rich alpha-2-glycoprotein1 gene interferes with regulation of apoptosis in leukemia KASUMI-1 cells. Med Sci Monit 24:8348–8356. https://doi.org/10.12659/MSM.911249
Xie ZB, Zhang YF, Jin C, Mao YS, Fu DL (2019) LRG-1 promotes pancreatic cancer growth and metastasis via modulation of the EGFR/p38 signaling. J Exp Clin Cancer Res 38:75. https://doi.org/10.1186/s13046-019-1088-0
Yamamoto M et al (2017) Overexpression of leucine-rich alpha2-glycoprotein-1 is a prognostic marker and enhances tumor migration in gastric cancer. Cancer Sci 108:2052–2060. https://doi.org/10.1111/cas.13329
Yang FJ et al (2020a) Plasma leucine-rich alpha-2-glycoprotein 1 predicts cardiovascular disease risk in end-stage renal disease. Sci Rep 10:5988. https://doi.org/10.1038/s41598-020-62989-7
Yang Y et al (2020b) Leucine-rich alpha2-glycoprotein-1 upregulation in plasma and kidney of patients with lupus nephritis. BMC Nephrol 21:122. https://doi.org/10.1186/s12882-020-01782-0
Yap TL et al (2019) A novel noninvasive appendicitis score with a urine biomarker. J Pediatr Surg 54:91–96. https://doi.org/10.1016/j.jpedsurg.2018.10.025
Yu J, Zhang J, Su XT, Han YQ (2019) Expression and clinical significance of serum LRG1 in patients with diffuse large B-cell lymphoma before Treatment. Zhongguo Shi Yan Xue Ye Xue Za Zhi 27:1850–1855. https://doi.org/10.19746/j.cnki.issn.1009-2137.2019.06.023
Zhang YE (2017) Non-smad signaling pathways of the TGF-beta family. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a022129
Zhang J et al (2014) TGF-beta-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci Signal 7:ra91. https://doi.org/10.1126/scisignal.2005304
Zhang Y et al (2015) LRG1 suppresses the migration and invasion of hepatocellular carcinoma cells. Med Oncol 32:146. https://doi.org/10.1007/s12032-015-0598-7
Zhang J, Zhu L, Fang J, Ge Z, Li X (2016) LRG1 modulates epithelial-mesenchymal transition and angiogenesis in colorectal cancer via HIF-1alpha activation. J Exp Clin Cancer Res 35:29. https://doi.org/10.1186/s13046-016-0306-2
Zhang N et al (2020) LRG1 suppresses migration and invasion of esophageal squamous cell carcinoma by modulating epithelial to mesenchymal transition. J Cancer 11:1486–1494. https://doi.org/10.7150/jca.36189
Zhong D et al (2015a) LRG1 modulates invasion and migration of glioma cell lines through TGF-beta signaling pathway. Acta Histochem 117:551–558. https://doi.org/10.1016/j.acthis.2015.05.001
Zhong D et al (2015b) Stable knockdown of LRG1 by RNA interference inhibits growth and promotes apoptosis of glioblastoma cells in vitro and in vivo. Tumour Biol 36:4271–4278. https://doi.org/10.1007/s13277-015-3065-3
Zhong ME et al (2019) Serum extracellular vesicles contain SPARC and LRG1 as biomarkers of colon cancer and differ by tumour primary location. EBioMedicine 50:211–223. https://doi.org/10.1016/j.ebiom.2019.11.003
Zhou Y et al (2017) LRG1 promotes proliferation and inhibits apoptosis in colorectal cancer cells via RUNX1 activation. PLoS ONE 12:e0175122. https://doi.org/10.1371/journal.pone.0175122
Zhou L, Shi DP, Chu WJ, Yang LL, Xu HF (2021) LRG1 promotes epithelial-mesenchymal transition of retinal pigment epithelium cells by activating NOX4. Int J Ophthalmol 14:349–355. https://doi.org/10.18240/ijo.2021.03.03
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This work was supported by the Shandong Province National Natural Science Foundation (ZR2020MH149, ZR2019BH060) and Shandong medical and health science and technology development plan project (Grant No.2019WS606).
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Lin, M., Liu, J., Zhang, F. et al. The role of leucine-rich alpha-2-glycoprotein-1 in proliferation, migration, and invasion of tumors. J Cancer Res Clin Oncol 148, 283–291 (2022). https://doi.org/10.1007/s00432-021-03876-0
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DOI: https://doi.org/10.1007/s00432-021-03876-0