Skip to main content
Top
Published in: Tumor Biology 2/2016

01-02-2016 | Original Article

FXR1 is elevated in colorectal cancer and acts as an oncogene

Authors: Xin Jin, Bo Zhai, Taishi Fang, Xiaohui Guo, Lishan Xu

Published in: Tumor Biology | Issue 2/2016

Login to get access

Abstract

Fragile X-related gene 1 (FXR1) is deregulated in a variety of human disorders including cancer. However, there is relatively little evidence concerning the relationship between FXR1 and colorectal cancer. Western blot, immunohistochemistry (IHC), and quantitative real-time PCR (qRT-PCR) were adopted to detect the FXR1 protein and messenger RNA (mRNA) expression, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the plasma FXR1 expression in our study. MTT assay and colony formation assay were used to examine the proliferation ability of cells in vitro. In addition, Transwell assays were performed to test the migration and invasion abilities of cancer cells. We found that the average plasma FXR1 level in CRC was significantly higher than that in healthy controls (P < 0.001). Moreover, the plasma expression of FXR1 in stage IV patients was dramatically higher than that in stage I, stage II, and stage III patients (P < 0.001). Consistently, FXR1 mRNA expression levels were much higher in cancer tissues than that in normal tissues. Moreover, IHC results showed that cancer tissues possessed higher FXR1 expression (P = 0.027). What’s more, plasma FXR1 was a risk factor of colorectal cancer indicated by univariate survival analysis (P = 0.021, HR = 1.685, 95 % CI 1.336–1.927). Multivariate analysis suggested that FXR1 was an independent risk factor of colorectal cancer (P = 0.008, HR = 1.381, 95 % CI 1.119–1.741). Kaplan-Meier analysis showed that the patients with higher plasma FXR1 expression had a poorer outcome (P < 0.001). Besides, FXR1 acted as an oncogene which could increase the proliferation, migration, and invasion of cancer cells. All these data indicate that FXR1 might act as a tumor promoter. Future investigations are warranted to explore whether FXR1 may represent a novel therapeutic target.
Literature
2.
go back to reference Kirkpatrick LL, McIlwain KA, Nelson DL. Comparative genomic sequence analysis of the fxr gene family: Fmr1, fxr1, and fxr2. Genomics. 2001;78:169–77.CrossRefPubMed Kirkpatrick LL, McIlwain KA, Nelson DL. Comparative genomic sequence analysis of the fxr gene family: Fmr1, fxr1, and fxr2. Genomics. 2001;78:169–77.CrossRefPubMed
3.
go back to reference Engels B, van 't Padje S, Blonden L, Severijnen LA, Oostra BA, Willemsen R. Characterization of fxr1 in danio rerio; a simple vertebrate model to study costamere development. J Exp Biol. 2004;207:3329–38.CrossRefPubMed Engels B, van 't Padje S, Blonden L, Severijnen LA, Oostra BA, Willemsen R. Characterization of fxr1 in danio rerio; a simple vertebrate model to study costamere development. J Exp Biol. 2004;207:3329–38.CrossRefPubMed
4.
go back to reference Tabrizi M, Khalili M, Vasei M, Nouraei N, Mansour Samaei N, Khavanin A, et al. Evaluating the mir-302b and mir-145 expression in formalin-fixed paraffin-embedded samples of esophageal squamous cell carcinoma. Arch Iran Med. 2015;18:173–8.PubMed Tabrizi M, Khalili M, Vasei M, Nouraei N, Mansour Samaei N, Khavanin A, et al. Evaluating the mir-302b and mir-145 expression in formalin-fixed paraffin-embedded samples of esophageal squamous cell carcinoma. Arch Iran Med. 2015;18:173–8.PubMed
5.
go back to reference Kumar P, Rawat A, Keshari AK, Singh AK, Maity S, De A, et al. Antiproliferative effect of isolated isoquinoline alkaloid from mucuna pruriens seeds in hepatic carcinoma cells. Nat Prod Res. 2015;16:1–4. Kumar P, Rawat A, Keshari AK, Singh AK, Maity S, De A, et al. Antiproliferative effect of isolated isoquinoline alkaloid from mucuna pruriens seeds in hepatic carcinoma cells. Nat Prod Res. 2015;16:1–4.
6.
go back to reference Kang MH, Moon SU, Sung JH, Kim JW, Lee KW, Lee HS, Lee JS, Kim JH. Antitumor activity of hm781-36b, alone or in combination with chemotherapeutic agents, in colorectal cancer cells. Cancer Res Treat. 2015 Kang MH, Moon SU, Sung JH, Kim JW, Lee KW, Lee HS, Lee JS, Kim JH. Antitumor activity of hm781-36b, alone or in combination with chemotherapeutic agents, in colorectal cancer cells. Cancer Res Treat. 2015
7.
go back to reference Davidovic L, Durand N, Khalfallah O, Tabet R, Barbry P, Mari B, et al. A novel role for the rna-binding protein fxr1p in myoblasts cell-cycle progression by modulating p21/cdkn1a/cip1/waf1 mrna stability. PLoS Genet. 2013;9:e1003367.CrossRefPubMedPubMedCentral Davidovic L, Durand N, Khalfallah O, Tabet R, Barbry P, Mari B, et al. A novel role for the rna-binding protein fxr1p in myoblasts cell-cycle progression by modulating p21/cdkn1a/cip1/waf1 mrna stability. PLoS Genet. 2013;9:e1003367.CrossRefPubMedPubMedCentral
8.
go back to reference Garnon J, Lachance C, Di Marco S, Hel Z, Marion D, Ruiz MC, et al. Fragile x-related protein fxr1p regulates proinflammatory cytokine tumor necrosis factor expression at the post-transcriptional level. J Biol Chem. 2005;280:5750–63.CrossRefPubMed Garnon J, Lachance C, Di Marco S, Hel Z, Marion D, Ruiz MC, et al. Fragile x-related protein fxr1p regulates proinflammatory cytokine tumor necrosis factor expression at the post-transcriptional level. J Biol Chem. 2005;280:5750–63.CrossRefPubMed
9.
go back to reference Edbauer D, Neilson JR, Foster KA, Wang CF, Seeburg DP, Batterton MN, et al. Regulation of synaptic structure and function by fmrp-associated micrornas mir-125b and mir-132. Neuron. 2010;65:373–84.CrossRefPubMedPubMedCentral Edbauer D, Neilson JR, Foster KA, Wang CF, Seeburg DP, Batterton MN, et al. Regulation of synaptic structure and function by fmrp-associated micrornas mir-125b and mir-132. Neuron. 2010;65:373–84.CrossRefPubMedPubMedCentral
10.
go back to reference Kirkpatrick LL, McIlwain KA, Nelson DL. Alternative splicing in the murine and human fxr1 genes. Genomics. 1999;59:193–202.CrossRefPubMed Kirkpatrick LL, McIlwain KA, Nelson DL. Alternative splicing in the murine and human fxr1 genes. Genomics. 1999;59:193–202.CrossRefPubMed
11.
go back to reference Mientjes EJ, Willemsen R, Kirkpatrick LL, Nieuwenhuizen IM, Hoogeveen-Westerveld M, Verweij M, et al. Fxr1 knockout mice show a striated muscle phenotype: implications for fxr1p function in vivo. Hum Mol Genet. 2004;13:1291–302.CrossRefPubMed Mientjes EJ, Willemsen R, Kirkpatrick LL, Nieuwenhuizen IM, Hoogeveen-Westerveld M, Verweij M, et al. Fxr1 knockout mice show a striated muscle phenotype: implications for fxr1p function in vivo. Hum Mol Genet. 2004;13:1291–302.CrossRefPubMed
12.
go back to reference Khandjian EW, Bardoni B, Corbin F, Sittler A, Giroux S, Heitz D, et al. Novel isoforms of the fragile x related protein fxr1p are expressed during myogenesis. Hum Mol Genet. 1998;7:2121–8.CrossRefPubMed Khandjian EW, Bardoni B, Corbin F, Sittler A, Giroux S, Heitz D, et al. Novel isoforms of the fragile x related protein fxr1p are expressed during myogenesis. Hum Mol Genet. 1998;7:2121–8.CrossRefPubMed
13.
go back to reference Huot ME, Bisson N, Davidovic L, Mazroui R, Labelle Y, Moss T, et al. The rna-binding protein fragile x-related 1 regulates somite formation in xenopus laevis. Mol Biol Cell. 2005;16:4350–61.CrossRefPubMedPubMedCentral Huot ME, Bisson N, Davidovic L, Mazroui R, Labelle Y, Moss T, et al. The rna-binding protein fragile x-related 1 regulates somite formation in xenopus laevis. Mol Biol Cell. 2005;16:4350–61.CrossRefPubMedPubMedCentral
14.
go back to reference Van't Padje S, Chaudhry B, Severijnen LA, van der Linde HC, Mientjes EJ, Oostra BA, et al. Reduction in fragile x related 1 protein causes cardiomyopathy and muscular dystrophy in zebrafish. J Exp Biol. 2009;212:2564–70.CrossRef Van't Padje S, Chaudhry B, Severijnen LA, van der Linde HC, Mientjes EJ, Oostra BA, et al. Reduction in fragile x related 1 protein causes cardiomyopathy and muscular dystrophy in zebrafish. J Exp Biol. 2009;212:2564–70.CrossRef
15.
go back to reference Davidovic L, Sacconi S, Bechara EG, Delplace S, Allegra M, Desnuelle C, et al. Alteration of expression of muscle specific isoforms of the fragile x related protein 1 (fxr1p) in facioscapulohumeral muscular dystrophy patients. J Med Genet. 2008;45:679–85.CrossRefPubMed Davidovic L, Sacconi S, Bechara EG, Delplace S, Allegra M, Desnuelle C, et al. Alteration of expression of muscle specific isoforms of the fragile x related protein 1 (fxr1p) in facioscapulohumeral muscular dystrophy patients. J Med Genet. 2008;45:679–85.CrossRefPubMed
16.
go back to reference Oldenburg AR, Delbarre E, Thiede B, Vigouroux C, Collas P. Deregulation of fragile x-related protein 1 by the lipodystrophic lamin a p.R482w mutation elicits a myogenic gene expression program in preadipocytes. Hum Mol Genet. 2014;23:1151–62.CrossRefPubMed Oldenburg AR, Delbarre E, Thiede B, Vigouroux C, Collas P. Deregulation of fragile x-related protein 1 by the lipodystrophic lamin a p.R482w mutation elicits a myogenic gene expression program in preadipocytes. Hum Mol Genet. 2014;23:1151–62.CrossRefPubMed
17.
go back to reference Cook D, Sanchez-Carbente Mdel R, Lachance C, Radzioch D, Tremblay S, Khandjian EW, et al. Fragile x related protein 1 clusters with ribosomes and messenger rnas at a subset of dendritic spines in the mouse hippocampus. PLoS One. 2011;6:e26120.CrossRefPubMedPubMedCentral Cook D, Sanchez-Carbente Mdel R, Lachance C, Radzioch D, Tremblay S, Khandjian EW, et al. Fragile x related protein 1 clusters with ribosomes and messenger rnas at a subset of dendritic spines in the mouse hippocampus. PLoS One. 2011;6:e26120.CrossRefPubMedPubMedCentral
18.
go back to reference Bolivar J, Guelman S, Iglesias C, Ortiz M, Valdivia MM. The fragile-x-related gene fxr1 is a human autoantigen processed during apoptosis. J Biol Chem. 1998;273:17122–7.CrossRefPubMed Bolivar J, Guelman S, Iglesias C, Ortiz M, Valdivia MM. The fragile-x-related gene fxr1 is a human autoantigen processed during apoptosis. J Biol Chem. 1998;273:17122–7.CrossRefPubMed
19.
go back to reference Xu XL, Zong R, Li Z, Biswas MH, Fang Z, Nelson DL, et al. Fxr1p but not fmrp regulates the levels of mammalian brain-specific microrna-9 and microrna-124. J Neurosci. 2011;31:13705–9.CrossRefPubMedPubMedCentral Xu XL, Zong R, Li Z, Biswas MH, Fang Z, Nelson DL, et al. Fxr1p but not fmrp regulates the levels of mammalian brain-specific microrna-9 and microrna-124. J Neurosci. 2011;31:13705–9.CrossRefPubMedPubMedCentral
21.
go back to reference Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318:1931–4.CrossRefPubMed Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318:1931–4.CrossRefPubMed
22.
go back to reference Qian J, Hassanein M, Hoeksema MD, Harris BK, Zou Y, Chen H, et al. The rna binding protein fxr1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers. Proc Natl Acad Sci U S A. 2015;112:3469–74.CrossRefPubMedPubMedCentral Qian J, Hassanein M, Hoeksema MD, Harris BK, Zou Y, Chen H, et al. The rna binding protein fxr1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers. Proc Natl Acad Sci U S A. 2015;112:3469–74.CrossRefPubMedPubMedCentral
23.
go back to reference Wang J, Qian J, Hoeksema MD, Zou Y, Espinosa AV, Rahman SM, et al. Integrative genomics analysis identifies candidate drivers at 3q26-29 amplicon in squamous cell carcinoma of the lung. Clin Cancer Res. 2013;19:5580–90.CrossRefPubMed Wang J, Qian J, Hoeksema MD, Zou Y, Espinosa AV, Rahman SM, et al. Integrative genomics analysis identifies candidate drivers at 3q26-29 amplicon in squamous cell carcinoma of the lung. Clin Cancer Res. 2013;19:5580–90.CrossRefPubMed
24.
go back to reference Comtesse N, Keller A, Diesinger I, Bauer C, Kayser K, Huwer H, et al. Frequent overexpression of the genes fxr1, clapm1 and eif4g located on amplicon 3q26-27 in squamous cell carcinoma of the lung. Int J Cancer. 2007;120:2538–44.CrossRefPubMed Comtesse N, Keller A, Diesinger I, Bauer C, Kayser K, Huwer H, et al. Frequent overexpression of the genes fxr1, clapm1 and eif4g located on amplicon 3q26-27 in squamous cell carcinoma of the lung. Int J Cancer. 2007;120:2538–44.CrossRefPubMed
25.
go back to reference Fields AP, Justilien V. The guanine nucleotide exchange factor (gef) ect2 is an oncogene in human cancer. Adv Enzyme Regul. 2010;50:190–200.CrossRefPubMed Fields AP, Justilien V. The guanine nucleotide exchange factor (gef) ect2 is an oncogene in human cancer. Adv Enzyme Regul. 2010;50:190–200.CrossRefPubMed
27.
go back to reference Ma Y, Wang C, Li B, Qin L, Su J, Yang M, et al. Bcl-2-associated transcription factor 1 interacts with fragile x-related protein 1. Acta Biochim Biophys Sin (Shanghai). 2014;46:119–27.CrossRef Ma Y, Wang C, Li B, Qin L, Su J, Yang M, et al. Bcl-2-associated transcription factor 1 interacts with fragile x-related protein 1. Acta Biochim Biophys Sin (Shanghai). 2014;46:119–27.CrossRef
28.
go back to reference Lejeune FJ, Ruegg C, Lienard D. Clinical applications of tnf-alpha in cancer. Curr Opin Immunol. 1998;10:573–80.CrossRefPubMed Lejeune FJ, Ruegg C, Lienard D. Clinical applications of tnf-alpha in cancer. Curr Opin Immunol. 1998;10:573–80.CrossRefPubMed
29.
Metadata
Title
FXR1 is elevated in colorectal cancer and acts as an oncogene
Authors
Xin Jin
Bo Zhai
Taishi Fang
Xiaohui Guo
Lishan Xu
Publication date
01-02-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 2/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4068-9

Other articles of this Issue 2/2016

Tumor Biology 2/2016 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine