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Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

REGγ is associated with multiple oncogenic pathways in human cancers

Authors: Jing He, Long Cui, Yu Zeng, Guangqiang Wang, Ping Zhou, Yuanyuan Yang, Lei Ji, Yanyan Zhao, Jiwu Chen, Zhuo Wang, Tieliu Shi, Pei Zhang, Rui Chen, Xiaotao Li

Published in: BMC Cancer | Issue 1/2012

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Abstract

Background

Recent studies suggest a role of the proteasome activator, REGγ, in cancer progression. Since there are limited numbers of known REGγ targets, it is not known which cancers and pathways are associated with REGγ.

Methods

REGγ protein expressions in four different cancers were investigated by immunohistochemistry (IHC) analysis. Following NCBI Gene Expression Omnibus (GEO) database search, microarray platform validation, differential expressions of REGγ in corresponding cancers were statistically analyzed. Genes highly correlated with REGγ were defined based on Pearson's correlation coefficient. Functional links were estimated by Ingenuity Core analysis. Finally, validation was performed by RT-PCR analysis in established cancer cell lines and IHC in human colon cancer tissues

Results

Here, we demonstrate overexpression of REGγ in four different cancer types by micro-tissue array analysis. Using meta-analysis of publicly available microarray databases and biological studies, we verified elevated REGγ gene expression in the four types of cancers and identified genes significantly correlated with REGγ expression, including genes in p53, Myc pathways, and multiple other cancer-related pathways. The predicted correlations were largely consistent with quantitative RT-PCR analysis.

Conclusions

This study provides us novel insights in REGγ gene expression profiles and its link to multiple cancer-related pathways in cancers. Our results indicate potentially important pathogenic roles of REGγ in multiple cancer types and implicate REGγ as a putative cancer marker.
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Literature
1.
go back to reference Mao I, Liu J, Li X, Luo H: REGgamma, a proteasome activator and beyond. Cellular Mol Life Sci. 2008, 65: 3971-3980. 10.1007/s00018-008-8291-z.CrossRef Mao I, Liu J, Li X, Luo H: REGgamma, a proteasome activator and beyond. Cellular Mol Life Sci. 2008, 65: 3971-3980. 10.1007/s00018-008-8291-z.CrossRef
2.
go back to reference Okamura T, Taniguchi S, Ohkura T, Yoshida A, Shimizu H, Hisatome I, Shiqemasa C: Abnormally high expression of proteasome activator-gamma in thyroid neoplasm. JCEM. 2003, 88: 1374-1383.PubMed Okamura T, Taniguchi S, Ohkura T, Yoshida A, Shimizu H, Hisatome I, Shiqemasa C: Abnormally high expression of proteasome activator-gamma in thyroid neoplasm. JCEM. 2003, 88: 1374-1383.PubMed
3.
go back to reference Markus R: Identification of PSME3 as a Novel Serum Tumor Marker for Colorectal Cancer by combing two-dimensional polyacrylamide gel electrophoresis with a strictly mass spectrometry-based approach for data analysis. Mol Cellular Proteomics. 2006, 1: 2092-2101. Markus R: Identification of PSME3 as a Novel Serum Tumor Marker for Colorectal Cancer by combing two-dimensional polyacrylamide gel electrophoresis with a strictly mass spectrometry-based approach for data analysis. Mol Cellular Proteomics. 2006, 1: 2092-2101.
4.
go back to reference Jia HL, Ye QH, Qin LX, Budhu A, Forgues M, Chen Y, Liu YK, Sun HC, Wang L, Lu HZ, et al: Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma. Clin Cancer Res. 2007, 13: 1133-1139. 10.1158/1078-0432.CCR-06-1025.CrossRefPubMed Jia HL, Ye QH, Qin LX, Budhu A, Forgues M, Chen Y, Liu YK, Sun HC, Wang L, Lu HZ, et al: Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma. Clin Cancer Res. 2007, 13: 1133-1139. 10.1158/1078-0432.CCR-06-1025.CrossRefPubMed
5.
go back to reference Jiang X, Tan J, Li J, Kivimae S, Yang X, Zhuang L, Lee PL, Chan MT, Stanton LW, Liu ET, et al: DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell. 2008, 13: 529-541. 10.1016/j.ccr.2008.04.019.CrossRefPubMedPubMedCentral Jiang X, Tan J, Li J, Kivimae S, Yang X, Zhuang L, Lee PL, Chan MT, Stanton LW, Liu ET, et al: DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell. 2008, 13: 529-541. 10.1016/j.ccr.2008.04.019.CrossRefPubMedPubMedCentral
6.
go back to reference Hong Y, Ho KS, Eu KW, Cheah PY: A susceptibility gene set for early onset colorectal cancer that integrates diverse signaling pathways: implication for tumorigenesis. Clin Cancer Res. 2007, 13: 1107-1114. 10.1158/1078-0432.CCR-06-1633.CrossRefPubMed Hong Y, Ho KS, Eu KW, Cheah PY: A susceptibility gene set for early onset colorectal cancer that integrates diverse signaling pathways: implication for tumorigenesis. Clin Cancer Res. 2007, 13: 1107-1114. 10.1158/1078-0432.CCR-06-1633.CrossRefPubMed
7.
go back to reference Chandran UR, Ma C, Dhir R, Bisceglia M, Lyons-Weiler M, Liang W, Michalopoulos G, Becich M, Monzon FA: Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process. BMC Cancer. 2007, 7: 64-10.1186/1471-2407-7-64.CrossRefPubMedPubMedCentral Chandran UR, Ma C, Dhir R, Bisceglia M, Lyons-Weiler M, Liang W, Michalopoulos G, Becich M, Monzon FA: Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process. BMC Cancer. 2007, 7: 64-10.1186/1471-2407-7-64.CrossRefPubMedPubMedCentral
8.
go back to reference Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, et al: Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003, 9: 416-423. 10.1038/nm843.CrossRefPubMed Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, et al: Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003, 9: 416-423. 10.1038/nm843.CrossRefPubMed
9.
go back to reference Okamura T, Taniguchi S, Ohkura T, Yoshida A, Shimizu H, Sakai M, Maeta H, Fukui H, Ueta Y, Hisatome I, Shigemasa C: Abnormally high expression of proteasome activator-gamma in thyroid neoplasm. J Clin Endocrinol Metab. 2003, 88: 1374-1383. 10.1210/jc.2002-021413.CrossRefPubMed Okamura T, Taniguchi S, Ohkura T, Yoshida A, Shimizu H, Sakai M, Maeta H, Fukui H, Ueta Y, Hisatome I, Shigemasa C: Abnormally high expression of proteasome activator-gamma in thyroid neoplasm. J Clin Endocrinol Metab. 2003, 88: 1374-1383. 10.1210/jc.2002-021413.CrossRefPubMed
10.
11.
go back to reference Shi L, Jones WD, Jensen RV, Harris SC, Perkins RG, Goodsaid FM, Guo L, Croner LJ, Boysen C, Fang H, et al: The balance of reproducibility, sensitivity, and specificity of lists of differentially expressed genes in microarray studies. BMC Bioinformatics. 2008, 9 (Suppl 9): S10-10.1186/1471-2105-9-S9-S10.CrossRefPubMedPubMedCentral Shi L, Jones WD, Jensen RV, Harris SC, Perkins RG, Goodsaid FM, Guo L, Croner LJ, Boysen C, Fang H, et al: The balance of reproducibility, sensitivity, and specificity of lists of differentially expressed genes in microarray studies. BMC Bioinformatics. 2008, 9 (Suppl 9): S10-10.1186/1471-2105-9-S9-S10.CrossRefPubMedPubMedCentral
12.
go back to reference Maouche S, Poirier O, Godefroy T, Olaso R, Gut I, Collet JP, Montalescot G, Cambien F: Performance comparison of two microarray platforms to assess differential gene expression in human monocyte and macrophage cells. BMC Genomics. 2008, 9: 302-10.1186/1471-2164-9-302.CrossRefPubMedPubMedCentral Maouche S, Poirier O, Godefroy T, Olaso R, Gut I, Collet JP, Montalescot G, Cambien F: Performance comparison of two microarray platforms to assess differential gene expression in human monocyte and macrophage cells. BMC Genomics. 2008, 9: 302-10.1186/1471-2164-9-302.CrossRefPubMedPubMedCentral
13.
go back to reference Sean D, Meltzer PS: GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics. 2007, 23: 1846-1847. 10.1093/bioinformatics/btm254.CrossRef Sean D, Meltzer PS: GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics. 2007, 23: 1846-1847. 10.1093/bioinformatics/btm254.CrossRef
15.
go back to reference Smyth GK: Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004, 3: Article3-PubMed Smyth GK: Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004, 3: Article3-PubMed
16.
go back to reference Baldi P, Long AD: A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes. Bioinformatics. 2001, 17: 509-519. 10.1093/bioinformatics/17.6.509.CrossRefPubMed Baldi P, Long AD: A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes. Bioinformatics. 2001, 17: 509-519. 10.1093/bioinformatics/17.6.509.CrossRefPubMed
17.
go back to reference Mansson R, Tsapogas P, Akerlund M, Lagergren A, Gisler R, Sigvardsson M: Pearson correlation analysis of microarray data allows for the identification of genetic targets for early B-cell factor. J Biol Chem. 2004, 279: 17905-17913. 10.1074/jbc.M400589200.CrossRefPubMed Mansson R, Tsapogas P, Akerlund M, Lagergren A, Gisler R, Sigvardsson M: Pearson correlation analysis of microarray data allows for the identification of genetic targets for early B-cell factor. J Biol Chem. 2004, 279: 17905-17913. 10.1074/jbc.M400589200.CrossRefPubMed
18.
go back to reference Rosner B: Fundamentals of Biostatistics. 2006, Belmont, CA: Thomson-Brooks/Cole, 6 Rosner B: Fundamentals of Biostatistics. 2006, Belmont, CA: Thomson-Brooks/Cole, 6
19.
go back to reference Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, Doerks T, Julien P, Roth A, Simonovic M, et al: STRING 8-a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res. 2009, 37: D412-416. 10.1093/nar/gkn760.CrossRefPubMed Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, Doerks T, Julien P, Roth A, Simonovic M, et al: STRING 8-a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res. 2009, 37: D412-416. 10.1093/nar/gkn760.CrossRefPubMed
20.
go back to reference Su LJ, Chang CW, Wu YC, Chen KC, Lin CJ, Liang SC, Lin CH, Whang-Peng J, Hsu SL, Chen CH, Huang CY: Selection of DDX5 as a novel internal control for Q-RT-PCR from microarray data using a block bootstrap re-sampling scheme. BMC Genomics. 2007, 8: 140-10.1186/1471-2164-8-140.CrossRefPubMedPubMedCentral Su LJ, Chang CW, Wu YC, Chen KC, Lin CJ, Liang SC, Lin CH, Whang-Peng J, Hsu SL, Chen CH, Huang CY: Selection of DDX5 as a novel internal control for Q-RT-PCR from microarray data using a block bootstrap re-sampling scheme. BMC Genomics. 2007, 8: 140-10.1186/1471-2164-8-140.CrossRefPubMedPubMedCentral
21.
go back to reference Fontaine JF, Mirebeau-Prunier D, Franc B, Triau S, Rodien P, Houlgatte R, Malthiery Y, Savagner F: Microarray analysis refines classification of non-medullary thyroid tumours of uncertain malignancy. Oncogene. 2008, 27: 2228-2236. 10.1038/sj.onc.1210853.CrossRefPubMed Fontaine JF, Mirebeau-Prunier D, Franc B, Triau S, Rodien P, Houlgatte R, Malthiery Y, Savagner F: Microarray analysis refines classification of non-medullary thyroid tumours of uncertain malignancy. Oncogene. 2008, 27: 2228-2236. 10.1038/sj.onc.1210853.CrossRefPubMed
22.
go back to reference Gyorffy B, Molnar B, Lage H, Szallasi Z, Eklund AC: Evaluation of microarray preprocessing algorithms based on concordance with RT-PCR in clinical samples. PLoS One. 2009, 4: e5645-10.1371/journal.pone.0005645.CrossRefPubMedPubMedCentral Gyorffy B, Molnar B, Lage H, Szallasi Z, Eklund AC: Evaluation of microarray preprocessing algorithms based on concordance with RT-PCR in clinical samples. PLoS One. 2009, 4: e5645-10.1371/journal.pone.0005645.CrossRefPubMedPubMedCentral
23.
go back to reference Wurmbach E, Chen YB, Khitrov G, Zhang W, Roayaie S, Schwartz M, Fiel I, Thung S, Mazzaferro V, Bruix J, et al: Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology. 2007, 45: 938-947. 10.1002/hep.21622.CrossRefPubMed Wurmbach E, Chen YB, Khitrov G, Zhang W, Roayaie S, Schwartz M, Fiel I, Thung S, Mazzaferro V, Bruix J, et al: Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology. 2007, 45: 938-947. 10.1002/hep.21622.CrossRefPubMed
24.
go back to reference Liu J, Yu G, Zhao Y, Zhao D, Wang Y, Wang L, Li L, Zeng Y, Dang Y, Wang C, et al: REG{gamma} modulates p53 activity by regulating its cellular localization. J Cell Sci. 2010, 123: 4076-4084. 10.1242/jcs.067405.CrossRefPubMedPubMedCentral Liu J, Yu G, Zhao Y, Zhao D, Wang Y, Wang L, Li L, Zeng Y, Dang Y, Wang C, et al: REG{gamma} modulates p53 activity by regulating its cellular localization. J Cell Sci. 2010, 123: 4076-4084. 10.1242/jcs.067405.CrossRefPubMedPubMedCentral
25.
go back to reference Zhang Z, Zhang R: Proteasome activator PA28 gamma regulates p53 by enhancing its MDM2-mediated degradation. EMBO J. 2008, 27: 852-864. 10.1038/emboj.2008.25.CrossRefPubMedPubMedCentral Zhang Z, Zhang R: Proteasome activator PA28 gamma regulates p53 by enhancing its MDM2-mediated degradation. EMBO J. 2008, 27: 852-864. 10.1038/emboj.2008.25.CrossRefPubMedPubMedCentral
26.
go back to reference Li X, Lonard DM, Jung SY, Malovannaya A, Feng Q, Qin J, Tsai SY, Tsai MJ, O'Malley BW: The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REGgamma proteasome. Cell. 2006, 124: 381-392. 10.1016/j.cell.2005.11.037.CrossRefPubMed Li X, Lonard DM, Jung SY, Malovannaya A, Feng Q, Qin J, Tsai SY, Tsai MJ, O'Malley BW: The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REGgamma proteasome. Cell. 2006, 124: 381-392. 10.1016/j.cell.2005.11.037.CrossRefPubMed
27.
go back to reference Salvatore G, Nappi TC, Salerno P, Jiang Y, Garbi C, Ugolini C, Miccoli P, Basolo F, Castellone MD, Cirafici AM, et al: A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. Cancer Res. 2007, 67: 10148-10158. 10.1158/0008-5472.CAN-07-1887.CrossRefPubMed Salvatore G, Nappi TC, Salerno P, Jiang Y, Garbi C, Ugolini C, Miccoli P, Basolo F, Castellone MD, Cirafici AM, et al: A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. Cancer Res. 2007, 67: 10148-10158. 10.1158/0008-5472.CAN-07-1887.CrossRefPubMed
28.
go back to reference Levine AJ, Puzio-Kuter AM: The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science. 2010, 330: 1340-1344. 10.1126/science.1193494.CrossRefPubMed Levine AJ, Puzio-Kuter AM: The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science. 2010, 330: 1340-1344. 10.1126/science.1193494.CrossRefPubMed
29.
go back to reference Burger AM, Seth AK: The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. Eur J Cancer. 2004, 40: 2217-2229. 10.1016/j.ejca.2004.07.006.CrossRefPubMed Burger AM, Seth AK: The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. Eur J Cancer. 2004, 40: 2217-2229. 10.1016/j.ejca.2004.07.006.CrossRefPubMed
30.
go back to reference Wellen KE, Thompson CB: Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell. 2010, 40: 323-332. 10.1016/j.molcel.2010.10.004.CrossRefPubMedPubMedCentral Wellen KE, Thompson CB: Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell. 2010, 40: 323-332. 10.1016/j.molcel.2010.10.004.CrossRefPubMedPubMedCentral
31.
go back to reference Yu G, Zhao Y, He J, Lonard DM, Mao CA, Wang G, Li M, Li X: Comparative analysis of REG{gamma} expression in mouse and human tissues. J Mol Cell Biol. 2010, 2: 192-198. 10.1093/jmcb/mjq009.CrossRefPubMedPubMedCentral Yu G, Zhao Y, He J, Lonard DM, Mao CA, Wang G, Li M, Li X: Comparative analysis of REG{gamma} expression in mouse and human tissues. J Mol Cell Biol. 2010, 2: 192-198. 10.1093/jmcb/mjq009.CrossRefPubMedPubMedCentral
32.
go back to reference Goh HS, Soong TW, Lee YS, Ho J, Goh CR: c-myc Oncogene expression in colorectal cancer: its use in prognosis and role in colorectal carcinogenesis. Ann Acad Med Singapore. 1990, 19: 139-141.PubMed Goh HS, Soong TW, Lee YS, Ho J, Goh CR: c-myc Oncogene expression in colorectal cancer: its use in prognosis and role in colorectal carcinogenesis. Ann Acad Med Singapore. 1990, 19: 139-141.PubMed
33.
go back to reference Sikora K, Chan S, Evan G, Gabra H, Markham N, Stewart J, Watson J: c-myc oncogene expression in colorectal cancer. Cancer. 1987, 59: 1289-1295. 10.1002/1097-0142(19870401)59:7<1289::AID-CNCR2820590710>3.0.CO;2-O.CrossRefPubMed Sikora K, Chan S, Evan G, Gabra H, Markham N, Stewart J, Watson J: c-myc oncogene expression in colorectal cancer. Cancer. 1987, 59: 1289-1295. 10.1002/1097-0142(19870401)59:7<1289::AID-CNCR2820590710>3.0.CO;2-O.CrossRefPubMed
Metadata
Title
REGγ is associated with multiple oncogenic pathways in human cancers
Authors
Jing He
Long Cui
Yu Zeng
Guangqiang Wang
Ping Zhou
Yuanyuan Yang
Lei Ji
Yanyan Zhao
Jiwu Chen
Zhuo Wang
Tieliu Shi
Pei Zhang
Rui Chen
Xiaotao Li
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-75

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