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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Copy number gain of granulin-epithelin precursor (GEP) at chromosome 17q21 associates with overexpression in human liver cancer

Authors: Man Kuen Yung, Kwok Wai Lo, Chi Wai Yip, Grace TY Chung, Carol YK Tong, Phyllis FY Cheung, Tan To Cheung, Ronnie TP Poon, Samuel So, Sheung Tat Fan, Siu Tim Cheung

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

Granulin-epithelin precursor (GEP), a secretory growth factor, demonstrated overexpression in various human cancers, however, mechanism remain elusive. Primary liver cancer, hepatocellular carcinoma (HCC), ranks the second in cancer-related death globally. GEP controlled growth, invasion, metastasis and chemo-resistance in liver cancer. Noted that GEP gene locates at 17q21 and the region has been frequently reported to be amplified in subset of HCC. The study aims to investigate if copy number gain would associate with GEP overexpression.

Methods

Quantitative Microsatellite Analysis (QuMA) was used to quantify the GEP DNA copy number, and fluorescent in situ hybridization (FISH) was performed to consolidate the amplification status. GEP gene copy number, mRNA expression level and clinico-pathological features were analyzed.

Results

GEP DNA copy number determined by QuMA corroborated well with the FISH data, and the gene copy number correlated with the expression levels (n = 60, r = 0.331, P = 0.010). Gain of GEP copy number was observed in 20% (12/60) HCC and associated with hepatitis B virus infection status (P = 0.015). In HCC with increased GEP copy number, tight association between GEP DNA and mRNA levels were observed (n = 12, r = 0.664, P = 0.019).

Conclusions

Gain of the GEP gene copy number was observed in 20% HCC and the frequency comparable to literatures reported on the chromosome region 17q. Increased gene copy number contributed to GEP overexpression in subset of HCC.
Appendix
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Literature
1.
Kleinberger G, Capell A, Haass C, Van Broeckhoven C. Mechanisms of granulin deficiency: lessons from cellular and animal models. Mol Neurobiol. 2013;47:337–60.CrossRefPubMed
2.
Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G. Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem. 2012;287:32298–306.CrossRefPubMedPubMedCentral
3.
Bateman A, Bennett HP. The granulin gene family: from cancer to dementia. Bioessays. 2009;31:1245–54.CrossRefPubMed
4.
He Z, Ong CH, Halper J, Bateman A. Progranulin is a mediator of the wound response. Nat Med. 2003;9:225–9.CrossRefPubMed
5.
Elkabets M, Gifford AM, Scheel C, Nilsson B, Reinhardt F, Bray MA, et al. Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. J Clin Invest. 2011;121:784–99.CrossRefPubMedPubMedCentral
6.
Monami G, Emiliozzi V, Bitto A, Lovat F, Xu SQ, Goldoni S, et al. Proepithelin regulates prostate cancer cell biology by promoting cell growth, migration, and anchorage-independent growth. Am J Pathol. 2009;174:1037–47.CrossRefPubMedPubMedCentral
7.
Kamrava M, Simpkins F, Alejandro E, Michener C, Meltzer E, Kohn EC. Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin-epithelin precursor (GEP), a prosurvival factor for ovarian cancer. Oncogene. 2005;24:7084–93.CrossRefPubMed
8.
Cheung ST, Cheung PF, Cheng CK, Wong NC, Fan ST. Granulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistance. Gastroenterology. 2011;140:344–55.CrossRefPubMed
9.
Cheung PF, Cheng CK, Wong NC, Ho JC, Yip CW, Lui VC, et al. Granulin-epithelin precursor is an oncofetal protein defining hepatic cancer stem cells. PLoS One. 2011;6:e28246.CrossRefPubMedPubMedCentral
10.
Serrero G. Autocrine growth factor revisited: PC-cell-derived growth factor (progranulin), a critical player in breast cancer tumorigenesis. Biochem Biophys Res Commun. 2003;308:409–13.CrossRefPubMed
11.
12.
13.
Fan ST. Hepatocellular carcinoma-resection or transplant? Nat Rev Gastroenterol Hepatol. 2012;9:732–7.CrossRefPubMed
14.
15.
Cheung ST, Wong SY, Leung KL, Chen X, So S, Ng IO, et al. Granulin-epithelin precursor overexpression promotes growth and invasion of hepatocellular carcinoma. Clin Cancer Res. 2004;10:7629–36.CrossRefPubMed
16.
Park MY, Park YS, Nam JH. RNA interference against granulin-epithelin precursor prevents hepatocellular carcinoma growth: its application as a therapeutic agent. Int J Oncol. 2011;39:853–61.PubMed
17.
Ho JC, Ip YC, Cheung ST, Lee YT, Chan KF, Wong SY, et al. Granulin-epithelin precursor as a therapeutic target for hepatocellular carcinoma. Hepatology. 2008;47:1524–32.CrossRefPubMed
18.
Wong NC, Cheung PF, Yip CW, Chan KF, Ng IO, Fan ST, et al. Antibody against granulin-epithelin precursor sensitizes hepatocellular carcinoma to chemotherapeutic agents. Mol Cancer Ther. 2014;13:3001–12.CrossRefPubMed
19.
Wong N, Lai P, Lee SW, Fan S, Pang E, Liew CT, et al. Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysis: relationship to disease stage, tumor size, and cirrhosis. Am J Pathol. 1999;154:37–43.CrossRefPubMedPubMedCentral
20.
Wong N, Lai P, Pang E, Leung TW, Lau JW, Johnson PJ. A comprehensive karyotypic study on human hepatocellular carcinoma by spectral karyotyping. Hepatology. 2000;32:1060–8.CrossRefPubMed
21.
Ginzinger DG, Godfrey TE, Nigro J, Moore 2nd DH, Suzuki S, Pallavicini MG, et al. Measurement of DNA copy number at microsatellite loci using quantitative PCR analysis. Cancer Res. 2000;60:5405–9.PubMed
22.
Patil MA, Chua MS, Pan KH, Lin R, Lih CJ, Cheung ST, et al. An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma. Oncogene. 2005;24:3737–47.CrossRefPubMed
23.
Or YY, Chung GT, To KF, Chow C, Choy KW, Tong CY, et al. Identification of a novel 12p13.3 amplicon in nasopharyngeal carcinoma. J Pathol. 2010;220:97–107.CrossRefPubMed
24.
Kim CH, Cheong JH, Kim JM. Correlation of granulin expression in intracranial meningiomas to clinical parameters. Exp Ther Med. 2010;1:493–6.PubMedPubMedCentral
25.
Kong WJ, Zhang SL, Chen X, Zhang S, Wang YJ, Zhang D, et al. PC cell-derived growth factor overexpression promotes proliferation and survival of laryngeal carcinoma. Anticancer Drugs. 2007;18:29–40.CrossRefPubMed
26.
Davidson B, Alejandro E, Flørenes VA, Goderstad JM, Risberg B, Kristensen GB, et al. Granulin-epithelin precursor is a novel prognostic marker in epithelial ovarian carcinoma. Cancer. 2004;100:2139–47.CrossRefPubMed
27.
Göbel M, Eisele L, Möllmann M, Hüttmann A, Johansson P, Scholtysik R, et al. Progranulin is a novel independent predictor of disease progression and overall survival in chronic lymphocytic leukemia. PLoS One. 2013;8:e72107.CrossRefPubMedPubMedCentral
28.
Tangkeangsirisin W, Hayashi J, Serrero G. PC cell-derived growth factor mediates tamoxifen resistance and promotes tumor growth of human breast cancer cells. Cancer Res. 2004;64:1737–43.CrossRefPubMed
29.
Wang W, Hayashi J, Kim WE, Serrero G. PC cell-derived growth factor (granulin precursor) expression and action in human multiple myeloma. Clin Cancer Res. 2003;9:2221–8.PubMed
30.
Pizarro GO, Zhou XC, Koch A, Gharib M, Raval S, Bible K, et al. Prosurvival function of the granulin-epithelin precursor is important in tumor progression and chemoresponse. Int J Cancer. 2007;120:2339–43.CrossRefPubMed
31.
Tangkeangsirisin W, Serrero G. PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells. Carcinogenesis. 2004;25:1587–92.CrossRefPubMed
32.
Wang W, Hayashi J, Serrero G. PC cell-derived growth factor confers resistance to dexamethasone and promotes tumorigenesis in human multiple myeloma. Clin Cancer Res. 2006;12:49–56.CrossRefPubMed
33.
Park B, Buti L, Lee S, Matsuwaki T, Spooner E, Brinkmann MM, et al. Granulin is a soluble cofactor for toll-like receptor 9 signaling. Immunity. 2011;34:505–13.CrossRefPubMed
34.
Cheung ST, Wong SY, Lee YT, Fan ST. GEP associates with wild-type p53 in hepatocellular carcinoma. Oncol Rep. 2006;15:1507–11.PubMed
35.
Diaz-Cueto L, Arechavaleta-Velasco F, Diaz-Arizaga A, Dominguez-Lopez P, Robles-Flores M. PKC signaling is involved in the regulation of progranulin (acrogranin/PC-cell-derived growth factor/granulin-epithelin precursor) protein expression in human ovarian cancer cell lines. Int J Gynecol Cancer. 2012;22:945–50.CrossRefPubMed
36.
Balakrishnan A, von Neuhoff N, Rudolph C, Kamphues K, Schraders M, Groenen P, et al. Quantitative microsatellite analysis to delineate the commonly deleted region 1p22.3 in mantle cell lymphomas. Genes Chromosomes Cancer. 2006;45:883–92.CrossRefPubMed
37.
Aghmesheh M, Suo Z, Friedlander M, Nesland JM, Kaern J, Stewart M, et al. Chromosome 2q24.2 is lost in sporadic but not in BRCA1-associated ovarian carcinomas. Pathology. 2006;38:145–51.CrossRefPubMed
38.
Yu Z, Liu Y, Shen Y, Wang M, Li A. CLImAT: accurate detection of copy number alteration and loss of heterozygosity in impure and aneuploid tumor samples using whole-genome sequencing data. Bioinformatics. 2014;30:2576–83.CrossRefPubMedPubMedCentral
39.
Li A, Liu Z, Lezon-Geyda K, Sarkar S, Lannin D, Schulz V, et al. GPHMM: an integrated hidden Markov model for identification of copy number alteration and loss of heterozygosity in complex tumor samples using whole genome SNP arrays. Nucleic Acids Res. 2011;39:4928–41.CrossRefPubMedPubMedCentral
40.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/college of American pathologists clinical practice guideline update. Arch Pathol Lab Med. 2014;138:241–56.CrossRefPubMed
41.
North JP, Garrido MC, Kolaitis NA, LeBoit PE, McCalmont TH, Bastian BC. Fluorescence in situ hybridization as an ancillary tool in the diagnosis of ambiguous melanocytic neoplasms: a review of 804 cases. Am J Surg Pathol. 2014;38:824–31.CrossRefPubMed
42.
Stewart CJ, Leung YC, Murch A, Peverall J: Evaluation of fluorescence in-situ hybridization in monomorphic endometrial stromal neoplasms and their histological mimics: a review of 49 cases. Histopathology. 2014. doi: 10.1111/his.12406
43.
Tseng YY, Moriarity BS, Gong W, Akiyama R, Tiwari A, Kawakami H, et al. PVT1 dependence in cancer with MYC copy-number increase. Nature. 2014;512:82–6.PubMedPubMedCentral
44.
Zitterbart K, Filkova H, Tomasikova L, Necesalova E, Zambo I, Kantorova D, et al. Low-level copy number changes of MYC genes have a prognostic impact in medulloblastoma. J Neurooncol. 2011;102:25–33.CrossRefPubMed
45.
Wolf M, Korja M, Karhu R, Edgren H, Kilpinen S, Ojala K, et al. Array-based gene expression, CGH and tissue data defines a 12q24 gain in neuroblastic tumors with prognostic implication. BMC Cancer. 2010;10:181.CrossRefPubMedPubMedCentral
46.
Midorikawa Y, Tsutsumi S, Nishimura K, Kamimura N, Kano M, Sakamoto H, et al. Distinct chromosomal bias of gene expression signatures in the progression of hepatocellular carcinoma. Cancer Res. 2004;64:7263–70.CrossRefPubMed
47.
Wong N, Yeo W, Wong WL, Wong NL, Chan KY, Mo FK, et al. TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance. Int J Cancer. 2009;124:644–52.CrossRefPubMed
48.
Nishida N, Nishimura T, Ito T, Komeda T, Fukuda Y, Nakao K. Chromosomal instability and human hepatocarcinogenesis. Histol Histopathol. 2003;18:897–909.PubMed
49.
Sakakura C, Hagiwara A, Taniguchi H, Yamaguchi T, Yamagishi H, Takahashi T, et al. Chromosomal aberrations in human hepatocellular carcinomas associated with hepatitis C virus infection detected by comparative genomic hybridization. Br J Cancer. 1999;80:2034–9.CrossRefPubMedPubMedCentral
50.
Fountzilas G, Dafni U, Bobos M, Kotoula V, Batistatou A, Xanthakis I, et al. Evaluation of the prognostic role of centromere 17 gain and HER2/topoisomerase II alpha gene status and protein expression in patients with breast cancer treated with anthracycline-containing adjuvant chemotherapy: pooled analysis of two Hellenic Cooperative Oncology Group (HeCOG) phase III trials. BMC Cancer. 2013;13:163.CrossRefPubMedPubMedCentral
51.
Liu J, Ahiekpor A, Li L, Li X, Arbuthnot P, Kew M, et al. Increased expression of ErbB-2 in liver is associated with hepatitis B x antigen and shorter survival in patients with liver cancer. Int J Cancer. 2009;125:1894–901.CrossRefPubMedPubMedCentral
52.
Yu MW, Chen CJ, Luo JC, Brandt-Rauf PW, Carney WP, Santella RM. Correlations of chronic hepatitis B virus infection and cigarette smoking with elevated expression of neu oncoprotein in the development of hepatocellular carcinoma. Cancer Res. 1994;54:5106–10.PubMed
53.
Hung CM, Huang WC, Pan HL, Chien PH, Lin CW, Chen LC, et al. Hepatitis B virus X upregulates HuR protein level to stabilize HER2 expression in hepatocellular carcinoma cells. Biomed Res Int. 2014;2014:827415.PubMedPubMedCentral
54.
Feitelson MA, Bonamassa B, Arzumanyan A. The roles of hepatitis B virus-encoded X protein in virus replication and the pathogenesis of chronic liver disease. Expert Opin Ther Targets. 2014;18:293–306.CrossRefPubMed
Metadata
Title
Copy number gain of granulin-epithelin precursor (GEP) at chromosome 17q21 associates with overexpression in human liver cancer
Authors
Man Kuen Yung
Kwok Wai Lo
Chi Wai Yip
Grace TY Chung
Carol YK Tong
Phyllis FY Cheung
Tan To Cheung
Ronnie TP Poon
Samuel So
Sheung Tat Fan
Siu Tim Cheung
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1294-x

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