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Gastric Cancer
Erschienen in: Gastric Cancer 4/2015

01.10.2015 | Original Article

A novel splice variant of XIAP-associated factor 1 (XAF1) is expressed in peripheral blood containing gastric cancer-derived circulating tumor cells

verfasst von: Keiichi Hatakeyama, Yushi Yamakawa, Yorikane Fukuda, Keiichi Ohshima, Kanako Wakabayashi-Nakao, Naoki Sakura, Yutaka Tanizawa, Yusuke Kinugasa, Ken Yamaguchi, Masanori Terashima, Tohru Mochizuki

Erschienen in: Gastric Cancer | Ausgabe 4/2015

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Abstract

Background

XIAP-associated factor 1 (XAF1) is ubiquitously expressed in normal tissues, but its suppression in cancer cells is strongly associated with tumor progression. Although downregulation of XAF1 is observed in tumors, its expression profile in the peripheral blood of cancer patients has not yet been investigated. Here, we identified a novel XAF1 splice variant in cancer cells and then investigated the expression level of this variant in peripheral blood containing gastric cancer-derived circulating tumor cells (CTCs).

Methods

To identify splice variants, RT-PCR and DNA sequencing were performed in mRNAs extracted from many cancer cells. We then carried out quantitative RT-PCR to investigate expression in peripheral blood from all 96 gastric cancer patients and 22 healthy volunteers.

Results

The XAF1 variant harbored a premature termination codon (PTC) and was differentially expressed in highly metastatic cancer cells versus the parental cells, and that nonsense-mediated mRNA decay (NMD) was suppressed in the variant-expressing cells. Furthermore, splice variants of XAF1 were upregulated in peripheral blood containing CTCs. In XAF1 variant-expressing patients, the expression levels of other NMD-targeted genes also increased, suggesting that the NMD pathway was suppressed in CTCs.

Conclusions

Our study identified a novel splice variant of XAF1 in cancer cells. This variant was regulated through the NMD pathway and accumulated in NMD-suppressed metastatic cancer cells and peripheral blood containing CTCs. The presence of XAF1 transcripts harboring the PTC in the peripheral blood may be useful as an indicator of NMD inhibition in CTCs.
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Literatur
1.
Liston P, Fong WG, Kelly NL, et al. Identification of XAF1 as an antagonist of XIAP anti-caspase activity. Nat Cell Biol. 2001;3(2):128–33.CrossRefPubMed
2.
Byun DS, Cho K, Ryu BK, et al. Hypermethylation of XIAP-associated factor 1, a putative tumor suppressor gene from the 17p13.2 locus, in human gastric adenocarcinomas. Cancer Res. 2003;63(21):7068–75.PubMed
3.
Arora V, Cheung HH, Plenchette S, et al. Degradation of survivin by the X-linked inhibitor of apoptosis (XIAP)-XAF1 complex. J Biol Chem. 2007;282(36):26202–9.CrossRefPubMed
4.
Tu SP, Liston P, Cui JT, et al. Restoration of XAF1 expression induces apoptosis and inhibits tumor growth in gastric cancer. Int J Cancer. 2009;125(3):688–97.CrossRefPubMed
5.
Huang J, Yao WY, Zhu Q, et al. XAF1 as a prognostic biomarker and therapeutic target in pancreatic cancer. Cancer Sci. 2010;101(2):559–67.CrossRefPubMed
6.
Sun PH, Zhu LM, Qiao MM, et al. The XAF1 tumor suppressor induces autophagic cell death via upregulation of Beclin-1 and inhibition of Akt pathway. Cancer Lett. 2011;310(2):170–80.PubMed
7.
Zou B, Chim CS, Pang R, et al. XIAP-associated factor 1 (XAF1), a novel target of p53, enhances p53-mediated apoptosis via post-translational modification. Mol Carcinog. 2012;51(5):422–32.CrossRefPubMed
8.
Fong WG, Liston P, Rajcan-Separovic E, et al. Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Genomics. 2000;70(1):113–22.CrossRefPubMed
9.
Zou B, Chim CS, Zeng H, et al. Correlation between the single-site CpG methylation and expression silencing of the XAF1 gene in human gastric and colon cancers. Gastroenterology. 2006;131(6):1835–43.CrossRefPubMed
10.
Lee MG, Huh JS, Chung SK, et al. Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses. Oncogene. 2006;25(42):5807–22.CrossRefPubMed
11.
Yin W, Cheepala S, Clifford JL. Identification of a novel splice variant of X-linked inhibitor of apoptosis-associated factor 1. Biochem Biophys Res Commun. 2006;339(4):1148–54.CrossRefPubMed
12.
Chung SK, Lee MG, Ryu BK, et al. Frequent alteration of XAF1 in human colorectal cancers: implication for tumor cell resistance to apoptotic stresses. Gastroenterology. 2007;132(7):2459–77.CrossRefPubMed
13.
Plenchette S, Cheung HH, Fong WG, et al. The role of XAF1 in cancer. Curr Opin Invest Drugs. 2007;8(6):469–76.
14.
Fang X, Liu Z, Fan Y, et al. Switch to full-length of XAF1 mRNA expression in prostate cancer cells by the DNA methylation inhibitor. Int J Cancer. 2006;118(10):2485–9.CrossRefPubMed
15.
16.
Mendell JT, Sharifi NA, Meyers JL, et al. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat Genet. 2004;36(10):1073–8.CrossRefPubMed
17.
18.
Gardner LB. Hypoxic inhibition of nonsense-mediated RNA decay regulates gene expression and the integrated stress response. Mol Cell Biol. 2008;28(11):3729–41.PubMedCentralCrossRefPubMed
19.
Wang D, Zavadil J, Martin L, et al. Inhibition of nonsense-mediated RNA decay by the tumor microenvironment promotes tumorigenesis. Mol Cell Biol. 2011;31(17):3670–80.PubMedCentralCrossRefPubMed
20.
Tani H, Torimura M, Akimitsu N. The RNA degradation pathway regulates the function of GAS5 a non-coding RNA in mammalian cells. PLoS One. 2013;8(1):e55684.PubMedCentralCrossRefPubMed
21.
Wang S, Zheng G, Cheng B, et al. Circulating tumor cells (CTCs) detected by RT-PCR and its prognostic role in gastric cancer: a meta-analysis of published literature. PLoS One. 2014;9(6):e99259.PubMedCentralCrossRefPubMed
22.
Powell AA, Talasaz AH, Zhang H, et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One. 2012;7(5):e33788.PubMedCentralCrossRefPubMed
23.
24.
25.
Savagner P, Valles AM, Jouanneau J, et al. Alternative splicing in fibroblast growth factor receptor 2 is associated with induced epithelial-mesenchymal transition in rat bladder carcinoma cells. Mol Biol Cell. 1994;5(8):851–62.PubMedCentralCrossRefPubMed
26.
Pino MS, Balsamo M, Di Modugno F, et al. Human Mena+11a isoform serves as a marker of epithelial phenotype and sensitivity to epidermal growth factor receptor inhibition in human pancreatic cancer cell lines. Clin Cancer Res. 2008;14(15):4943–50.PubMedCentralCrossRefPubMed
27.
Warzecha CC, Sato TK, Nabet B, et al. ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol Cell. 2009;33(5):591–601.PubMedCentralCrossRefPubMed
28.
Shapiro IM, Cheng AW, Flytzanis NC, et al. An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet. 2011;7(8):e1002218.PubMedCentralCrossRefPubMed
29.
Valacca C, Bonomi S, Buratti E, et al. Sam68 regulates EMT through alternative splicing-activated nonsense-mediated mRNA decay of the SF2/ASF proto-oncogene. J Cell Biol. 2010;191(1):87–99.PubMedCentralCrossRefPubMed
30.
Fujita Y, Terashima M, Hoshino Y, et al. Detection of cancer cells disseminated in bone marrow using real-time quantitative RT-PCR of CEA, CK19, and CK20 mRNA in patients with gastric cancer. Gastric Cancer. 2006;9(4):308–14.CrossRefPubMed
31.
Huang P, Wang J, Guo Y, et al. Molecular detection of disseminated tumor cells in the peripheral blood in patients with gastrointestinal cancer. J Cancer Res Clin Oncol. 2003;129(3):192–8.PubMed
32.
Ishigami S, Sakamoto A, Uenosono Y, et al. Carcinoembryonic antigen messenger RNA expression in blood can predict relapse in gastric cancer. J Surg Res. 2008;148(2):205–9.CrossRefPubMed
33.
Helo P, Cronin AM, Danila DC, et al. Circulating prostate tumor cells detected by reverse transcription-PCR in men with localized or castration-refractory prostate cancer: concordance with Cell Search assay and association with bone metastases and with survival. Clin Chem. 2009;55(4):765–73.PubMedCentralCrossRefPubMed
34.
Danila DC, Anand A, Schultz N, et al. Analytic and clinical validation of a prostate cancer-enhanced messenger RNA detection assay in whole blood as a prognostic biomarker for survival. Eur Urol 2014;65(6):1191–7
35.
Cao W, Yang W, Li H, et al. Using detection of survivin-expressing circulating tumor cells in peripheral blood to predict tumor recurrence following curative resection of gastric cancer. J Surg Oncol. 2011;103(2):110–5.CrossRefPubMed
36.
Cao M, Yie SM, Wu SM, et al. Detection of survivin-expressing circulating cancer cells in the peripheral blood of patients with esophageal squamous cell carcinoma and its clinical significance. Clin Exp Metastasis. 2009;26(7):751–8.CrossRefPubMed
37.
Ivanov I, Lo KC, Hawthorn L, et al. Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells. Oncogene. 2007;26(20):2873–84.CrossRefPubMed
38.
Robin X, Turck N, Hainard A, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinform. 2011;12:77.CrossRef
39.
Xia J, Broadhurst DI, Wilson M, et al. Translational biomarker discovery in clinical metabolomics: an introductory tutorial. Metabolomics. 2013;9(2):280–99.PubMedCentralCrossRefPubMed
40.
Huang L, Lou CH, Chan W, et al. RNA homeostasis governed by cell type-specific and branched feedback loops acting on NMD. Mol Cell. 2011;43(6):950–61.PubMedCentralCrossRefPubMed
41.
42.
Schroeder A, Mueller O, Stocker S, et al. The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC Mol Biol. 2006;7:3.PubMedCentralCrossRefPubMed
43.
44.
Yie SM, Lou B, Ye SR, et al. Detection of survivin-expressing circulating cancer cells (CCCs) in peripheral blood of patients with gastric and colorectal cancer reveals high risks of relapse. Ann Surg Oncol. 2008;15(11):3073–82.CrossRefPubMed
45.
Bertazza L, Mocellin S, Marchet A, et al. Survivin gene levels in the peripheral blood of patients with gastric cancer independently predict survival. J Transl Med. 2009;7:111.PubMedCentralCrossRefPubMed
46.
Hoffmann AC, Warnecke-Eberz U, Luebke T, et al. Survivin mRNA in peripheral blood is frequently detected and significantly decreased following resection of gastrointestinal cancers. J Surg Oncol. 2007;95(1):51–4.CrossRefPubMed
47.
Terashima M, Yamakawa Y, Hatakeyama K, et al. Survivin expression in peripheral blood as a prognostic marker in patients with gastric cancer. J Clin Oncol 2014;32(suppl 15).
48.
Black DL. Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem. 2003;72:291–336.CrossRefPubMed
49.
Birney E, Andrews D, Bevan P, et al. Ensembl 2004. Nucleic Acids Res 2004;32(database issue):D468–D470.
50.
51.
Furuta K, Arao T, Sakai K, et al. Integrated analysis of whole genome exon array and array-comparative genomic hybridization in gastric and colorectal cancer cells. Cancer Sci. 2012;103(2):221–7.CrossRefPubMed
52.
Hatakeyama K, Ohshima K, Fukuda Y, et al. Identification of a novel protein isoform derived from cancer-related splicing variants using combined analysis of transcriptome and proteome. Proteomics. 2011;11(11):2275–82.CrossRefPubMed
53.
Pastor F, Kolonias D, Giangrande PH, et al. Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay. Nature (Lond). 2010;465(7295):227–30.CrossRef
54.
Bonomi S, di Matteo A, Buratti E, et al. HnRNP A1 controls a splicing regulatory circuit promoting mesenchymal-to-epithelial transition. Nucleic Acids Res. 2013;41(18):8665–79.PubMedCentralCrossRefPubMed
55.
Garcia-Olmo DC, Ruiz-Piqueras R, Garcia-Olmo D. Circulating nucleic acids in plasma and serum (CNAPS) and its relation to stem cells and cancer metastasis: state of the issue. Histol Histopathol. 2004;19(2):575–83.PubMed
56.
Valadi H, Ekstrom K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.CrossRefPubMed
57.
Ohshima K, Inoue K, Fujiwara A, et al. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One. 2010;5(10):e13247.PubMedCentralCrossRefPubMed
58.
Meng S, Tripathy D, Shete S, et al. HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci USA. 2004;101(25):9393–8.PubMedCentralCrossRefPubMed
59.
Gradilone A, Petracca A, Nicolazzo C, et al. Prognostic significance of survivin-expressing circulating tumour cells in T1G3 bladder cancer. BJU Int. 2010;106(5):710–5.CrossRefPubMed
60.
Krebs MG, Hou JM, Sloane R, et al. Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches. J Thorac Oncol. 2012;7(2):306–15.CrossRefPubMed
61.
Zhao L, Li P, Li F, et al. The prognostic value of circulating tumor cells lacking cytokeratins in metastatic breast cancer patients. J Cancer Res Ther. 2013;9(1):29–37.CrossRefPubMed
62.
Hosokawa M, Kenmotsu H, Koh Y, et al. Size-based isolation of circulating tumor cells in lung cancer patients using a microcavity array system. PLoS One. 2013;8(6):e67466.PubMedCentralCrossRefPubMed
63.
Wang J, He H, Yu L, et al. HSF1 down-regulates XAF1 through transcriptional regulation. J Biol Chem. 2006;281(5):2451–9.CrossRefPubMed
64.
Zhang W, Guo Z, Jiang B, et al. Identification of a functional p53 responsive element within the promoter of XAF1 gene in gastrointestinal cancer cells. Int J Oncol. 2010;36(4):1031–7.PubMed
65.
Leaman DW, Chawla-Sarkar M, Vyas K, et al. Identification of X-linked inhibitor of apoptosis-associated factor-1 as an interferon-stimulated gene that augments TRAIL Apo2L-induced apoptosis. J Biol Chem. 2002;277(32):28504–11.CrossRefPubMed
66.
Chawla-Sarkar M, Lindner DJ, Liu YF, et al. Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. Apoptosis. 2003;8(3):237–49.CrossRefPubMed
67.
Wang J, Peng Y, Sun YW, et al. All-trans retinoic acid induces XAF1 expression through an interferon regulatory factor-1 element in colon cancer. Gastroenterology. 2006;130(3):747–58.CrossRefPubMed
68.
Micali OC, Cheung HH, Plenchette S, et al. Silencing of the XAF1 gene by promoter hypermethylation in cancer cells and reactivation to TRAIL-sensitization by IFN-beta. BMC Cancer. 2007;7:52.PubMedCentralCrossRefPubMed
69.
Reu FJ, Bae SI, Cherkassky L, et al. Overcoming resistance to interferon-induced apoptosis of renal carcinoma and melanoma cells by DNA demethylation. J Clin Oncol. 2006;24(23):3771–9.CrossRefPubMed
70.
71.
Gakhar G, Navarro VN, Jurish M, et al. Circulating tumor cells from prostate cancer patients interact with E-selectin under physiologic blood flow. PLoS One. 2013;8(12):e85143.PubMedCentralCrossRefPubMed
72.
Kutun S, Celik A, Cem Kockar M, et al. Expression of CK-19 and CEA mRNA in peripheral blood of gastric cancer patients. Exp Oncol. 2010;32(4):263–8.PubMed
73.
Schulze K, Gasch C, Staufer K, et al. Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Int J Cancer. 2013;133(9):2165–71.CrossRefPubMed
74.
Partridge M, Brakenhoff R, Phillips E, et al. Detection of rare disseminated tumor cells identifies head and neck cancer patients at risk of treatment failure. Clin Cancer Res. 2003;9(14):5287–94.PubMed
75.
Hristozova T, Konschak R, Stromberger C, et al. The presence of circulating tumor cells (CTCs) correlates with lymph node metastasis in nonresectable squamous cell carcinoma of the head and neck region (SCCHN). Ann Oncol. 2011;22(8):1878–85.CrossRefPubMed
76.
Metadaten
Titel
A novel splice variant of XIAP-associated factor 1 (XAF1) is expressed in peripheral blood containing gastric cancer-derived circulating tumor cells
verfasst von
Keiichi Hatakeyama
Yushi Yamakawa
Yorikane Fukuda
Keiichi Ohshima
Kanako Wakabayashi-Nakao
Naoki Sakura
Yutaka Tanizawa
Yusuke Kinugasa
Ken Yamaguchi
Masanori Terashima
Tohru Mochizuki
Publikationsdatum
01.10.2015
Verlag
Springer Japan
Erschienen in
Gastric Cancer / Ausgabe 4/2015
Print ISSN: 1436-3291
Elektronische ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-014-0426-3

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