Esophageal cancer is a major global health burden with a strong host–environment interaction component and epigenomics underpinnings that remain to be elucidated further. Certain populations such as the Northeast Indians suffer at a disproportionately higher rate from this devastating disease. Promoter methylation is correlated with transcriptional silencing of various genes in esophageal cancer. Very few studies on genome-wide methylation for esophageal cancer exist and yet, no one has carried out an integromics analysis of methylation and gene expression. In the present study, genome-wide methylation was measured in samples collected from the Northeast Indian population by Infinium 450k array, and integration of the methylation data was performed. To prepare a network of genes displaying enriched pathways, together with the list of genes exhibiting promoter hypermethylation or hypomethylation with inversely correlated expression, we performed an integrome analysis. We identified 23 Integrome network enriched genes with relevance to tumor progression and associated with the processes involved in metastasis such as cell adhesion, integrin signaling, cytoskeleton, and extracellular matrix organizations. These included four genes (PTK2, RND1, RND3, and UBL3) with promoter hypermethylation and downregulation, and 19 genes (SEMG2, CD97, CTNND2, CADM3, OMD, NEFM, FBN2, CTNNB1, DLX6, UGT2B4, CCDC80, PZP, SERPINA4, TNFSF13B, NPC1, COL1A1, TAC3, BMP8A, and IL22RA2) with promoter hypomethylation and upregulation. A Methylation Efficiency Index was further calculated for these genes; the top five gene with the highest index were COL1A1, TAC3, SERPINA4, TNFSF13B, and IL22RA2. In conclusion, we recommend that the circulatory proteins IL22RA2, TNFSF13B, SERPINA4, and TAC3 in serum of patients and disease-free healthy controls can be examined in the future as putative noninvasive biomarkers.
Get full access to this article
View all access options for this article.
References
1.
AhnJM, SungHJ, YoonYH, et al. (2014). Integrated glycoproteomics demonstrates fucosylated serum paraoxonase 1 alterations in small cell lung cancer. Mol Cell Proteomics, 13, 30–48.
2.
BakerM. (2013). Big biology: The 'omes puzzle. Nature, 494, 416–419.
3.
BibikovaM, BarnesB, TsanC, et al. (2011). High density DNA methylation array with single CpG site resolution. Genomics, 98, 288–295.
4.
ChattopadhyayI, SinghA, PhukanR, et al. (2010). Genome-wide analysis of chromosomal alterations in patients with esophageal squamous cell carcinoma exposed to tobacco and betel quid from high-risk area in India. Mutat Res, 696, 130–138.
5.
ChattopadhyayI, KapurS, PurkayasthaJ, et al. (2007). Gene expression profile of esophageal cancer in North East India by cDNA microarray analysis. World J Gastroenterol, 13, 1438–1444.
6.
ChattopadhyayI, PhukanR, SinghA, et al. (2009). Molecular profiling to identify molecular mechanism in esophageal cancer with familial clustering. Oncol Rep, 21, 1135–1146.
7.
ChiangJH, ChengWS, HoodL, and TianQ. (2014). An epigenetic biomarker panel for glioblastoma multiforme personalized medicine through DNA methylation analysis of human embryonic stem cell-like signature. OMICS, 18, 310–323.
8.
ChongY, Mia-JanK, RyuH, et al. (2014). DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis. Oncol Rep, 31, 2535–2544.
9.
DasM, SaikiaBJ, SharmaSK, SekhonGS, MahantaJ, and PhukanRK. (2015). p16 hypermethylation: A biomarker for increased esophageal cancer susceptibility in high incidence region of North East India. Tumour Biol, 36, 1627–1642.
10.
DasM, SharmaSK, SekhonGS, SaikiaBJ, MahantaJ, and PhukanRK. (2014). Promoter methylation of MGMT gene in serum of patients with esophageal squamous cell carcinoma in North East India. Asian Pac J Cancer Prev, 15, 9955–9960.
11.
Di CarloE, D'AntuonoT, PompaP, et al. (2009). The lack of epithelial interleukin-7 and BAFF/BLyS gene expression in prostate cancer as a possible mechanism of tumor escape from immunosurveillance. Clin Cancer Res, 15, 2979–2987.
12.
DimitrakopoulouK, DimitrakopoulosGN, SgarbasKN, and BezerianosA. (2014). Tamoxifen integromics and personalized medicine: Dynamic modular transformations underpinning response to tamoxifen in breast cancer treatment. OMICS, 18, 15–33.
13.
DumoutierL, LejeuneD, ColauD, and RenauldJC. (2001). Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22. J Immunol, 166, 7090–7095.
14.
FangMZ, JinZ, WangY, et al. (2005). Promoter hypermethylation and inactivation of O(6)-methylguanine-DNA methyltransferase in esophageal squamous cell carcinomas and its reactivation in cell lines. Int J Oncol, 26, 615–622.
15.
FridleyBL, AboR, TanXL, et al. (2014). Integrative gene set analysis: Application to platinum pharmacogenomics. OMICS, 18, 34–41.
16.
HermanJG, and BaylinSB. (2003). Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med, 349, 2042–2054.
17.
HuangKF, HuangXP, XiaoGQ, YangHY, LinJS, and DiaoY. (2014). Kallistatin, a novel anti-angiogenesis agent, inhibits angiogenesis via inhibition of the NF-κB signaling pathway. Biomed Pharmacother, 68, 455–461.
18.
HuberO, BertrandC, BunnettNW, et al. (1993). Tachykinins contract the circular muscle of the human esophageal body in vitro via NK2 receptors. Gastroenterology, 105, 981–987.
19.
HuberS, GaglianiN, ZenewiczLA, et al. (2012). IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature, 491, 259–263.
20.
Ibanez de CaceresI, DulaimiE, HoffmanAM, Al-SaleemT, UzzoRG, and CairnsP. (2006). Identification of novel target genes by an epigenetic reactivation screen of renal cancer. Cancer Res, 66, 5021–5028.
21.
JablonskaE, SlodczykB, Wawrusiewicz-KurylonekN, et al. (2011). Overexpression of B cell-activating factor (BAFF) in neutrophils of oral cavity cancer patients—Preliminary study. Neoplasma, 58, 211–216.
22.
JabłońskaE, Wawrusiewicz-KurylonekN, GarleyM, et al. (2012). A proliferation-inducing ligand (APRIL) in neutrophils of patients with oral cavity squamous cell carcinoma. Eur Cytokine Netw, 23, 93–100.
23.
JiangX, LiH, QiaoH, JiangH, XuR, and SunX. (2009). Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice. Cancer Sci, 100, 2226–2233.
24.
JinZ, OlaruA, YangJ, et al. (2007) Hypermethylation of tachykinin-1 is a potential biomarker in human esophageal cancer. Clin Cancer Res, 13, 6293–6300.
25.
KalledSL, AmbroseC, and HsuYM. (2005). The biochemistry and biology of BAFF, APRIL and their receptors. Curr Dir Autoimmun, 8, 206–242.
26.
KarlssonA, JönssonM, LaussM, et al. (2014). Genome-wide DNA methylation analysis of lung carcinoma reveals one neuroendocrine and four adenocarcinoma epitypes associated with patient outcome. Clin Cancer Res, 20, 6127–6140.
27.
KoppertLB, WijnhovenBP, van DekkenH, TilanusHW, and DinjensWN. (2005). The molecular biology of esophageal adenocarcinoma. J Surg Oncol, 92, 169–190.
28.
KrysiakPS, and PreiksaitisHG. (2001). Tachykinins contribute to nerve-mediated contractions in the human esophagus. Gastroenterology, 120, 39–48.
29.
LiJS, YingJM, WangXW, WangZH, TaoQ, and LiLL. (2013). Promoter methylation of tumor suppressor genes in esophageal squamous cell carcinoma. Chin J Cancer, 32, 3–11.
30.
LiX, ZhouF, JiangC, et al. (2014). Identification of a DNA methylome profile of esophageal squamous cell carcinoma and potential plasma epigenetic biomarkers for early diagnosis. PLoS One, 9, e103162.
31.
LimaSC, Hernández-VargasH, SimãoT, et al. (2011). Identification of a DNA methylome signature of esophageal squamous cell carcinoma and potential epigenetic biomarkers. Epigenetics, 6, 1217–1227.
32.
LindqvistBM, WingrenS, MotlaghPB, and NilssonTK. (2014). Whole genome DNA methylation signature of HER2-positive breast cancer. Epigenetics, 9, 1149–1162.
33.
Milutin GašperovN, FarkasSA, NilssonTK, and GrceM. (2014). Epigenetic activation of immune genes in cervical cancer. Immunol Lett, 162, 256–257.
34.
O'ConnellJ, O'SullivanGC, CollinsJK, and ShanahanF. (1996). The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med, 184, 1075–1082.
35.
OhashiH, and Miyamoto-SatoE. (2014). Towards personalized medicine mediated by in vitro virus-based interactome approaches. Int J Mol Sci, 15, 6717–6724.
36.
PennefatherJN, LecciA, CandenasML, PatakE, PintoFM, and MaggiCA. (2004). Tachykinins and tachykinin receptors: A growing family. Life Sci, 74, 1445–1463.
37.
PhukanRK, AliMS, ChetiaCK, and MahantaJ. (2001). Betel nut and tobacco chewing; potential risk factors of cancer of oesophagus in Assam, India. Br J Cancer, 85, 661–667.
38.
PodderA, and LathaN. (2014). New insights into schizophrenia disease genes interactome in the human brain: Emerging targets and therapeutic implications in the postgenomics era. OMICS, 18, 754–766.
39.
SchulmannK, SterianA, BerkiA, et al. (2005). Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk. Oncogene, 24, 4138–4148.
40.
SharmaP, and SharmaR. (2015). miRNA–mRNA crosstalk in esophageal cancer: From diagnosis to therapy. Crit Rev Oncol Hematol. pii: S1040-8428(15)30002-0. doi: 10.1016/j.critrevonc.2015.07.002.
41.
ShiauAL, TeoML, ChenSY, et al. (2010). Inhibition of experimental lung metastasis by systemic lentiviral delivery of kallistatin. BMC Cancer, 10, 245.
42.
SonnenbergGF, FouserLA, and ArtisD. (2010). Functional biology of the IL-22-IL-22R pathway in regulating immunity and inflammation at barrier surfaces. Adv Immunol, 107, 1–29.
43.
StrandS, HofmannWJ, HugH, et al. (1996). Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells—A mechanism of immune evasion?. Nat Med, 2, 1361–1336.
44.
TecchioC, ScapiniP, PizzoloG, and CassatellaMA. (2013). On the cytokines produced by human neutrophils in tumors. Semin Cancer Biol, 23, 159–170.
45.
TseLY, SunX, JiangH, et al. (2008). Adeno-associated virus-mediated expression of kallistatin suppresses local and remote hepatocellular carcinomas. J Gene Med, 10, 508–517.
46.
VidalM, CusickME, and BarabásiAL. (2011). Interactome networks and human disease. Cell, 144, 986–998.
47.
WalchAK, ZitzelsbergerHF, BruchJ, et al. (2000). Chromosomal imbalances in Barrett's adenocarcinoma and the metaplasia-dysplasia-carcinoma sequence. Am J Pathol, 156, 555–566.
48.
WardenCD, LeeH, TompkinsJD, et al. (2013). COHCAP: An integrative genomic pipeline for single-nucleotide resolution DNA methylation analysis. Nucleic Acids Res, 41, e117.
49.
WongFH, HuangCY, SuLJ, et al. (2009). Combination of microarray profiling and protein-protein interaction databases delineates the minimal discriminators as a metastasis network for esophageal squamous cell carcinoma. Int J Oncol, 34, 117–128.
50.
ZhangJ, YangZ, LiP, BledsoeG, ChaoL, and ChaoJ. (2013). Kallistatin antagonizes Wnt/β-catenin signaling and cancer cell motility via binding to low-density lipoprotein receptor-related protein 6. Mol Cell Biochem, 379, 295–301.
51.
ZhiX, LinL, YangS, et al. (2015). βII-Spectrin (SPTBN1) suppresses progression of hepatocellular carcinoma and Wnt signaling by regulation of Wnt inhibitor kallistatin. Hepatology, 61, 598–612.
52.
ZhuB, LuL, CaiW, et al. (2007). Kallikrein-binding protein inhibits growth of gastric carcinoma by reducing vascular endothelial growth factor production and angiogenesis. Mol Cancer Ther, 6, 3297–3306.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
