Roles of ZIC family genes in human gastric cancer

Ma,Gang; Dai,Weijie; Sang,Aiyu; Yang,Xiaozhong; Li,Qianjun

doi:10.3892/ijmm.2016.2587

Roles of ZIC family genes in human gastric cancer

Authors:
- Gang Ma
- Weijie Dai
- Aiyu Sang
- Xiaozhong Yang
- Qianjun Li
View Affiliations

Affiliations: Department of Gastroenterology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China, Department of Internal Medicine, Lianshui Third People's Hospital, Lianshui, Jiangsu 223411, P.R. China
Published online on: May 12, 2016 https://doi.org/10.3892/ijmm.2016.2587
Pages: 259-266

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The human zinc finger of the cerebellum (ZIC)family genes, comprised of 5 members, which are vertebrate homologues of the Drosophila odd-paired gene and encode zinc-finger transcription factors, have been shown to be involved in various diseases, including cancer. However, the roles of ZICs in human gastric cancer (GC) have not yet been fully elucidated. This study aimed to investigate the expression patterns of ZICs and determine their clinical significance in GC. The mRNA and protein expression levels of ZIC1-5 were detected by RT-qPCR and western blot analysis, respectively using 60 pairs of human GC and matched normal mucosa tissues. The expression pattern and subcellular localization of ZIC1 in 160 pairs of human GC and matched normal mucosa tissues were verified by immunohistochemistry. Moreover, the associations of ZIC1 expression with various clinicopathological characteristics and patient prognosis were evaluated. The mRNA and protein expression levels of ZIC1 were both found to be significantly decreased in the GC tissues compared to matched normal mucosa tissues (GC vs. normal, 2.15±0.69 vs. 4.28±0.95; P<0.001); however, ZIC2-5 expression exhibited no significant difference between the cancer and normal tissue samples. In addition, the downregulation of ZIC1 (ZIC1-low) was more frequently observed in the GC tissues with positive lymph node metastasis (P=0.006), an advanced TNM stage (P<0.001) and a great depth of invasion (P=0.01). Notably, a low ZIC1 expression was significantly associated with a poor disease-free and overall survival. Furthermore, multivariate analysis revealed that ZIC1 expression was an independent prognostic marker for patients with GC. In conclusion, among the human ZIC family genes, the dysregulation of ZIC1, but not of ZIC2, ZIC3, ZIC4 and ZIC5, may play a crucial role in the progression of GC. ZIC1 may thus serve as a novel molecular marker to predict the progression, survival and relapse of patients with GC.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Colquhoun A, Arnold M, Ferlay J, Goodman KJ, Forman D and Soerjomataram I: Global patterns of cardia and non-cardia gastric cancer incidence in 2012. Gut. 64:1881–1888. 2015. View Article : Google Scholar : PubMed/NCBI
3	Qian X, Hu J, Zhao J and Chen H: ATP citrate lyase expression is associated with advanced stage and prognosis in gastric adenocarcinoma. Int J Clin Exp Med. 8:7855–7860. 2015.PubMed/NCBI
4	Rahman R, Asombang AW and Ibdah JA: Characteristics of gastric cancer in Asia. World J Gastroenterol. 20:4483–4490. 2014. View Article : Google Scholar : PubMed/NCBI
5	He ZX and Li B: Recent progress in genetic and epigenetic profile of diffuse gastric cancer. Cancer Transl Med. 1:80–93. 2015. View Article : Google Scholar
6	Hashimoto T, Arai K, Yamashita Y, Iwasaki Y and Hishima T: Characteristics of intramural metastasis in gastric cancer. Gastric Cancer. 16:537–542. 2013. View Article : Google Scholar : PubMed/NCBI
7	Kanda M and Kodera Y: Recent advances in the molecular diagnostics of gastric cancer. World J Gastroenterol. 21:9838–9852. 2015. View Article : Google Scholar : PubMed/NCBI
8	Ali RG, Bellchambers HM and Arkell RM: Zinc fingers of the cerebellum (Zic): Transcription factors and co-factors. Int J Biochem Cell Biol. 44:2065–2068. 2012. View Article : Google Scholar : PubMed/NCBI
9	Houtmeyers R, Souopgui J, Tejpar S and Arkell R: The ZIC gene family encodes multi-functional proteins essential for patterning and morphogenesis. Cell Mol Life Sci. 70:3791–3811. 2013. View Article : Google Scholar : PubMed/NCBI
10	Bataller L, Wade DF, Fuller GN, Rosenfeld MR and Dalmau J: Cerebellar degeneration and autoimmunity to zinc-finger proteins of the cerebellum. Neurology. 59:1985–1987. 2002. View Article : Google Scholar : PubMed/NCBI
11	Sakurai H, Kikuchi K, Tsuchiya T, Kanazawa H and Tsuda M: Developmentally and regionally regulated alterations of octamer- and GC-box-binding activities during the postnatal development of mouse cerebellum. Brain Res Dev Brain Res. 61:161–168. 1991. View Article : Google Scholar : PubMed/NCBI
12	Aruga J, Nagai T, Tokuyama T, Hayashizaki Y, Okazaki Y, Chapman VM and Mikoshiba K: The mouse zic gene family. Homologues of the Drosophila pair-rule gene odd-paired. J Biol Chem. 271:1043–1047. 1996. View Article : Google Scholar : PubMed/NCBI
13	Lacroix J, Schlund F, Leuchs B, Adolph K, Sturm D, Bender S, Hielscher T, Pfister SM, Witt O, Rommelaere J, et al: Oncolytic effects of parvovirus H-1 in medulloblastoma are associated with repression of master regulators of early neurogenesis. Int J Cancer. 134:703–716. 2014. View Article : Google Scholar :
14	Qiang W, Zhao Y, Yang Q, Liu W, Guan H, Lv S, Ji M, Shi B and Hou P: ZIC1 is a putative tumor suppressor in thyroid cancer by modulating major signaling pathways and transcription factor FOXO3a. J Clin Endocrinol Metab. 99:E1163–E1172. 2014. View Article : Google Scholar : PubMed/NCBI
15	Wang LJ, Jin HC, Wang X, Lam EK, Zhang JB, Liu X, Chan FK, Si JM and Sung JJ: ZIC1 is downregulated through promoter hypermethylation in gastric cancer. Biochem Biophys Res Commun. 379:959–963. 2009. View Article : Google Scholar : PubMed/NCBI
16	Zhong J, Chen S, Xue M, Du Q, Cai J, Jin H, Si J and Wang L: ZIC1 modulates cell-cycle distributions and cell migration through regulation of sonic hedgehog, PI(3)K and MAPK signaling pathways in gastric cancer. BMC Cancer. 12:2902012. View Article : Google Scholar : PubMed/NCBI
17	Chen X, Lin Z, Xue M, Si J and Chen S: Zic1 promoter hypermethylation in plasma DNA is a potential biomarker for gastric cancer and intraepithelial neoplasia. PLoS One. 10:e01339062015. View Article : Google Scholar : PubMed/NCBI
18	Gan L, Chen S, Zhong J, Wang X, Lam EK, Liu X, Zhang J, Zhou T, Yu J, Si J, et al: ZIC1 is downregulated through promoter hypermethylation, and functions as a tumor suppressor gene in colorectal cancer. PLoS One. 6:e169162011. View Article : Google Scholar : PubMed/NCBI
19	Wong YF, Cheung TH, Lo KW, Yim SF, Siu NS, Chan SC, Ho TW, Wong KW, Yu MY, Wang VW, et al: Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling. Oncogene. 26:1971–1982. 2007. View Article : Google Scholar
20	Pourebrahim R, Van Dam K, Bauters M, De Wever I, Sciot R, Cassiman JJ and Tejpar S: ZIC1 gene expression is controlled by DNA and histone methylation in mesenchymal proliferations. FEBS Lett. 581:5122–5126. 2007. View Article : Google Scholar : PubMed/NCBI
21	Vural B, Chen LC, Saip P, Chen YT, Ustuner Z, Gonen M, Simpson AJ, Old LJ, Ozbek U and Gure AO: Frequency of SOX Group B (SOX1, 2, 3) and ZIC2 antibodies in Turkish patients with small cell lung carcinoma and their correlation with clinical parameters. Cancer. 103:2575–2583. 2005. View Article : Google Scholar : PubMed/NCBI
22	Inaguma S, Ito H, Riku M, Ikeda H and Kasai K: Addiction of pancreatic cancer cells to zinc-finger transcription factor ZIC2. Oncotarget. 6:28257–28268. 2015. View Article : Google Scholar : PubMed/NCBI
23	Marchini S, Poynor E, Barakat RR, Clivio L, Cinquini M, Fruscio R, Porcu L, Bussani C, D'Incalci M, Erba E, et al: The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical course of epithelial ovarian cancer. Clin Cancer Res. 18:4313–4324. 2012. View Article : Google Scholar : PubMed/NCBI
24	Chan DW, Liu VW, Leung LY, Yao KM, Chan KK, Cheung AN and Ngan HY: Zic2 synergistically enhances hedgehog signalling through nuclear retention of Gli1 in cervical cancer cells. J Pathol. 225:525–534. 2011. View Article : Google Scholar : PubMed/NCBI
25	Kandimalla R, van Tilborg AA, Kompier LC, Stumpel DJ, Stam RW, Bangma CH and Zwarthoff EC: Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers. Eur Urol. 61:1245–1256. 2012. View Article : Google Scholar : PubMed/NCBI
26	Aruga J, Nozaki Y, Hatayama M, Odaka YS and Yokota N: Expression of ZIC family genes in meningiomas and other brain tumors. BMC Cancer. 10:792010. View Article : Google Scholar : PubMed/NCBI
27	Degreef I, De Smet L, Sciot R, Cassiman JJ and Tejpar S: Immunohistochemical evidence for Zic1 coexpression with beta-catenin in the myofibroblast of Dupuytren disease. Scand J Plast Reconstr Surg Hand Surg. 43:36–40. 2009. View Article : Google Scholar : PubMed/NCBI
28	Sabater L, Bataller L, Suárez-Calvet M, Saiz A, Dalmau J and Graus F: ZIC antibodies in paraneoplastic cerebellar degeneration and small cell lung cancer. J Neuroimmunol. 201–202:163–165. 2008. View Article : Google Scholar
29	Merzdorf CS: Emerging roles for zic genes in early development. Dev Dyn. 236:922–940. 2007. View Article : Google Scholar : PubMed/NCBI
30	Brill E, Gobble R, Angeles C, Lagos-Quintana M, Crago A, Laxa B, Decarolis P, Zhang L, Antonescu C, Socci ND, et al: ZIC1 overexpression is oncogenic in liposarcoma. Cancer Res. 70:6891–6901. 2010. View Article : Google Scholar : PubMed/NCBI