High level of homeobox A9 and PBX homeobox 3 expression in gastric cancer correlates with poor prognosis

Ma,Ying‑Yu; Zhang,Yuancheng; Mou,Xiao‑Zhou; Liu,Zheng‑Chuang; Ru,Guo‑Qing; Li,Erguang

doi:10.3892/ol.2017.6937

High level of homeobox A9 and PBX homeobox 3 expression in gastric cancer correlates with poor prognosis

Authors:
- Ying‑Yu Ma
- Yuancheng Zhang
- Xiao‑Zhou Mou
- Zheng‑Chuang Liu
- Guo‑Qing Ru
- Erguang Li
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Affiliations: Medical School and Jiangsu Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, P.R. China, Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China, Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China, Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
Published online on: September 14, 2017 https://doi.org/10.3892/ol.2017.6937
Pages: 5883-5889
Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The homeobox protein homeobox (HOXA9) is a transcriptional factor that regulates patterning during embryogenesis and controls cell differentiation. HOXA9 dysfunction has been implicated in certain cancers. However, the role of HOXA9 in gastric cancer is poorly understood. The present study investigated HOXA9 and its cofactor PBX homeobox 3 (PBX3) expression in patients with gastric cancer. Paired tissue samples from 24 patients and paraffin embedded tissues of gastric cancer patients (104 males and 24 females) were included. HOXA9 and PBX3 expression levels were determined by reverse transcription quantitative polymerase chain reaction in fresh tissues, and by immunohistochemical staining in paraffin embedded tissues. The association between HOXA9/PBX3 expression and clinicopathological features was established. The results demonstrated that HOXA9 and PBX3 mRNA levels were significantly upregulated (P=0.032 for HOXA9 and P=0.031 for PBX3) in gastric cancer tissue. Immunohistochemical staining revealed that HOXA9 expression was associated with differentiation, lymph node metastasis and tumor‑node‑metastasis (TNM) stage, and PBX3 expression was associated with lymph node metastasis and TNM stage. Correlation analysis revealed a high coincidental expression of HOXA9 and PBX3 levels in gastric cancer (r=0.391; P<0.001). Survival analysis showed that high expression of HOXA9 or PBX3 was associated with poor survival of gastric cancer, and multivariate analysis using Cox's regression model showed that PBX3 expression was an independent prognostic factor in gastric cancer. There was elevated expression of HOXA9 and PBX3 in gastric cancer patients, and high‑level expression of those proteins was associated with poor prognosis of gastric cancer. The present study underlines the significance of HOXA9/PBX3 in the development of gastric cancer.

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1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
2	Mullen JT and Ryan DP: Neoadjuvant chemotherapy for gastric cancer: What are we trying to accomplish? Ann Surg Oncol. 21:13–15. 2014. View Article : Google Scholar : PubMed/NCBI
3	Waddell T, Verheij M, Allum W, Cunningham D, Cervantes A and Arnold D: European Society for Medical Oncology (ESMO); European Society of Surgical Oncology (ESSO); European Society of Radiotherapy and Oncology (ESTRO): Gastric cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Eur J Surg Oncol. 40:584–591. 2014. View Article : Google Scholar : PubMed/NCBI
4	Bogenrieder T and Herlyn M: Axis of evil: Molecular mechanisms of cancer metastasis. Oncogene. 22:6524–6536. 2003. View Article : Google Scholar : PubMed/NCBI
5	Pearson JC, Lemons D and McGinnis W: Modulating Hox gene functions during animal body patterning. Nat Rev Genet. 6:893–904. 2005. View Article : Google Scholar : PubMed/NCBI
6	Samuel S and Naora H: Homeobox gene expression in cancer: Insights from developmental regulation and deregulation. Eur J Cancer. 41:2428–2437. 2005. View Article : Google Scholar : PubMed/NCBI
7	Krumlauf R: Hox genes in vertebrate development. Cell. 78:191–201. 1994. View Article : Google Scholar : PubMed/NCBI
8	Rauch T, Wang Z, Zhang X, Zhong X, Wu X, Lau SK, Kernstine KH, Riggs AD and Pfeifer GP: Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay. Proc Natl Acad Sci USA. 104:5527–5532. 2007. View Article : Google Scholar : PubMed/NCBI
9	Cheng W, Liu J, Yoshida H, Rosen D and Naora H: Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract. Nat Med. 11:531–537. 2005. View Article : Google Scholar : PubMed/NCBI
10	Vitiello D, Kodaman PH and Taylor HS: HOX genes in implantation. Semin Reprod Med. 25:431–436. 2007. View Article : Google Scholar : PubMed/NCBI
11	Shah N and Sukumar S: The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 10:361–371. 2010. View Article : Google Scholar : PubMed/NCBI
12	Gilbert PM, Mouw JK, Unger MA, Lakins JN, Gbegnon MK, Clemmer VB, Benezra M, Licht JD, Boudreau NJ, Tsai KK, et al: HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. J Clin Invest. 120:1535–1550. 2010. View Article : Google Scholar : PubMed/NCBI
13	Uchida K, Veeramachaneni R, Huey B, Bhattacharya A, Schmidt BL and Albertson DG: Investigation of HOXA9 promoter methylation as a biomarker to distinguish oral cancer patients at low risk of neck metastasis. BMC Cancer. 14:3532014. View Article : Google Scholar : PubMed/NCBI
14	Guerrero-Preston R, Soudry E, Acero J, Orera M, Moreno-López L, Macía-Colón G, Jaffe A, Berdasco M, Ili-Gangas C, Brebi-Mieville P, et al: NID2 and HOXA9 promoter hypermethylation as biomarkers for prevention and early detection in oral cavity squamous cell carcinoma tissues and saliva. Cancer Prev Res (Phila). 4:1061–1072. 2011. View Article : Google Scholar : PubMed/NCBI
15	Reynolds PA, Sigaroudinia M, Zardo G, Wilson MB, Benton GM, Miller CJ, Hong C, Fridlyand J, Costello JF and Tlsty TD: Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells. J Biol Chem. 281:24790–24802. 2006. View Article : Google Scholar : PubMed/NCBI
16	Sun M, Song CX, Huang H, Frankenberger CA, Sankarasharma D, Gomes S, Chen P, Chen J, Chada KK, He C and Rosner MR: HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis. Proc Natl Acad Sci USA. 110:9920–9925. 2013. View Article : Google Scholar : PubMed/NCBI
17	Son JW, Jeong KJ, Jean WS, Park SY, Jheon S, Cho HM, Park CG, Lee HY and Kang J: Genome-wide combination profiling of DNA copy number and methylation for deciphering biomarkers in non-small cell lung cancer patients. Cancer Lett. 311:29–37. 2011. View Article : Google Scholar : PubMed/NCBI
18	Wu Q, Lothe RA, Ahlquist T, Silins I, Tropé CG, Micci F, Nesland JM, Suo Z and Lind GE: DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets. Mol Cancer. 6:452007. View Article : Google Scholar : PubMed/NCBI
19	Reinert T, Borre M, Christiansen A, Hermann GG, Ørntoft TF and Dyrskjot L: Diagnosis of bladder cancer recurrence based on urinary levels of EOMES, HOXA9, POU4F2, TWIST1, VIM and ZNF154 hypermethylation. PLoS One. 7:e462972012. View Article : Google Scholar : PubMed/NCBI
20	Ko SY, Barengo N, Ladanyi A, Lee JS, Marini F, Lengyel E and Naora H: HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts. J Clin Invest. 122:3603–3617. 2012. View Article : Google Scholar : PubMed/NCBI
21	Chang CP, Brocchieri L, Shen WF, Largman C and Cleary ML: Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA-binding specificities across the Hox locus. Mol Cell Biol. 16:1734–1745. 1996. View Article : Google Scholar : PubMed/NCBI
22	Li Z, Zhang Z, Li Y, Arnovitz S, Chen P, Huang H, Jiang X, Hong GM, Kunjamma RB, Ren H, et al: PBX3 is an important cofactor of HOXA9 in leukemogenesis. Blood. 121:1422–1431. 2013. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Muratovska A, Zhou C, He S, Goodyer P and Eccles MR: Paired-Box genes are frequently expressed in cancer and often required for cancer cell survival. Oncogene. 22:7989–7997. 2003. View Article : Google Scholar : PubMed/NCBI
25	Tan Y, Cheung M, Pei J, Menges CW, Godwin AK and Testa JR: Upregulation of DLX5 promotes ovarian cancer cell proliferation by enhancing IRS-2-AKT signaling. Cancer Res. 70:9197–9206. 2010. View Article : Google Scholar : PubMed/NCBI
26	Trinh BQ, Ko SY, Barengo N, Lin SY and Naora H: Dual functions of the homeoprotein DLX4 in modulating responsiveness of tumor cells to topoisomerase II-targeting drugs. Cancer Res. 73:1000–1010. 2013. View Article : Google Scholar : PubMed/NCBI
27	Bruhl T, Urbich C, Aicher D, Acker-Palmer A, Zeiher AM and Dimmeler S: Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation. Circ Res. 94:743–751. 2004. View Article : Google Scholar : PubMed/NCBI
28	Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K, Chen SJ, Willman CL, Chen IM, Feinberg AP, et al: Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet. 12:154–158. 1996. View Article : Google Scholar : PubMed/NCBI
29	Bandyopadhyay S, Ashraf MZ, Daher P, Howe PH and DiCorleto PE: HOXA9 participates in the transcriptional activation of E-selectin in endothelial cells. Mol Cell Biol. 27:4207–4216. 2007. View Article : Google Scholar : PubMed/NCBI
30	Costa BM, Smith JS, Chen Y, Chen J, Phillips HS, Aldape KD, Zardo G, Nigro J, James CD, Fridlyand J, et al: Reversing HOXA9 oncogene activation by PI3K inhibition: Epigenetic mechanism and prognostic significance in human glioblastoma. Cancer Res. 70:453–462. 2010. View Article : Google Scholar : PubMed/NCBI
31	Chang CP, Shen WF, Rozenfeld S, Lawrence HJ, Largman C and Cleary ML: Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins. Genes Dev. 9:663–674. 1995. View Article : Google Scholar : PubMed/NCBI
32	Milech N, Kees UR and Watt PM: Novel alternative PBX3 isoforms in leukemia cells with distinct interaction specificities. Genes Chromosomes Cancer. 32:275–280. 2001. View Article : Google Scholar : PubMed/NCBI
33	Li Z, Huang H, Li Y, Jiang X, Chen P, Arnovitz S, Radmacher MD, Maharry K, Elkahloun A, Yang X, et al: Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML. Blood. 119:2314–2324. 2012. View Article : Google Scholar : PubMed/NCBI