Genetic alterations following ionizing radiation in human ovarian cancer‑derived endothelial cells

Liu,Ting; Du,Xuelian; Sheng,Xiugui

doi:10.3892/mmr.2014.2096

Genetic alterations following ionizing radiation in human ovarian cancer‑derived endothelial cells

Authors:
- Ting Liu
- Xuelian Du
- Xiugui Sheng
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Affiliations: Department of Gynecologic Oncology, Shandong Cancer Hospital, Jinan, Shandong 250117, P.R. China
Published online on: March 31, 2014 https://doi.org/10.3892/mmr.2014.2096
Pages: 2257-2264

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Abstract

Recent studies have focused on the role of endothelial cells during tumor radiotherapy, and the majority of studies have found that the rate of endothelial cell apoptosis determines the response of the tumor to ionizing radiation treatment. However, gene expression changes in human ovarian cancer‑derived endothelial cells in response to X‑ray radiation remains poorly understood. The present study was conducted to investigate the radiation‑induced gene alterations in human ovarian cancer‑derived endothelial cells and to provide novel potential targets for combined anti‑angiogenesis and radiation therapy for the treatment of human ovarian cancer. Ovarian cancer‑derived endothelial cells, which were harvested from six human ovarian epithelial carcinomas prior to and 4 h after 400 cGy X‑ray irradiation, were analyzed using cDNA microarray technology. Significant genes were selected to corroborate the microarray experiments using a quantitative polymerase chain reaction (qPCR). A total of 28 genes common to all the cDNA microarray results were identified, of which 22 genes were found to be consistently upregulated or downregulated. Thirteen genes were upregulated persistently and nine genes downregulated persistently following irradiation with 400 cGy X‑ray in comparison with the matched group. The majority of the significantly altered genes (≥2‑fold change in expression) were found to have a role in vasculogenesis, cell cycle regulation, inflammation and the immune response, cell growth and apoptosis, nicotinamide metabolism, cell signaling, chemokines and cell adhesion. Eight randomly selected genes were corroborated using qPCR technology. Radiation‑induced gene alterations in ovarian cancer‑derived endothelial cells and gene‑related pathways were associated with vasculogenesis and the radiosensitivity of human ovarian cancer, and may provide promising biomarkers for radiation and anti‑angiogenesis treatments against ovarian carcinoma.

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1	Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 82:4–6. 1990. View Article : Google Scholar : PubMed/NCBI
2	Carmeliet P and Jain RK: Angiogenesis in cancer and other diseases. Nature. 407:249–257. 2000. View Article : Google Scholar : PubMed/NCBI
3	Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1:27–31. 1995. View Article : Google Scholar : PubMed/NCBI
4	Fuks Z and Kolesnick R: Engaging the vascular component of the tumor response. Cancer Cell. 8:89–91. 2005. View Article : Google Scholar : PubMed/NCBI
5	Cooper BC, Ritchie JM, Broghammer CL, et al: Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer. Clin Cancer Res. 8:3193–3197. 2002.PubMed/NCBI
6	Davis GE and Senger DR: Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res. 97:1093–1107. 2005. View Article : Google Scholar
7	Hu Z, Lin D, Yuan J, et al: Overexpression of osteopontin associated with more aggressive phenotypes in human non-small cell lung cancer. Clin Cancer Res. 11:4646–4652. 2005. View Article : Google Scholar : PubMed/NCBI
8	Eto M, Kodama S, Nomi N, Uemura N and Suzuki M: Clinical significance of elevated ostopontin levels in head and neck cancer patients. Auris Nasus LaryU. 34:343–346. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kerbel R and Folkman J: Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2:727–739. 2002. View Article : Google Scholar : PubMed/NCBI
10	Lu C, Bonome T, Li Y, Kamat AA, et al: Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma. Cancer Res. 67:1757–1768. 2007. View Article : Google Scholar : PubMed/NCBI
11	Peltenburg LT: Radiosensitivity of tumor cells. Oncogenes and apoptosis Q. J Nucl Med. 44:355–364. 2000.PubMed/NCBI
12	Du XL, Jiang T, Zhao WB, et al: Gene alterations in tumor-associated endothelial cells from endometrial cancer. Int J Mol Med. 22:619–632. 2008.PubMed/NCBI
13	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
14	Kufe D and Weichselbaum R: Radiation therapy: activation for gene transcription and the development of genetic radiotherapy-therapeutic strategies in oncology. Cancer Biol Ther. 2:326–329. 2003. View Article : Google Scholar : PubMed/NCBI
15	Raman D, Baugher PJ, Thu YM and Richmond A: Role of chemokines in tumor growth. Cancer Lett. 256:137–165. 2007. View Article : Google Scholar : PubMed/NCBI
16	Wolff HA, Rolke D, Rave-Fränk M, et al: Analysis of chemokine and chemokine receptor expression in squamous cell carcinoma of the head and neck (SCCHN) cell lines. Radiat Environ Biophys. 50:145–154. 2011. View Article : Google Scholar : PubMed/NCBI
17	Kryczek I, Wei S, Keller E, Liu R and Zou W: Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol Cell Physiol. 292:C987–C995. 2007. View Article : Google Scholar : PubMed/NCBI
18	Chang CC, Lerman OZ, Thanik VD, et al: Dose-dependent effect of radiation on angiogenic and angiostatic CXC chemokine expression in human endothelial cells. Cytokine. 48:295–302. 2009. View Article : Google Scholar : PubMed/NCBI
19	Hu X, Li D, Zhang W, et al: Matrix metalloproteinase-9 expression correlates with prognosis and involved in ovarian cancer cell invasion. Arch Gynecol Obstet. 286:1537–1543. 2012. View Article : Google Scholar : PubMed/NCBI
20	Peng F, Xu Z, Wang J, et al: Recombinant human endostatin normalizes tumor vasculature and enhances radiation response in xenografted human nasopharyngeal carcinoma models. PLoS One. 7:e346462012. View Article : Google Scholar
21	Pratheeshkumar P and Kuttan G: Vernolide-A inhibits radiation-induced hypoxia-mediated tumor angiogenesis by regulating HIF-1α, MMP-2, MMP-9, and VEGF. J Environ Pathol Toxicol Oncol. 30:139–151. 2011.PubMed/NCBI
22	Badiga AV, Chetty C, Kesanakurti D, et al: MMP-2 siRNA inhibits radiation-enhanced invasiveness in glioma cells. PLoS One. 6:e206142011. View Article : Google Scholar : PubMed/NCBI
23	Kaliski A, Maggiorella L, Cengel KA, et al: Angiogenesis and tumor growth inhibition by a matrix metalloproteinase inhibitor targeting radiation-induced invasion. Mol Cancer Ther. 4:1717–1728. 2005. View Article : Google Scholar : PubMed/NCBI
24	Nilsson MB, Langley RR and Fidler IJ: Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res. 65:10794–10800. 2005. View Article : Google Scholar : PubMed/NCBI
25	Lo CW, Chen MW, Hsiao M, et al: IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Res. 71:424–434. 2011. View Article : Google Scholar : PubMed/NCBI
26	Duan Z, Foster R, Bell DA, et al: Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res. 12:5055–5063. 2006. View Article : Google Scholar : PubMed/NCBI
27	Oh ET, Park MT, Song MJ, et al: Radiation-induced angiogenic signaling pathway in endothelial cells obtained from normal and cancer tissue of human breast. Oncogene. Mar 18–2013.(Epub ahead of print).
28	Yu YC, Yang PM, Chuah QY, et al: Radiation-induced senescence in securin-deficient cancer cells promotes cell invasion involving the IL-6/STAT3and PDGF-BB/PDGFR pathways. Sci Rep. 3:16752013.PubMed/NCBI
29	Rofstad EK, Henriksen K, Galappathi K and Mathiesen B: Antiangiogenic treatment with thrombospondin-1 enhances primary tumor radiation response and prevents growth of dormant pulmonary micrometastases after curative radiation therapy in human melanoma xenografts. Cancer Res. 63:4055–4061. 2003.
30	Maxhimer JB, Soto-Pantoja DR, Ridnour LA, et al: Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling. Sci Transl Med. 1:3ra72009.PubMed/NCBI
31	Liebmann J, DeLuca AM, Coffin D, et al: In vivo radiation protection by nitric oxide modulation. Cancer Res. 54:3365–3368. 1994.PubMed/NCBI
32	Isenberg JS, Martin-Manso G, Maxhimer JB and Roberts DD: Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies. Nat Rev Cancer. 9:182–194. 2009. View Article : Google Scholar : PubMed/NCBI
33	Kwon M, Hanna E, Lorang D, et al: Functional characterization of filamin a interacting protein 1-like, a novel candidate for antivascular cancer therapy. Cancer Res. 68:7332–7341. 2008. View Article : Google Scholar : PubMed/NCBI
34	Lu H and Hallstrom TC: Sensitivity to TOP2 targeting chemotherapeutics is regulated by Oct1 and FILIP1L. PLoS One. 7:e429212012. View Article : Google Scholar : PubMed/NCBI
35	Aksoy S, Szumlanski CL and Weinshilboum RM: Human liver nicotinamide N-methyltransferase cDNA cloning, expression, and biochemical characterization. J Biol Chem. 269:14835–14840. 1994.PubMed/NCBI
36	Sun LQ, Coucke PA, Mirimanoff RO and Buchegger F: Fractionated irradiation combined with carbogen breathing and nicotinamide of two human glioblastomas grafted in nude mice. Radiat Res. 155:26–31. 2001. View Article : Google Scholar : PubMed/NCBI
37	Hoskin PJ, Saunders MI, Phillips H, et al: Carbogen and nicotinamide in the treatment of bladder cancer with radical radiotherapy. Br J Cancer. 76:260–263. 1997. View Article : Google Scholar : PubMed/NCBI
38	Kassem HSh, Sangar V, Cowan R, Clarke N and Margison GP: A potential role of heat shock proteins and nicotinamide N-methyl transferase in predicting response to radiation in bladder cancer. Int J Cancer. 101:454–460. 2002. View Article : Google Scholar : PubMed/NCBI