Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Elevated 14,15- epoxyeicosatrienoic acid by increasing of cytochrome P450 2C8, 2C9 and 2J2 and decreasing of soluble epoxide hydrolase associated with aggressiveness of human breast cancer

Authors: Xiaolong Wei, Donghong Zhang, Xiaowei Dou, Na Niu, Wenhe Huang, Jingwen Bai, Guojun Zhang

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

Background

Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid by cytochrome P450 (CYP) and metabolized by soluble epoxide hydrolase (sEH). EETs have been associated with cardiovascular disease, diabetes and several cancer diseases. However, the distribution in tissue and role of CYP2C8, 2C9, 2J2 and sEH in human breast carcinogenesis remains uncertain.

Methods

Breast cancer (BC) and adjacent noncancerous tissue was obtained from 40 breast cancer patients in the Chaoshan region in China from 2010 to 2012. The level of 14,15-EET/14,15-DHET in BC patients was detected by ELISA; the expression and distribution of CYP2C8, 2C9, 2J2 and sEH was determined by quantitative RT-PCR and immunohistochemical staining; and cell proliferation and migration was analyzed by MTT and transwell assays, respectively.

Results

The median 14,15-EET and 14,15-EET/DHET level was 2.5-fold higher in BC than noncancerous tissue. The mRNA and protein levels of CYP2C8, 2C9 and 2J2 were higher, and sEH was lower in BC than noncancerous tissue. Furthermore, CYP2C8 and 2C9 protein levels positively correlated with Ki67 status, and CYP2J2 levels positively correlated with histological grade and tumor size. The sEH protein level negatively correlated with tumor size, estrogen receptors and Ki67. In MDA-MB-231 cells, siRNA knockdown of CYP2C8, 2C9 or 2J2 reduced cell proliferation, by 24.5%, 29.13%, or 22.7% and decreased cell migration by 49.1%, 44.9%, and 50.9%, respectively. Similarly, with adenovirus overexpression of sEH, both cell proliferation and migration rates were reduced by 31.4% and 45.8%, respectively.

Conclusions

The present study shows that elevated EET levels in BC tissues are associated with upregulation of CYP2C8, 2C9, and 2J2, and downregulation of sEH, and are also associated with aggressive cell behavior in BC patients.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61 (2): 69-90. 10.3322/caac.20107.CrossRefPubMed
2.
Lizarraga IM, Sugg SL, Weigel RJ, Scott-Conner CE: Review of risk factors for the development of contralateral breast cancer. Am J Surg. 2013, 206 (5): 704-708. 10.1016/j.amjsurg.2013.08.002.CrossRefPubMed
3.
Jiang JG, Chen CL, Card JW, Yang S, Chen JX, Fu XN, Ning YG, Xiao X, Zeldin DC, Wang DW: Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res. 2005, 65 (11): 4707-4715. 10.1158/0008-5472.CAN-04-4173.CrossRefPubMed
4.
Zhang D, Zhang Q, Zhou L, Huo L, Zhang Y, Shen Z, Zhu Y: Comparison of prevalence, viral load, physical status and expression of human papillomavirus-16, −18 and −58 in esophageal and cervical cancer: a case–control study. BMC Cancer. 2010, 10: 650-10.1186/1471-2407-10-650.CrossRefPubMedPubMedCentral
5.
6.
Panigrahy D, Edin ML, Lee CR, Huang S, Bielenberg DR, Butterfield CE, Barnés CM, Mammoto A, Mammoto T, Luria A, Benny O, Chaponis DM, Dudley AC, Greene ER, Vergilio JA, Pietramaggiori G, Scherer-Pietramaggiori SS, Short SM, Seth M, Lih FB, Tomer KB, Yang J, Schwendener RA, Hammock BD, Falck JR, Manthati VL, Ingber DE, Kaipainen A, D'Amore PA, Kieran MW, et al: Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest. 2012, 122 (1): 178-191. 10.1172/JCI58128.CrossRefPubMed
7.
Yang S, Lin L, Chen JX, Lee CR, Seubert JM, Wang Y, Wang H, Chao ZR, Tao DD, Gong JP, Lu ZY, Wang DW, Zeldin DC: Cytochrome P-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor-alpha via MAPK and PI3K/Akt signaling pathways. Am J Physiol Heart Circ Physiol. 2007, 293 (1): H142-H151. 10.1152/ajpheart.00783.2006.CrossRefPubMedPubMedCentral
8.
Guo M, Roman RJ, Falck JR, Edwards PA, Scicli AG: Human U251 glioma cell proliferation is suppressed by HET0016 [N-hydroxy-N’-(4-butyl-2-methylphenyl)formamidine], a selective inhibitor of CYP4A. J Pharmacol Exp Ther. 2005, 315 (2): 526-533. 10.1124/jpet.105.088567.CrossRefPubMed
9.
Imig JD, Hammock BD: Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat Rev Drug Discov. 2009, 8 (10): 794-805. 10.1038/nrd2875.CrossRefPubMedPubMedCentral
10.
Enayetallah AE, French RA, Grant DF: Distribution of soluble epoxide hydrolase, cytochrome P450 2C8, 2C9 and 2J2 in human malignant neoplasms. J Mol Histol. 2006, 37 (3–4): 133-141.CrossRefPubMed
11.
Chen C, Wei X, Rao X, Wu J, Yang S, Chen F, Ma D, Zhou J, Dackor RT, Zeldin DC, Wang DW: Cytochrome P450 2J2 is highly expressed in hematologic malignant diseases and promotes tumor cell growth. J Pharmacol Exp Ther. 2011, 336 (2): 344-355. 10.1124/jpet.110.174805.CrossRefPubMedPubMedCentral
12.
Leclerc J, Tournel G, Courcot-Ngoubo NE, Pottier N, Lafitte JJ, Jaillard S, Mensier E, Lhermitte M, Broly F, Lo-Guidice JM: Profiling gene expression of whole cytochrome P450 superfamily in human bronchial and peripheral lung tissues: Differential expression in non-small cell lung cancers. Biochimie. 2010, 92 (3): 292-306. 10.1016/j.biochi.2009.12.007.CrossRefPubMed
13.
Murray GI, Patimalla S, Stewart KN, Miller ID, Heys SD: Profiling the expression of cytochrome P450 in breast cancer. Histopathology. 2010, 57 (2): 202-211. 10.1111/j.1365-2559.2010.03606.x.CrossRefPubMed
14.
Roques M, Bagrel D, Magdalou J, Siest G: Expression of arylhydrocarbon hydroxylase, epoxide hydrolases, glutathione S-transferase and UDP-glucuronosyltransferases in H5-6 hepatoma cells. Gen Pharmacol. 1991, 22 (4): 677-684. 10.1016/0306-3623(91)90077-J.CrossRefPubMed
15.
Yang MD, Wu CC, Chiou SH, Chiu CF, Lin TY, Chiang IP, Chow KC: Reduction of dihydrodiol dehydrogenase expression in resected hepatocellular carcinoma. Oncol Rep. 2003, 10 (2): 271-276.PubMed
16.
Okumura M, Ohta M, Tateyama H, Nakagawa K, Matsumura A, Maeda H, Tada H, Eimoto T, Matsuda H, Masaoka A: The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer. 2002, 94 (3): 624-632. 10.1002/cncr.10226.CrossRefPubMed
17.
Zhang D, Xie X, Chen Y, Hammock BD, Kong W, Zhu Y: Homocysteine upregulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo. Circ Res. 2012, 110 (6): 808-817. 10.1161/CIRCRESAHA.111.259325.CrossRefPubMedPubMedCentral
18.
Liu Y, Chen Z, Niu N, Chang Q, Deng R, Korteweg C, Gu J: IgG gene expression and its possible significance in prostate cancers. Prostate. 2012, 72 (6): 690-701. 10.1002/pros.21476.CrossRefPubMed
19.
Zhang D, Ai D, Tanaka H, Hammock BD, Zhu Y: DNA methylation of the promoter of soluble epoxide hydrolase silences its expression by an SP-1-dependent mechanism. Biochim Biophys Acta. 2010, 1799 (9): 659-667. 10.1016/j.bbagrm.2010.09.006.CrossRefPubMed
20.
Mitra R, Guo Z, Milani M, Mesaros C, Rodriguez M, Nguyen J, Luo X, Clarke D, Lamba J, Schuetz E, Donner DB, Puli N, Falck JR, Capdevila J, Gupta K, Blair IA, Potter DA: CYP3A4 mediates growth of estrogen receptor-positive breast cancer cells in part by inducing nuclear translocation of phospho-Stat3 through biosynthesis of (+/−)-14,15-epoxyeicosatrienoic acid (EET). J Biol Chem. 2011, 286 (20): 17543-17559. 10.1074/jbc.M110.198515.CrossRefPubMedPubMedCentral
21.
Jiang JG, Ning YG, Chen C, Ma D, Liu ZJ, Yang S, Zhou J, Xiao X, Zhang XA, Edin ML, Card JW, Wang J, Zeldin DC, Wang DW: Cytochrome p450 epoxygenase promotes human cancer metastasis. Cancer Res. 2007, 67 (14): 6665-6674. 10.1158/0008-5472.CAN-06-3643.CrossRefPubMed
22.
Wang D, Dubois RN: Epoxyeicosatrienoic acids: a double-edged sword in cardiovascular diseases and cancer. J Clin Invest. 2012, 122 (1): 19-22. 10.1172/JCI61453.CrossRefPubMed
23.
Zhang D, Chen Y, Xie X, Liu J, Wang Q, Kong W, Zhu Y: Homocysteine activates vascular smooth muscle cells by DNA demethylation of platelet-derived growth factor in endothelial cells. J Mol Cell Cardiol. 2012, 53 (4): 487-496. 10.1016/j.yjmcc.2012.07.010.CrossRefPubMed
24.
Skrypnyk N, Chen X, Hu W, Su Y, Mont S, Yang S, Gangadhariah M, Wei S, Falck JR, Jat JL, Zent R, Capdevila JH, Pozzi A: PPARalpha Activation Can Help Prevent and Treat Non-Small Cell Lung Cancer. Cancer Res. 2014, 74 (2): 621-631. 10.1158/0008-5472.CAN-13-1928.CrossRefPubMed
25.
Zagorac D, Jakovcevic D, Gebremedhin D, Harder DR: Antiangiogenic effect of inhibitors of cytochrome P450 on rats with glioblastoma multiforme. J Cereb Blood Flow Metab. 2008, 28 (8): 1431-1439. 10.1038/jcbfm.2008.31.CrossRefPubMedPubMedCentral
26.
Homma S1, Koido S, Sagawa Y, Suzuki H, Komita H, Nagasaki E, Takahara A, Horiguchi-Yamada J, Tajiri H, Zeldin DC, Obata T: Antigenic stimulation with cytochrome P450 2 J expressed in mouse hepatocellular carcinoma cells regulates host anti-tumour immunity. Clin Exp Immunol. 2009, 156 (2): 344-352. 10.1111/j.1365-2249.2009.03900.x.CrossRefPubMedPubMedCentral
27.
Chen F, Chen C, Yang S, Gong W, Wang Y, Cianflone K, Tang J, Wang DW: Let-7b inhibits human cancer phenotype by targeting cytochrome P450 epoxygenase 2J2. PLoS One. 2012, 7 (6): e39197-10.1371/journal.pone.0039197.CrossRefPubMedPubMedCentral
28.
Zhang SY, Surapureddi S, Coulter S, Ferguson SS, Goldstein JA: Human CYP2C8 is post-transcriptionally regulated by microRNAs 103 and 107 in human liver. Mol Pharmacol. 2012, 82 (3): 529-540. 10.1124/mol.112.078386.CrossRefPubMedPubMedCentral
29.
30.
Liu L, Chen C, Gong W, Li Y, Edin ML, Zeldin DC, Wang DW: Epoxyeicosatrienoic acids attenuate reactive oxygen species level, mitochondrial dysfunction, caspase activation, and apoptosis in carcinoma cells treated with arsenic trioxide. J Pharmacol Exp Ther. 2011, 339 (2): 451-463. 10.1124/jpet.111.180505.CrossRefPubMedPubMedCentral
Metadata
Title
Elevated 14,15- epoxyeicosatrienoic acid by increasing of cytochrome P450 2C8, 2C9 and 2J2 and decreasing of soluble epoxide hydrolase associated with aggressiveness of human breast cancer
Authors
Xiaolong Wei
Donghong Zhang
Xiaowei Dou
Na Niu
Wenhe Huang
Jingwen Bai
Guojun Zhang
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-841

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue

Research article

Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor α signalling and results in tamoxifen insensitive proliferation

Research article

Protein kinase C-delta inactivation inhibits the proliferation and survival of cancer stem cells in culture and in vivo

Research article

Epigenetic inactivation of ST6GAL1 in human bladder cancer

Research article

Matrix metalloproteinase-10 promotes tumor progression through regulation of angiogenic and apoptotic pathways in cervical tumors

Research article

Transarterial infusion chemotherapy with cisplatin plus S-1 for hepatocellular carcinoma treatment: a phase I trial

Research article

A longitudinal study investigating quality of life and nutritional outcomes in advanced cancer patients receiving home parenteral nutrition
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits