Distribution of soluble epoxide hydrolase, cytochrome P450 2C8, 2C9 and 2J2 in human malignant neoplasms

Abstract

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme with a C-terminal epoxide hydrolase activity and an N-terminal phosphatase activity. Arachidonic acid epoxides, previously suggested to be involved in apoptosis, oncogenesis and cell proliferation, are generated by cytochrome P450 epoxygenases and are good substrates of the sEH C-terminal domain. In addition, the N-terminal phosphatase domain hydrolyzes isoprenoid mono- and pyrophosphates, which are involved in cell signaling and apoptosis. Here we provide a comprehensive analysis of the distribution of sEH, CYP2C8, 2C9 and 2J2 in human neoplastic tissues using tissue micro-arrays. The human neoplastic tissue micro-arrays provide a well-controlled side by side analysis of a wide array of neoplastic tissues and their surrounding normal tissue controls. Many of the neoplastic tissues showed altered expression of these enzymes as compared to normal tissues. Altered expression was not limited to the neoplastic tissues but also found in the surrounding non-neoplastic tissues. For example, sEH expression in renal and hepatic malignant neoplasms and surrounding non-neoplastic tissues was found to be significantly decreased, whereas expression was found to be increased in seminoma as compared to normal tissues. Our study warrants further investigation of the role of altered expression of these enzymes in neoplastic tissues.

Transcriptional regulation of the human soluble epoxide hydrolase gene EPHX2

“…For example, increased EPHX2 transcription could reduce or inhibit angiogenesis that is caused by EETs in cancerous tissues [56]. In agreement with this, sEH expression is generally reduced in human malignant tissues [57]. Furthermore, a variety of lipid epoxides including both fatty acids and terpenes [58] are excellent substrates for sEH.…”

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)

“…After transfection of MCF7 cells, 120 clones were isolated by ring cloning under G418 selection and analyzed by quantitative PCR for CYP3A4 expression levels. Two clones, one expressing sequence III (supplemental Table S1) (clone [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] and the other sequence IV (supplemental Table S1) (clone [4][5][6][7][8][9][10][11][12][13][14] showing greater than 70% reductions in CYP3A4 mRNA expression by real time PCR and Western analysis, were selected for our studies. Six nontarget clones, NT-1 to NT-6 were isolated using the manufacturer's recommended nontarget sequence (SABiosciences, Frederick, MD).…”

“…Although CYP2C was expressed in 80% of unselected breast cancers, similar to CYP3A4, the intensity of CYP2C staining was weaker (5). Remarkably, CYP2J2 immunoreactivity was nearly undetectable in breast cancer (5), whereas others had previously reported modest immunoreactivity (14). Of the 21 CYPs profiled in breast cancer, only CYP2S1 and CYP4X1 exhibited higher prevalence of strong expression compared with CYP3A4 (5).…”

Lysophosphatidic acids are new substrates for the phosphatase domain of soluble epoxide hydrolase

“…VEGF plays a signifi cant role in tumor development and angiogenesis. Indeed, it has been shown to be decreased sEH levels in renal and hepatic malignant neoplasm ( 30 ). The relation between tumor and LPAs is also reported; in ovarian cancer, the levels of LPAs are elevated in malignant effusions of patients ( 31 ), and LPAs contribute to the development, progression, and metastasis in ovarian and breast cancer ( 32,33 ).…”