Abstract：Objective: The relationship between the NOX4(NADPH oxidase 4) expression and glucose metabolism in breast cancer is unclear. This present study intends to study the expression levels of NOX4 and 18F-FDG uptake. And to further explore the clinical significance. Methods: The patients diagnosed as breast cancer who underwent preoperative 18F-FDG PET were enrolled. We examined the maximum standardized uptake values(SUVmax) of lesions. The levels of NOX4 were measured with immunohistochemical analysis. The clinical, histopathology of breast cancer patients were collected and recorded, and the correlation between NOX4 and clinical and histological predictors and metastasis were analyzed. Results: Fifty-six patients met the inclusion criteria and were included in the study, a total of 56 breast lesions. The SUVmax of lesions were 4.78±2.96. Thirty-three cases had positive expression of NOX4, 23 cases had negative expression. The SUVmax in the positive expression of NOX4 group was 6.42±3.23, the negative NOX expression group was 3.22±1.57. The SUVmax was higher in the NOX4 positive expression group than negative expression group, the difference was statistically significant(t=4.83, P<0.05). NOX4 expression levels were significantly correlated with lymph node metastasis(χ2=4.52, P<0.05). The expression of NOX4 and histological types have no significant correlation(χ2=2.88, P>0.05). The expression of NOX4 and histological grading were significantly related to histological grade, the positive rate of NOX4 expression in the group Ⅲ was higher than Ⅰ+Ⅱ Group(χ2=6.32, P<0.01). The SUVmax in infiltrating ductal carcinoma was higher than lobular carcinoma(t=2.97, P<0.05). The SUVmax in lymph node metastasis was higher than no lymph node metastasis(t=2.04, P=0.04). The SUVmax in the group Ⅲ was higher than Ⅰ+Ⅱ Group(t=-2.5, P<0.05). Conclusions: The levels of NOX4 expression were correlated with the 18F-FDG uptake. The expression of NOX4 and the 18F-FDG uptake are associated with lymph node metastasis and histological grade.
李雪娜，尹雅芙，杜补林，李亚明. NOX4蛋白在乳腺癌中的表达及与18F-FDG摄取值的相关性研究[J]. 中国临床医学影像杂志, 2016, 27(8): 547-550.
LI Xue-na, YIN Ya-fu, DU Bu-lin, LI Ya-ming. Relationships between NOX4 expression and 18F-FDG uptake in patients with breast cancer. JOURNAL OF CHINA MEDICAL IMAGING, 2016, 27(8): 547-550.
[1]O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer[J]. Oncologist, 2005, 10(suppl 3): 20-29.
[2]Ferraro D, Corso S, Fasano E, et al. Pro-metastatic signaling by C-Met through RAC-1 and reactive oxygen species(ROS)[J]. Oncogene, 2006, 25(26): 3689-3698.
[3]Suh YA, Arnold RS, Lassegue B, et al. Cell transformation by the superoxide-generating oxidase Mox1[J]. Nature, 1999, 401(6748): 79-82.
[4]Chen K, Craige SE, Keaney JF. Downstream targets and intracellular compartmentalization in Nox signaling[J]. Antioxid Redox Signal, 2009, 11(10): 2467-2480.
[5]Fukuyama M, Rokutan K, Sano T, et al. Overexpression of a novel superoxide-producing enzyme, NADPH oxidase 1, in adenoma and well differentiated adenocarcinoma of the human colon[J]. Cancer Lett, 2005, 221(1): 97-104.
[6]Lim SD, Sun C, Lambeth JD, et al. Increased Nox1 and hydrogen peroxide in prostate cancer[J]. Prostate, 2005, 62(2): 200-207.
[7]Fleming I, Michaelis UR, Bredenkotter D, et al. Endothelium-derived hyperpolarizing factor synthase(Cytochrome P450 2C9) is a functionally significant source of reactive oxygen species in coronary arteries[J]. Circ Res, 2001, 88(1): 44-51.
[8]Martyn KD, Frederick LM, von Loehneysen K, et al. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases[J]. Cell Signal, 2006, 18(1): 69-82.
[9]Kuroda J, Ago T, Matsushima S, et al. NADPH oxidase 4(Nox4) is a major source of oxidative stress in the failing heart[J]. Proc Natl Acad Sci USA, 2010, 107(35): 15565-15570.
[10]Piccoli C, Ria R, Scrima R, et al. Characterization of mitochondrial and extra-mitochondrial oxygen consuming reactions in human hematopoietic stem cells. Novel evidence of the occurrence of NAD(P)H oxidase activity[J]. J Biol Chem, 2005, 280(28): 26467-26476.
[11]Graham KA, Kulawiec M, Owens KM, et al. NADPH oxidase 4 is an oncoprotein localized to mitochondria[J]. Cancer Biol Ther, 2010, 10(3): 223-231.
[12]De Cicco C, Gilardi L, Botteri E, et al. Is [18F] fluorodeoxyglucose uptake by the primary tumor a prognostic factor in breast cancer?[J]. Breast, 2013, 22(1): 39-43.
[13]Shono T, Yokoyama N, Uesaka T, et al. Enhanced expression of NADPH oxidase Nox4 in human gliomas and its roles in cell proliferation and survival[J]. Int J Cancer, 2008, 123(4): 787-792.
[14]Edderkaoui M, Nitsche C, Zheng L, et al. NADPH oxidase activation in pancreatic cancer cells is mediated through Akt-dependent up-regulation of p22phox[J]. J Biol Chem, 2013, 288(51): 36259.
[15]Yamaura M, Mitsushita J, Furuta S, et al. NADPH oxidase 4 contributes to transformation phenotype of melanoma cells by regulating G2-M cell cycle progression[J]. Cancer Res, 2009, 69(6): 2647-2654.
[16]Weyemi U, Caillou B, Talbot M, et al. Intracellular expression of reactive oxygen species-generating NADPH oxidase NOX4 in normal and cancer thyroid tissues[J]. Endocr Relat Cancer, 2010, 17(1): 27-37.
[17]Lu W, Hu Y, Chen G, et al. Novel Role of NOX in supporting aerobic glycolysis in cancer cells with mitochondrial dysfunction and as potential target for cancer therapy[J]. Plos One, 2012, 10(5): e1001326.
[18]Bos R, van Der Hoeven JJ, van Der Wall E, et al. Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography[J]. J Clin Oncol, 2002, 20(2): 379-387.
[19]Brown RS, Goodman TM, Zasadny KR, et al. Expression of hexokinase Ⅱ and Glut-1 in untreated human breast cancer[J]. Nucl Med Biol, 2002, 29(4): 443-453.
[20]Cochet A, Dygai-Cochet I, Riedinger JM, et al. 18F-FDG PET/CT provides powerful prognostic stratification in the primary staging of large breast cancer when compared with conventional explorations[J]. Eur J Nucl Med Mol Imaging, 2014, 41(3): 428-437.
[21]Zhang B, Liu Z, Hu X. Inhibiting cancer metastasis via targeting NAPDH oxidase[J]. Biochem Pharmacol, 2013, 86(2): 253-266.
[22]Boudreau HE, Casterline BW, Rada B, et al. Nox4 involvement in TGF-beta and SMAD3-driven induction of the epithelial-to-mesenchymal transition and migration of breast epithelial cells[J]. Free Radic Biol Med, 2012, 53(7): 1489-1499.
[23]Groheux D, Giacchetti S, Moretti JL, et al. Correlation of high 18F-FDG uptake to clinical, pathological and biological prognostic factors in breast cancer[J]. Eur J Nucl Med Mol Imaging, 2011, 38(3): 426-435.
[24]Sanli Y, Kuyumcu S, Ozkan ZG, et al. Increased FDG uptake in breast cancer is associated with prognostic factors[J]. Ann Nucl Med, 2012, 26(4): 345-350.
