Division of Gynecologic Oncology, Obstetrics and Gynecology Department, University of Virginia Health System, Charlottesville, VA 22908-0712, USA.
Int J Gynecol Cancer. 2012 Jun;22(5):732-41. doi: 10.1097/IGC.0b013e3182510496.
To identify obesity-related cancer genes in endometrial and adipose tissue depots of body mass index-matched morbidly obese women with and without endometrial cancer.
Eight women undergoing hysterectomy (4 women with and 4 women without endometrial cancer) were matched by age (52.6 years) and body mass index (44.5 kg/m). Endometrium, visceral adipose tissue, and subcutaneous adipose tissue were collected and subjected to microarray analysis using Affymetrix Human Genome U133 Plus 2.0 Arrays. Gene set enrichment analysis used to extract biological information from the gene expression data and t test metric ranked and compared genes in the expression data set. Protein expression was measured in the endometrial samples, and serum was collected for hormone/metabolite assays.
No significant differences were detected in hormone/metabolite levels between groups. Gene set enrichment analysis comparisons demonstrated that endometrial, visceral adipose and subcutaneous adipose tissues displayed 40, 47, and 38 alternatively regulated gene set pathways when comparing patients with and without cancer. Nineteen gene sets were alternately regulated in both visceral and subcutaneous adipose tissues; however, eighteen of these were regulated in the opposite direction. Five pathways were significantly and alternately regulated in all 3 tissue types and included glycolysis/gluconeogenesis, ribosome, peroxisome proliferator activated receptor signaling, pathogenic Escherichia coli infection, and natural killer-mediated cytotoxicity. In the malignant endometrium, liver kinase B1 underexpression was observed in all patients with cancer. Liver kinase B1 underexpression decreased adenosine monophosphate-activated protein kinase activity toward acetyl-CoA carboxylase and implied enhanced lipid biosynthesis in obesity-induced endometrial cancer.
Subcutaneous and visceral adipose tissue depots have opposite patterns of gene expression in obese patients with and without endometrial cancer. The altered de novo lipogenesis and individual gene targets identified provide new potential targets for cancer treatment and prevention for at-risk obese women.
鉴定体质量指数匹配的病态肥胖女性伴或不伴子宫内膜癌的子宫内膜和脂肪组织中与肥胖相关的癌症基因。
对 8 例行子宫切除术的女性（4 例伴子宫内膜癌，4 例不伴子宫内膜癌）进行年龄（52.6 岁）和体质量指数（44.5kg/m）匹配。收集子宫内膜、内脏脂肪组织和皮下脂肪组织，并使用 Affymetrix Human Genome U133 Plus 2.0 阵列进行微阵列分析。使用基因集富集分析从基因表达数据中提取生物学信息，并使用 t 检验指标对表达数据集进行基因排序和比较。在子宫内膜样本中测量蛋白表达，并收集血清进行激素/代谢物检测。
两组之间的激素/代谢物水平无显著差异。基因集富集分析比较表明，比较癌症患者和非癌症患者时，子宫内膜、内脏脂肪和皮下脂肪组织显示 40、47 和 38 个替代调控基因集途径。19 个基因集在内脏和皮下脂肪组织中均被替代调控；然而，其中 18 个呈相反方向调控。有 5 个途径在所有 3 种组织类型中均显著且呈替代调控，包括糖酵解/糖异生、核糖体、过氧化物酶体增殖物激活受体信号转导、致病性大肠杆菌感染和自然杀伤细胞介导的细胞毒性。在恶性子宫内膜中，所有癌症患者均观察到肝激酶 B1 低表达。肝激酶 B1 低表达降低了乙酰辅酶 A 羧化酶的腺苷单磷酸激活蛋白激酶活性，并暗示肥胖诱导的子宫内膜癌中增强了脂质生物合成。
肥胖患者伴或不伴子宫内膜癌的皮下和内脏脂肪组织中存在相反的基因表达模式。鉴定出的新的从头脂肪生成和个体基因靶标为高危肥胖女性的癌症治疗和预防提供了新的潜在靶点。
