Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Clin Cancer Res. 2012 Nov 15;18(22):6188-98. doi: 10.1158/1078-0432.CCR-12-1789. Epub 2012 Sep 12.
To study the expression and function of a novel cell-cycle regulatory protein, human ecdysoneless (Ecd), during pancreatic cancer pathogenesis.
Immunohistochemical expression profiling of Ecd was done in nonneoplastic normal pancreatic tissues and pancreatic ductal adenocarcinoma lesions (from tissue microarray and Rapid Autopsy program) as well as precancerous PanIN lesions and metastatic organs. To analyze the biological significance of Ecd in pancreatic cancer progression, Ecd was stably knocked down in pancreatic cancer cell line followed by in vitro and in vivo functional assays.
Normal pancreatic ducts showed very weak to no Ecd expression compared to significant positive expression in pancreatic cancer tissues (mean ± SE composite score: 0.3 ± 0.2 and 3.8 ± 0.2 respectively, P < 0.0001) as well as in PanIN precursor lesions with a progressive increase in Ecd expression with increasing dysplasia (PanIN-1-PanIN-3). Analysis of matched primary tumors and metastases from patients with pancreatic cancer revealed that Ecd is highly expressed in both primary pancreatic tumor and in distant metastatic sites. Furthermore, knockdown of Ecd suppressed cell proliferation in vitro and tumorigenicity of pancreatic cancer cells in mice orthotopic tumors. Microarray study revealed that Ecd regulates expression of glucose transporter GLUT4 in pancreatic cancer cells and was subsequently shown to modulate glucose uptake, lactate production, and ATP generation by pancreatic cancer cells. Finally, knockdown of Ecd also reduced level of pAkt, key signaling molecule known to regulate aerobic glycolysis in cancer cells.
Ecd is a novel tumor-promoting factor that is differentially expressed in pancreatic cancer and potentially regulates glucose metabolism within cancer cells.
研究一种新型细胞周期调控蛋白——人蜕皮甾酮（Ecd）在胰腺癌发病机制中的表达和功能。
采用免疫组织化学方法对非肿瘤性正常胰腺组织和胰腺导管腺癌病变（来自组织微阵列和快速尸检计划）以及癌前 PanIN 病变和转移性器官中的 Ecd 进行表达谱分析。为了分析 Ecd 在胰腺癌进展中的生物学意义，我们在胰腺癌细胞系中稳定敲低 Ecd，然后进行体外和体内功能测定。
与胰腺癌组织（平均 ± SE 复合评分：0.3 ± 0.2 和 3.8 ± 0.2，P < 0.0001）以及随着发育不良程度增加而逐渐增加 Ecd 表达的 PanIN 前体病变相比，正常胰腺导管显示出非常弱或无 Ecd 表达。在分析来自胰腺癌患者的匹配原发性肿瘤和转移灶时，发现 Ecd 在原发性胰腺肿瘤和远处转移部位均高度表达。此外，Ecd 的敲低抑制了胰腺癌细胞的体外增殖和小鼠原位肿瘤中的致瘤性。微阵列研究表明，Ecd 调节胰腺癌细胞中葡萄糖转运体 GLUT4 的表达，并随后调节胰腺癌细胞的葡萄糖摄取、乳酸生成和 ATP 生成。最后，Ecd 的敲低也降低了关键信号分子 pAkt 的水平，该分子已知可调节癌细胞中的有氧糖酵解。
Ecd 是一种新型的肿瘤促进因子，在胰腺癌中差异表达，并可能调节癌细胞内的葡萄糖代谢。
