Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kamigyo-ku, Kyoto, Japan.
Int J Gynecol Cancer. 2011 May;21(4):609-15. doi: 10.1097/IGC.0b013e3182017e9b.
Estrogen-related receptor α (ERRα), one of orphan nuclear receptors with an unknown ligand, is expressed in various types of cancer. Increased ERRα levels are associated with a higher risk of recurrence and poor clinical outcome in breast cancer, suggesting that ERRα could be a negative prognostic factor. Recently, it has been suggested that vascular endothelial growth factor (VEGF) could be one of the transcriptional targets of ERRα in breast cancer. Here, we examined the expression of ERRα and the association of ERRα with VEGF in uterine cervical cancer cells and tissues.
We evaluated the expression of ERRα and VEGF by immunohistologic analysis using specimens from 40 patients with invasive cervical cancer. We also evaluated the VEGF promoter activity of ERRα in cervical cancer cell lines by transfection and luciferase assay. We overexpressed or knocked down ERRα and examined VEGF expression by real-time polymerase chain reaction. Finally, cell proliferation assay was performed to examine whether ERRα affects tumor growth in cervical cancer.
Immunohistologic analysis demonstrated that ERRα expression in cervical cancer tissues was higher than that in noncancerous tissues and that there was a positive association between ERRα and VEGF expression in cancer tissues (P < 0.05). We showed that ERRα stimulated the VEGF promoter activity in cervical cancer cell lines. We further showed the overexpression and knockdown of ERRα-regulated VEGF expression level by real-time polymerase chain reaction. Moreover, we showed that ERRα and VEGF knockdown by small interfering RNA or an inverse agonist of ERRα, XCT 790, could suppress cell growth compared with control cells in cervical cancer.
We have provided compelling evidence that ERRα affects VEGF expression and tumor growth in cervical cancer. These results justify further investigation into the use of ERRα as a therapeutic target for patients with uterine cervical cancer.
雌激素相关受体α（ERRα）是一种未知配体的孤儿核受体，在各种类型的癌症中表达。ERRα 水平升高与乳腺癌复发风险增加和临床预后不良相关，提示 ERRα 可能是一个负预后因素。最近，有人提出血管内皮生长因子（VEGF）可能是乳腺癌中 ERRα 的转录靶标之一。在这里，我们研究了 ERRα 在子宫颈癌细胞和组织中的表达及其与 VEGF 的相关性。
我们使用 40 例浸润性宫颈癌患者的标本通过免疫组织化学分析评估 ERRα 和 VEGF 的表达。我们还通过转染和荧光素酶测定评估了 ERRα 在宫颈癌细胞系中的 VEGF 启动子活性。我们过表达或敲低 ERRα，并通过实时聚合酶链反应检测 VEGF 表达。最后，进行细胞增殖测定以检查 ERRα 是否影响宫颈癌中的肿瘤生长。
免疫组织化学分析表明，宫颈癌组织中 ERRα 的表达高于非癌组织，并且癌症组织中 ERRα 与 VEGF 表达之间存在正相关（P <0.05）。我们表明 ERRα 刺激了宫颈癌细胞系中的 VEGF 启动子活性。我们进一步通过实时聚合酶链反应显示 ERRα 的过表达和敲低调节了 VEGF 表达水平。此外，我们表明与对照细胞相比，用小干扰 RNA 或 ERRα 的反向激动剂 XCT 790 敲低 ERRα 和 VEGF 可抑制宫颈癌中的细胞生长。
我们提供了令人信服的证据表明 ERRα 影响宫颈癌中的 VEGF 表达和肿瘤生长。这些结果证明进一步研究将 ERRα 作为子宫颈癌患者的治疗靶标是合理的。
