Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin, China.
Int J Gynecol Cancer. 2011 Aug;21(6):1004-12. doi: 10.1097/IGC.0b013e31821c45b7.
Macrophage migration inhibitory factor (MIF) and CD74 emerge as important players in pathogenesis and angiogenesis of several types of malignant tumors. The purpose of this study was to evaluate the expression of MIF and CD74 in cervical squamous cell carcinoma and explore the potential roles they play in cervical tumor angiogenesis.
Macrophage migration inhibitory factor and CD74 expression was assessed by immunohistochemistry in 209 cases with various degrees of cervical epithelial lesions, including 40 normal cervical epithelia, 43 mild cervical intraepithelial neoplasia 1 (CIN 1), 41 moderate-severe cervical intraepithelial neoplasia (CIN 2 to 3), and 85 cervical squamous cell carcinomas (SCCs). CD34 staining was used for counting microvessel density. Semiquantitative reverse transcription polymerase chain reaction and Western blot were used to detect messenger RNA and protein levels of MIF and CD74 in normal and malignant cervical tissues and cervical cancer cell lines SiHa and C-33A. The concentration of vascular endothelial growth factor (VEGF) in the conditioned media of cervical cancer cells was analyzed by enzyme-linked immunosorbent assay.
Immunohistochemical analysis showed that MIF and CD74 expression was significantly higher in CIN than in the normal samples and higher in SCC than in CIN. The overexpression of MIF was correlated with deep stromal infiltration but not with the other clinicopathologic features of SCC. Correlation analyses revealed that MIF was positively related to CD74, and both protein levels were associated with microvessel density. Exogenous MIF induced VEGF secretion in SiHa and C-33A cells in a dose-dependent manner, which can be inhibited by MIF-specific inhibitor (ISO-1) or anti-CD74 antibody.
Overexpression of MIF and CD74 in SCC and its precancerous lesions and the up-regulation of VEGF secretion in cervical cancer cells indicate that MIF and CD74 may play critical roles in the pathogenesis and angiogenesis of cervical cancer.
巨噬细胞移动抑制因子（MIF）和 CD74 作为多种恶性肿瘤发病机制和血管生成的重要参与者而出现。本研究的目的是评估 MIF 和 CD74 在宫颈鳞状细胞癌中的表达，并探讨它们在宫颈肿瘤血管生成中的潜在作用。
采用免疫组织化学法检测 209 例不同程度宫颈上皮病变患者（包括 40 例正常宫颈上皮、43 例轻度宫颈上皮内瘤变 1 级（CIN1）、41 例中重度宫颈上皮内瘤变（CIN2-3）和 85 例宫颈鳞状细胞癌（SCC））中 MIF 和 CD74 的表达。用 CD34 染色计数微血管密度。半定量逆转录聚合酶链反应和 Western blot 检测正常和恶性宫颈组织及宫颈癌细胞系 SiHa 和 C-33A 中 MIF 和 CD74 的信使 RNA 和蛋白水平。酶联免疫吸附试验分析宫颈癌细胞条件培养基中血管内皮生长因子（VEGF）的浓度。
免疫组织化学分析显示，CIN 中 MIF 和 CD74 的表达明显高于正常样本，SCC 中 MIF 和 CD74 的表达明显高于 CIN。MIF 的过表达与深基质浸润相关，但与 SCC 的其他临床病理特征无关。相关性分析显示，MIF 与 CD74 呈正相关，两者的蛋白水平均与微血管密度相关。外源性 MIF 以剂量依赖性方式诱导 SiHa 和 C-33A 细胞中 VEGF 的分泌，该分泌可被 MIF 特异性抑制剂（ISO-1）或抗-CD74 抗体抑制。
SCC 及其癌前病变中 MIF 和 CD74 的过度表达以及宫颈癌细胞中 VEGF 分泌的上调表明，MIF 和 CD74 可能在宫颈癌的发病机制和血管生成中发挥关键作用。
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