Baritaki Stavroula, Sifakis Stavros, Huerta-Yepez Sara, Neonakis Ioannis K, Soufla Giannoula, Bonavida Benjamin, Spandidos Demetrios A
Department of Virology, Medical School, University of Crete, Heraklion, Crete, Greece.
Int J Oncol. 2007 Jul;31(1):69-79.
The screening of neo-angiogenesis related gene expression has uncovered many disrupted molecular pathways which may significantly confer to malignant transformation of various cell types including cervical cells. The objective of the present study was to delineate whether changes in certain gene expression profiles during the malignant conversion of the uterine cervix can be potentially used to predict the clinical course and outcome of the cervical pathology. Total RNA was isolated from Pap smears obtained from healthy females or patients diagnosed with low-grade squamous cervical intraepithelial lesions (LG-SIL), high-grade (HG)-SIL or cervical carcinoma. VEGF, TGF-beta1 and YY1 mRNA expression levels were assessed by QRT-PCR. Confirmation of YY1 protein discrepancy among cervical tissues of different histopathology was performed by immunohistochemistry. All tested genes showed statistically significant expression variations among the indicated groups. VEGF and TGF-beta1 mRNA overexpression was found to be associated with progression from low-grade to high-grade cervical intraepithelial neoplasia (CIN), while YY1 showed constitutively elevated transcript levels in CIN and cervical cancer compared to controls. At the protein level YY1 was also overexpressed in HG-SIL and cancer tissues compared to LG-SIL. Both YY1 transcript and protein overexpression were associated with HPV18- or HPV16-infected samples. Spearman analysis revealed a co-expression pattern for VEGF and TGF-beta1 mRNAs in normal cervix and LG-SIL; however, YY1 expression correlated negatively with VEGF and TGF-beta1 transcript levels upon the onset of the cervical neoplastic transformation. Our findings provide for the first time evidence for the implication of YY1 in uterine cervix carcinogenesis and suggest that VEGF, TGF-beta1 and YY1 could be useful biomarkers of cervical malignant transformation as well as potential targets for therapeutic approaches.
对新血管生成相关基因表达的筛查揭示了许多被破坏的分子途径，这些途径可能显著促成包括宫颈细胞在内的各种细胞类型的恶性转化。本研究的目的是确定子宫颈恶性转化过程中某些基因表达谱的变化是否可潜在用于预测宫颈病变的临床病程和结果。从健康女性或被诊断为低度鳞状宫颈上皮内瘤变（LG-SIL）、高度（HG）-SIL或宫颈癌的患者的巴氏涂片样本中分离总RNA。通过定量逆转录聚合酶链反应（QRT-PCR）评估血管内皮生长因子（VEGF）、转化生长因子-β1（TGF-β1）和YY1 mRNA的表达水平。通过免疫组织化学对不同组织病理学的宫颈组织中YY1蛋白差异进行确认。所有检测基因在指定组间均显示出具有统计学意义的表达差异。发现VEGF和TGF-β1 mRNA的过表达与低度至高度宫颈上皮内瘤变（CIN）的进展相关，而与对照组相比，YY1在CIN和宫颈癌中显示出转录水平持续升高。在蛋白水平上，与LG-SIL相比，YY1在HG-SIL和癌组织中也过表达。YY1转录本和蛋白的过表达均与HPV18或HPV16感染的样本相关。Spearman分析显示，在正常宫颈和LG-SIL中，VEGF和TGF-β1 mRNA存在共表达模式；然而，在宫颈肿瘤转化开始时，YY1表达与VEGF和TGF-β1转录水平呈负相关。我们的研究结果首次为YY1参与子宫颈癌发生提供了证据，并表明VEGF、TGF-β1和YY1可能是宫颈恶性转化的有用生物标志物以及治疗方法的潜在靶点。
