Baldini Enke, Tuccilli Chiara, Arlot-Bonnemains Yannick, Chesnel Frank, Sorrenti Salvatore, De Vito Corrado, Catania Antonio, D'Armiento Eleonora, Antonelli Alessandro, Fallahi Poupak, Watutantrige-Fernando Sara, Tartaglia Francesco, Barollo Susi, Mian Caterina, Bononi Marco, Arceri Stefano, Mascagni Domenico, Vergine Massimo, Pironi Daniele, Monti Massimo, Filippini Angelo, Ulisse Salvatore
Department of Surgical Sciences, "Sapienza" University of Rome, Italy.
Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
Mol Cell Endocrinol. 2017 Mar 5;443:121-127. doi: 10.1016/j.mce.2017.01.019. Epub 2017 Jan 12.
Recent findings demonstrated that a subset of papillary thyroid cancers (PTCs) is characterized by reduced expression of the von Hippel-Lindau (VHL) tumor suppressor gene, and that lowest levels associated with more aggressive PTCs. In the present study, the levels of the two VHL mRNA splicing variants, VHL-213 (V1) and VHL-172 (V2), were measured in a series of 96 PTC and corresponding normal matched tissues by means of quantitative RT-PCR. Variations in the mRNA levels were correlated with patients' clinicopathological parameters and disease-free interval (DFI). The analysis of VHL mRNA in tumor tissues, compared to normal matched tissues, revealed that its expression was either up- or down-regulated in the majority of PTC. In particular, V1 and V2 mRNA levels were altered, respectively, in 78 (81.3%) and 65 (67.7%) out of the 96 PTCs analyzed. A significant positive correlation between the two mRNA variants was observed (p < 0.001). Univariate analysis documented the lack of association between each variant and clinicopathological parameters such as age, tumor size, histology, TNM stage, lymph node metastases, and BRAF mutational status. However, a strong correlation was found between altered V1 or V2 mRNA levels and DFI. Multivariate regression analysis indicated higher V1 mRNA values, along with lymph node metastases at diagnosis, as independent prognostic factors predicting DFI. In conclusion, the data reported demonstrate that VHL gene expression is deregulated in the majority of PTC tissues. Of particular interest is the apparent protective role exerted by VHL transcripts against PTC recurrences.
近期研究结果表明，一部分甲状腺乳头状癌（PTC）的特征是von Hippel-Lindau（VHL）肿瘤抑制基因表达降低，且最低水平与侵袭性更强的PTC相关。在本研究中，通过定量逆转录聚合酶链反应（RT-PCR）检测了96例PTC及其相应正常配对组织中两种VHL mRNA剪接变体VHL-213（V1）和VHL-172（V2）的水平。mRNA水平的变化与患者的临床病理参数及无病生存期（DFI）相关。与正常配对组织相比，肿瘤组织中VHL mRNA的分析显示，其表达在大多数PTC中要么上调要么下调。特别是，在分析的96例PTC中，分别有78例（81.3%）和65例（67.7%）的V1和V2 mRNA水平发生改变。观察到两种mRNA变体之间存在显著正相关（p<0.001）。单因素分析表明，每个变体与年龄、肿瘤大小、组织学、TNM分期、淋巴结转移和BRAF突变状态等临床病理参数之间均无关联。然而，发现V1或V2 mRNA水平改变与DFI之间存在强相关性。多因素回归分析表明，较高的V1 mRNA值以及诊断时的淋巴结转移是预测DFI的独立预后因素。总之，报告的数据表明VHL基因表达在大多数PTC组织中失调。特别值得关注的是VHL转录本对PTC复发所发挥的明显保护作用。
