Department of Obstetrics and Gynecology, Freiburg University Medical Center, Freiburg, Germany.
Int J Gynecol Cancer. 2010 May;20(4):492-9. doi: 10.1111/IGC.0b013e3181d66ffe.
YT521 is a splicing factor involved in alternative splicing regulation of several tumor biological important genes. Two messenger RNA (mRNA) isoforms due to YT521 exon6 alternative splicing exist, with so far unknown functional consequences. Further evidence exists for a direct influence of YT521 expression in tumorigenesis because its mRNA level is changed in tumors compared with physiological tissue. We investigated the potential impact of YT521 expression on tumor biological parameters in endometrial cancer (EC).
Real-time reverse transcription-polymerase chain reaction specifically detecting YT521 exon6-retention and exon6-skipping mRNA isoforms and immunohistochemistry were performed in a cohort of 130 EC tissue samples.
Whereas YT521 exon6-retention mRNA was detectable in 86 (66.2%), the exon6-skipping isoform mRNA was expressed in only 8 (6.2%) of all EC samples. On the protein level, 104 (80%) of EC samples showed nuclear expression. The mRNA levels of exon6-skipping isoform were not correlated to any of the clinicopathological parameters of EC. In contrast, YT521 exon6-retention mRNA expression was positively correlated to metastasis (R = 0.196, P = 0.026) and inversely correlated to the protein expression levels (R = -0.205, P = 0.019). In univariate analyses, higher levels of YT521 exon6-retention mRNA were correlated to a poorer progression-free survival (P = 0.003), and this is confirmed by multivariate analyses (P = 0.019). The negative YT521 protein expression was correlated to poorer overall and disease-specific survival (P = 0.036 and P = 0.034), respectively, in univariate analyses. They are also confirmed by multivariate analyses (P = 0.021 and P = 0.010, respectively).
We characterized for the first time in a clinical setting a new but rare exon6-skipping mRNA splicing isoform of YT521. Furthermore, we identified YT521 as a potential new independent prognostic factor for patients with EC: the lack of YT521 protein in tumor cells was highly predictive for a poor overall and disease-specific survival and independent from the histological subtypes.
YT521 是一种剪接因子，参与几种肿瘤生物学重要基因的可变剪接调控。由于 YT521 外显子 6 的可变剪接，存在两种信使 RNA（mRNA）异构体，其功能后果尚不清楚。进一步的证据表明，YT521 的表达直接影响肿瘤发生，因为与生理组织相比，其 mRNA 水平在肿瘤中发生改变。我们研究了 YT521 表达对子宫内膜癌（EC）肿瘤生物学参数的潜在影响。
对 130 例 EC 组织样本进行实时逆转录聚合酶链反应（RT-PCR）特异性检测 YT521 外显子 6 保留和外显子 6 跳跃 mRNA 异构体，并用免疫组织化学法检测。
86%（66.2%）的 EC 样本中可检测到 YT521 外显子 6 保留 mRNA，而外显子 6 跳跃异构体 mRNA 仅在 8 例（6.2%）EC 样本中表达。在蛋白质水平上，104 例（80%）EC 样本显示核表达。外显子 6 跳跃异构体的 mRNA 水平与 EC 的任何临床病理参数均无相关性。相比之下，YT521 外显子 6 保留 mRNA 表达与转移呈正相关（R=0.196，P=0.026），与蛋白表达水平呈负相关（R=-0.205，P=0.019）。单因素分析显示，较高水平的 YT521 外显子 6 保留 mRNA 与无进展生存期（P=0.003）较差相关，这一结果在多因素分析中得到证实（P=0.019）。YT521 蛋白表达阴性与总生存期（P=0.036）和疾病特异性生存期（P=0.034）较差相关，这一结果在单因素分析中得到证实。在多因素分析中，这两个结果分别为（P=0.021 和 P=0.010）。
我们首次在临床环境中对 YT521 的一种新型但罕见的外显子 6 跳跃 mRNA 剪接异构体进行了描述。此外，我们将 YT521 鉴定为 EC 患者的潜在新的独立预后因素：肿瘤细胞中缺乏 YT521 蛋白高度预测总生存期和疾病特异性生存期较差，且独立于组织学亚型。
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