Department of Medical Biochemistry and Genetics, and MediCity Research Laboratory, University of Turku, Turku, Finland.
Gynecol Oncol. 2013 Apr;129(1):179-87. doi: 10.1016/j.ygyno.2012.12.044. Epub 2013 Jan 9.
ErbB4 is a member of the ErbB subfamily of receptor tyrosine kinases with a poorly understood biological role in ovarian cancer. Here, we have addressed the expression, subcellular localization, and prognostic relevance of ErbB4 and its alternatively spliced isoforms in serous ovarian adenocarcinoma.
A tissue microarray including 482 samples was analyzed by immunohistochemistry, and a series of 198 samples by isoform-specific real-time RT-PCR. The data were statistically analyzed for associations with clinicopathological markers and survival. The functional effect of expressing the relevant ErbB4 isoforms in ovarian cancer cells was addressed by measuring colony formation in soft agar.
While ErbB4 immunoreactivity was present in 90% of the samples, total ErbB4 protein expression was not significantly associated with prognostic markers. However, real-time RT-PCR analysis of serous ovarian cancer samples indicated the presence of two alternatively spliced cytoplasmic isoforms of ERBB4, CYT-1 and CYT-2, previously demonstrated to mediate significantly different cellular activities. Expression of CYT-1, but not of CYT-2, was significantly associated with tumor grade (P=0.014) and poor overall survival (P=0.0028). CYT-1 expression was also an independent prognostic factor (P=0.021) in multivariate analysis of survival. Consistent with a biological effect specific for the one isoform, overexpression of ErbB4 CYT-1, but not of ErbB4 CYT-2, increased anchorage-independent growth of ovarian adenocarcinoma cells in vitro.
These results suggest that expression of a specific ErbB4 isoform, CYT-1, is associated with poor survival and enhanced growth in serous ovarian cancer.
ErbB4 是受体酪氨酸激酶 ErbB 亚家族的成员，其在卵巢癌中的生物学作用尚不清楚。在这里，我们研究了 ErbB4 及其选择性剪接异构体在浆液性卵巢腺癌中的表达、亚细胞定位和预后相关性。
通过免疫组织化学分析了包含 482 个样本的组织微阵列，并通过同工型特异性实时 RT-PCR 分析了一系列 198 个样本。对数据进行了统计学分析，以关联临床病理标志物和生存情况。通过在软琼脂中测量集落形成，研究了在卵巢癌细胞中表达相关 ErbB4 同工型的功能影响。
虽然 90%的样本中存在 ErbB4 免疫反应性，但总 ErbB4 蛋白表达与预后标志物无显著相关性。然而，对浆液性卵巢癌样本的实时 RT-PCR 分析表明，存在两种先前证明可介导明显不同细胞活性的 ERBB4 细胞质选择性剪接异构体 CYT-1 和 CYT-2。表达 CYT-1，但不是 CYT-2，与肿瘤分级显著相关（P=0.014），总生存期不良（P=0.0028）。在多变量生存分析中，CYT-1 表达也是独立的预后因素（P=0.021）。与一个同工型具有特定生物学效应一致，过表达 ErbB4 CYT-1，但不是 ErbB4 CYT-2，增加了卵巢腺癌体外的锚定非依赖性生长。
这些结果表明，特定 ErbB4 同工型 CYT-1 的表达与浆液性卵巢癌中的不良生存和增强生长相关。
