Department of Internal Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Clin Cancer Res. 2011 Dec 15;17(24):7816-27. doi: 10.1158/1078-0432.CCR-11-0408. Epub 2011 Oct 20.
Although prognostic and predictive factors in ovarian cancer have been extensively studied for decades, only few have been identified and introduced to clinical practice. Here, we evaluate hVps37A (HCRP1) as a possible novel predictive marker for ovarian cancer. hVps37A was originally described as a member of the membrane-trafficking ESCRT-I complex mediating the internalization and degradation of ubiquitinated membrane receptors.
We analyzed an ovarian cancer tissue microarray for HCRP1, EGFR, and HER2 expression. We used a tetracycline inducible ovarian cancer cell culture model to show the effects of hVps37A knockdown in vitro and in vivo. In addition, we studied the effects of epidermal growth factor receptor (EGFR) inhibitors cetuximab and lapatinib on ovarian cancer cells under conditions of hVps37A knockdown.
We find that hVps37A is significantly downregulated in ovarian cancer and modifies the prognostic value of EGFR and HER2 expression. In addition, hVps37A downregulation in ovarian cancer cells leads to cytoplasmic pEGFR retention and hyperactivation of downstream pathways and is associated with enhanced xenograft growth in nude mice and invasion of the collagen matrix. Furthermore, due to subsequent sustained Akt- and MAPK-pathway activation, hVps37A-deficient cells become irresponsive to inhibition by the therapeutic antibody cetuximab.
We propose that hVps37A status could become a novel prognostic and therapeutic marker for EGFR or HER2 driven tumors.
尽管几十年来一直在广泛研究卵巢癌的预后和预测因素，但仅确定并引入了少数因素用于临床实践。在这里，我们评估 hVps37A（HCRP1）作为卵巢癌的一种潜在新型预测标志物。hVps37A 最初被描述为膜运输 ESCRT-I 复合物的成员，介导泛素化膜受体的内化和降解。
我们分析了卵巢癌组织微阵列中 HCRP1、EGFR 和 HER2 的表达。我们使用四环素诱导的卵巢癌细胞培养模型来显示体外和体内 hVps37A 敲低的影响。此外，我们研究了表皮生长因子受体 (EGFR) 抑制剂西妥昔单抗和拉帕替尼在 hVps37A 敲低条件下对卵巢癌细胞的影响。
我们发现 hVps37A 在卵巢癌中明显下调，并改变了 EGFR 和 HER2 表达的预后价值。此外，卵巢癌细胞中 hVps37A 的下调导致细胞质 pEGFR 保留和下游途径的过度激活，并与裸鼠异种移植生长增强和胶原基质浸润相关。此外，由于随后 Akt 和 MAPK 途径的持续激活，hVps37A 缺陷细胞对治疗性抗体西妥昔单抗的抑制作用变得无反应。
我们提出 hVps37A 状态可能成为 EGFR 或 HER2 驱动肿瘤的一种新型预后和治疗标志物。
