Mayer Sebastian, Hirschfeld Marc, Jaeger Markus, Pies Susanne, Iborra Severine, Erbes Thalia, Stickeler Elmar
Department of Obstetrics and Gynecology, University Medical Center Freiburg, Freiburg, Germany.
Oncol Rep. 2015 Jul;34(1):423-30. doi: 10.3892/or.2015.3995. Epub 2015 May 19.
The proto-oncogene recepteur d'origine nantais (RON, MST1R) and its alternatively spliced variants are involved in various tumor biological processes, such as cell motility, adhesion, proliferation, apoptosis and epithelial-to-mesenchymal transition (EMT). RON overexpression and the occurrence of specific alternatively spliced RON isoforms have been detected in ovarian cancer. In the present study, we evaluated the role and regulation of cancer-related RON splicing isoforms in primary ovarian cancer. Expression of RON variants (RONΔ165, RONΔ160) was determined in 45 primary ovarian cancer and 4 physiological ovarian tissue specimens by RT-PCR and western blot analysis. The results were correlated to clinicopathological parameters. Additionally, expression of splicing factors with known involvement in RON alternative splicing regulation was examined. Increased RON levels were detected in all tumor samples (p=0.001) without differences between the primary tumors and metastases. Alternative RON variants were present in the majority of tumor samples (39 of 45; 86.67%). Potential RONΔ165 occurred more often (82.22%) than potential RONΔ160 or RONΔ155 (24.40%). Several significant correlations of RON and splicing factor expression [e.g. ASF/SFRS1 (p=0.035)] were detected. Correlations of RON expression to clinicopathological parameters were not observed. Significant splicing factor interactions (e.g. SRp55/SRp75: p<0.001) were observed in tumor samples with alternative RON splicing. Our data demonstrated upregulated RON isoform expression and significant changes in splicing factor expression in primary ovarian cancer. These findings account for an essential regulatory interplay of splicing factor-driven alterations in the RON alternative splicing pattern with subsequent tumor biological consequences in ovarian cancer.
原癌基因南特起源受体（RON，MST1R）及其可变剪接变体参与多种肿瘤生物学过程，如细胞运动、黏附、增殖、凋亡和上皮-间质转化（EMT）。在卵巢癌中已检测到RON的过表达以及特定可变剪接RON异构体的出现。在本研究中，我们评估了癌症相关RON剪接异构体在原发性卵巢癌中的作用和调控。通过RT-PCR和蛋白质免疫印迹分析，在45例原发性卵巢癌和4例生理性卵巢组织标本中检测RON变体（RONΔ165、RONΔ160）的表达。将结果与临床病理参数相关联。此外，还检测了已知参与RON可变剪接调控的剪接因子的表达。在所有肿瘤样本中均检测到RON水平升高（p = 0.001），原发性肿瘤与转移灶之间无差异。大多数肿瘤样本（45例中的39例；86.67%）存在可变RON变体。潜在的RONΔ165出现频率更高（82.22%），高于潜在的RONΔ160或RONΔ155（24.40%）。检测到RON与剪接因子表达之间存在若干显著相关性[例如ASF/SFRS1（p = 0.035）]。未观察到RON表达与临床病理参数之间的相关性。在具有可变RON剪接的肿瘤样本中观察到显著的剪接因子相互作用（例如SRp55/SRp75：p < 0.001）。我们的数据表明原发性卵巢癌中RON异构体表达上调以及剪接因子表达发生显著变化。这些发现解释了剪接因子驱动的RON可变剪接模式改变与卵巢癌后续肿瘤生物学后果之间的重要调控相互作用。
