Yang Chun-Ming, Ji Shan, Li Yan, Fu Li-Ye, Jiang Tao, Meng Fan-Dong
Department of Urology, The First Affiliated Hospital, China Medical University, Shenyang, P.R. China.
Oncol Res. 2017 Jan 26;25(2):195-205. doi: 10.3727/096504016X14732772150424.
Renal cell carcinoma (RCC) represents one of the most resistant tumors to radiation and chemotherapy. Current therapies for RCC patients are inefficient due to the lack of diagnostic and therapeutic markers. The expression of novel tumor-associated kinases has the potential to dramatically shape tumor cell behavior. Identifying tumor-associated kinases can lend insight into patterns of tumor growth and characteristics. In the present study, we investigated the receptor tyrosine kinase-like orphan receptor 2 (Ror2), a new tumor-associated kinase, in RCC primary tumors and cell lines. Knockdown of Ror2 expression in RCC cells with specific shRNA significantly reduced cell proliferation and induced apoptosis. Using in vitro migration and Matrigel invasion assays, we found that cell migration and invasive ability were also significantly inhibited. In RCC, Ror2 expression correlated with expression of genes involved at the cell cycle and migration, including PCNA, CDK1, TWIST, and MMP-2. Furthermore, in vivo xenograft studies in nude mice revealed that administration of a Ror2 shRNA plasmid significantly inhibited tumor growth. These findings suggest a novel pathway of tumor-promoting activity by Ror2 within renal carcinomas, with significant implications for unraveling the tumorigenesis of RCC.
肾细胞癌（RCC）是对放疗和化疗最具抗性的肿瘤之一。由于缺乏诊断和治疗标志物，目前针对RCC患者的治疗方法效率低下。新型肿瘤相关激酶的表达有可能显著影响肿瘤细胞行为。识别肿瘤相关激酶有助于深入了解肿瘤生长模式和特征。在本研究中，我们在RCC原发性肿瘤和细胞系中研究了一种新的肿瘤相关激酶——受体酪氨酸激酶样孤儿受体2（Ror2）。用特异性短发夹RNA（shRNA）敲低RCC细胞中Ror2的表达可显著降低细胞增殖并诱导凋亡。通过体外迁移和基质胶侵袭试验，我们发现细胞迁移和侵袭能力也受到显著抑制。在RCC中，Ror2表达与参与细胞周期和迁移的基因表达相关，包括增殖细胞核抗原（PCNA）、细胞周期蛋白依赖性激酶1（CDK1）、 Twist蛋白和基质金属蛋白酶2（MMP-2）。此外，在裸鼠体内异种移植研究表明，给予Ror2 shRNA质粒可显著抑制肿瘤生长。这些发现提示了Ror2在肾癌中促进肿瘤活性的新途径，对阐明RCC的肿瘤发生具有重要意义。
