Sun Meng-Shun, Yuan Lan-Ting, Kuei Chia-Hao, Lin Hui-Yu, Chen Yen-Lin, Chiu Hui-Wen, Lin Yuan-Feng
Department of Internal Medicine, Division of Gastroenterology, Yuan's General Hospital, Kaohsiung 80249, Taiwan.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Cancers (Basel). 2021 Apr 7;13(8):1763. doi: 10.3390/cancers13081763.
Colorectal cancer (CRC) is one of the most common cancers and results in high mortality worldwide, owing to cancer progression, i.e., metastasis. However, the molecular mechanism underlying the metastatic evolution of CRC remains largely unknown. Here, we find that the upregulation of Ral Guanine Nucleotide Dissociation Stimulator Like 2 (RGL2) is commonly detected in primary tumors compared normal tissues and is significantly associated with a poorer prognosis in CRC patients. Moreover, RGL2 expression appeared to positively correlate with the metastatic potentials of CRC cells. Whereas RGL2 knockdown dramatically suppresses the metastatic potentials of CRC cells in vitro and in vivo, RGL2 overexpression in the poorly metastatic CRC cells and reconstitution in the RGL2-silenced CRC cells enhanced and rescued the cellular metastatic ability, respectively. Computational simulation using Gene Set Enrichment Analysis program and cell-based assays demonstrated that RGL2 expression causally associated with the activity of Wnt/β-catenin signaling axis and Kirsten ras (KRAS)S, as well as the progression of epithelial-mesenchymal transition (EMT) in the detected CRC cells. Importantly, RGL2 upregulation was capable of preventing the protein degradation of β-catenin and KRAS in CRC cells. These findings suggest that RGL2 acts as a driver to promote the metastatic progression of CRC and also serves as a poor prognostic biomarker in CRC patients.
结直肠癌（CRC）是最常见的癌症之一，在全球范围内导致高死亡率，这归因于癌症进展，即转移。然而，CRC转移演变的分子机制在很大程度上仍然未知。在这里，我们发现与正常组织相比，原发性肿瘤中通常检测到Ral鸟嘌呤核苷酸解离刺激因子样2（RGL2）上调，并且这与CRC患者较差的预后显著相关。此外，RGL2表达似乎与CRC细胞的转移潜能呈正相关。虽然RGL2敲低在体外和体内均显著抑制CRC细胞的转移潜能，但在低转移CRC细胞中RGL2过表达以及在RGL2沉默的CRC细胞中进行恢复分别增强和挽救了细胞的转移能力。使用基因集富集分析程序进行的计算模拟和基于细胞的实验表明，RGL2表达与Wnt/β-连环蛋白信号轴和 Kirsten 大鼠肉瘤病毒癌基因（KRAS）的活性以及所检测CRC细胞中的上皮-间质转化（EMT）进程存在因果关系。重要的是，RGL2上调能够防止CRC细胞中β-连环蛋白和KRAS的蛋白质降解。这些发现表明，RGL2是促进CRC转移进展的驱动因素，也是CRC患者预后不良的生物标志物。
