1 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .
2 Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University , Hangzhou, China .
Hum Gene Ther. 2017 Aug;28(8):690-700. doi: 10.1089/hum.2017.041. Epub 2017 May 19.
SNORD44 is a C/D box small nucleolar RNA, and exhibits low expression in breast cancer and head and neck squamous cell carcinoma tissues. Its host gene is growth arrest specific transcript 5 (GAS5), which is a long noncoding RNA. GAS5 is downregulated in colorectal cancer (CRC), and overexpression of GAS5 suppresses cell proliferation. However, the function of SNORD44 in CRC remains largely unknown, and the application of SNORD44 combined with GAS5 in CRC treatment has not been reported. In this study, the expression levels of SNORD44 and GAS5 were measured in CRC tissues by quantitative RT-PCR. The correlation between SNORD44 and GAS5 was evaluated by Pearson correlation analysis. An oncolytic adenovirus expressing SNORD44 and GAS5 (SPDD-UG) was constructed. The biological effects of SPDD-UG were investigated in CRC cell line SW620 and LS174T in vitro and in xenografts. The synergistic effect of rapamycin and SPDD-UG was explored in SW620 and LS174T cells and tumors. We demonstrated that SNORD44 expression level was markedly decreased in CRC tissues and positively correlated with GAS5 expression. SPDD-UG significantly inhibited SW620 and LS174T cell growth and induced cell apoptosis. Intratumoral injection of SPDD-UG significantly suppressed xenografts growth in nude mice. Moreover, the mechanistic target of rapamycin (mTOR) inhibitor, rapamycin, enhanced the antitumor effect through antagonizing the PI3K/Akt pathway activated by SPDD-UG. These results suggest that overexpression of SNORD44 and GAS5 by oncolytic adenovirus provides a promising method for CRC therapy.
SNORD44 是一种 C/D 框小核仁 RNA，在乳腺癌和头颈部鳞状细胞癌组织中表达水平较低。其宿主基因为生长停滞特异性转录物 5（GAS5），它是一种长非编码 RNA。GAS5 在结直肠癌（CRC）中下调，过表达 GAS5 可抑制细胞增殖。然而，SNORD44 在 CRC 中的功能在很大程度上尚不清楚，也没有报道过将 SNORD44 与 GAS5 联合应用于 CRC 治疗。在本研究中，通过定量 RT-PCR 检测 CRC 组织中 SNORD44 和 GAS5 的表达水平。通过 Pearson 相关性分析评估 SNORD44 和 GAS5 之间的相关性。构建了表达 SNORD44 和 GAS5 的溶瘤腺病毒（SPDD-UG）。在 CRC 细胞系 SW620 和 LS174T 中以及异种移植瘤中研究了 SPDD-UG 的生物学效应。在 SW620 和 LS174T 细胞和肿瘤中探讨了雷帕霉素和 SPDD-UG 的协同作用。结果表明，CRC 组织中 SNORD44 的表达水平明显降低，与 GAS5 的表达呈正相关。SPDD-UG 显著抑制 SW620 和 LS174T 细胞生长并诱导细胞凋亡。瘤内注射 SPDD-UG 显著抑制裸鼠异种移植瘤的生长。此外，mTOR 抑制剂雷帕霉素通过拮抗 SPDD-UG 激活的 PI3K/Akt 通路增强了抗肿瘤作用。这些结果表明，溶瘤腺病毒过表达 SNORD44 和 GAS5 为 CRC 治疗提供了一种有前途的方法。
