环状 RNA circPIP5K1A 通过 miR-515-5p/YAP 轴促进骨肉瘤的肿瘤干性。

Circular RNA circPIP5K1A contributes to cancer stemness of osteosarcoma by miR-515-5p/YAP axis.

机构信息

Department of Bone Surgery, The People's Hospital of Liaoning Province, No. 33 Wenyi Road, Shenhe District, Shenyang, 110016, Liaoning, People's Republic of China.

Department of Breast Surgery, Cancer Hospital of China Medical University, No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, People's Republic of China.

出版信息

J Transl Med. 2021 Nov 13;19(1):464. doi: 10.1186/s12967-021-03124-6.

DOI:10.1186/s12967-021-03124-6

PMID:34774083

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8590363/

Abstract

BACKGROUND

Osteosarcoma is a common type of bone tumors and frequently occurs in children and adolescents. Cancer stem cells (CSCs) are a unique sub-type of self-renewal cancer cells and the stemness of cancer cells are involved in the spread, recurrence, metastasis, and even therapeutic resistance. However, the regulation mechanisms of CSCs in osteosarcoma are poorly understood. Circular RNA (circRNA) is a unique sort of non-coding RNAs and widely participate in the modulation of cancer progression.

METHODS

In this study, we identified the critical function of circular RNA circPIP5K1A in stemness of osteosarcoma cells.

RESULTS

CircPIP5K1A expression was significantly enhanced in clinical osteosarcoma tissues compared with the adjacent normal tissues. The depletion of circPIP5K1A by siRNA repressed osteosarcoma cell viabilities and induced osteosarcoma cell apoptosis. The suppression of circPIP5K1A attenuated the capabilities of invasion and migration of osteosarcoma cells. The circPIP5K1A knockdown increased E-Cadherin expression and decreased Vimentin expression in osteosarcoma cells. The sphere formation abilities of osteosarcoma cells were repressed by the depletion of circPIP5K1A. The CD133CD44 cell population of osteosarcoma cells was reduced by circPIP5K1A knockdown. The expression of ALDH1 and Nanog was decreased by the inhibition of circPIP5K1A in osteosarcoma cells. Mechanically, circPIP5K1A enhanced YAP expression by targeting miR-515-5p. MiR-515-5p inhibited stemness of osteosarcoma cells. The CSCs properties of osteosarcoma cells were repressed by circPIP5K1A knockdown or miR-515-5p mimic, while miR-515-5p inhibitor or YAP overexpression reversed circPIP5K1A knockdown-induced repression. Tumor xenograft analysis in nude mice demonstrated that the depletion of circPIP5K1A represses osteosarcoma cell growth in vivo.

CONCLUSION

In conclusion, we identified that circular RNA circPIP5K1A contributed to cancer stemness of osteosarcoma by miR-515-5p/YAP axis. Targeting circPIP5K1A may be considered as a potential therapeutic strategy for osteosarcoma treatment.

摘要

背景

骨肉瘤是一种常见的骨肿瘤类型，常发生于儿童和青少年。癌症干细胞（CSC）是一种具有自我更新能力的独特肿瘤细胞亚群，肿瘤细胞的干性参与了肿瘤的扩散、复发、转移，甚至治疗抵抗。然而，骨肉瘤中 CSC 的调控机制还知之甚少。环状 RNA（circRNA）是一种独特的非编码 RNA，广泛参与了癌症进展的调控。

方法

在本研究中，我们鉴定了环状 RNA circPIP5K1A 在骨肉瘤细胞干性中的关键作用。

结果

与相邻正常组织相比，circPIP5K1A 在临床骨肉瘤组织中的表达明显升高。siRNA 敲低 circPIP5K1A 抑制骨肉瘤细胞活力并诱导骨肉瘤细胞凋亡。circPIP5K1A 的抑制减弱了骨肉瘤细胞的侵袭和迁移能力。circPIP5K1A 敲低增加了骨肉瘤细胞中 E-钙黏蛋白的表达，降低了波形蛋白的表达。circPIP5K1A 敲低抑制了骨肉瘤细胞的球体形成能力。circPIP5K1A 敲低减少了骨肉瘤细胞中 CD133CD44 细胞群。circPIP5K1A 敲低降低了骨肉瘤细胞中 ALDH1 和 Nanog 的表达。在骨肉瘤细胞中，circPIP5K1A 通过靶向 miR-515-5p 增强了 YAP 的表达。miR-515-5p 抑制了骨肉瘤细胞的干性。circPIP5K1A 敲低或 miR-515-5p 模拟抑制了骨肉瘤细胞的 CSC 特性，而 miR-515-5p 抑制剂或 YAP 过表达逆转了 circPIP5K1A 敲低诱导的抑制作用。裸鼠肿瘤异种移植分析表明，circPIP5K1A 的缺失抑制了骨肉瘤细胞在体内的生长。