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

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 CD133+CD44+ 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.

The Roles of Noncoding RNAs in the Development of Osteosarcoma Stem Cells and Potential Therapeutic Targets

“…CircNRIP1 encapsulated by BMSC-EVs aggravated osteosarcoma via targeting miR-532-3p and PI3K/AKT axis ( Shi Z. et al, 2021 ). Shi et al reported that circPIP5K1A depletion reduced the sphere formation abilities in osteosarcoma cells and decreased the CD133 + CD44 + cell population ( Shi P. et al, 2021 ). Knockdown of circPIP5K1A reduced the expression of Nanog ad ALDH1 in osteosarcoma cells.…”

“…Knockdown of circPIP5K1A reduced the expression of Nanog ad ALDH1 in osteosarcoma cells. Moreover, circPIP5K1A increased YAP expression via regulating miR-515-5p, and miR-515-5p suppressed cancer stemness in osteosarcoma cells ( Shi P. et al, 2021 ). Notably, circPIP5K1A depletion or miR-515-5p mimic inhibited the CSC properties in osteosarcoma cells, suggesting that circPIP5K1A can control CSCs in osteosarcoma ( Shi P. et al, 2021 ).…”

The interplay between noncoding RNA and YAP/TAZ signaling in cancers: molecular functions and mechanisms

“…Mechanistically, circPIP5K1A was found to enhance YAP expression by targeting miR-515-5p. Knockdown of circPIP5K1A inhibited the CSC properties of osteosarcoma cells, while miR-515-5p inhibitor treatment or YAP overexpression reversed this circPIP5K1A knockdown-induced inhibition [ 154 ]. In colorectal cancer, circ_0128846 was found to sponge miR-1184 to release the suppression of AJUBA expression, leading to reduced YAP phosphorylation and activated YAP signaling, thereby promoting proliferation, migration, and invasion and inhibiting apoptosis in colorectal cells [ 155 ].…”

Advances in the research of osteosarcoma stem cells and its related genes

“…The TGFβ‐miR‐499a‐SHKBP1 pathway coordinates EMT‐related kinase signaling, which induces resistance of osteosarcoma CSCs to EGFR inhibitors (T. Wang et al, 2019). Other genes influencing the chemotherapy resistance by altering the stemness of OSCs have been described (Lee et al, 2017; F. Liu et al, 2018; Qi et al, 2019; Shang et al, 2017; Shi et al, 2021; L. Xu et al, 2020; Y. Yu et al, 2021; L. Zhang et al, 2020).…”

“…Other genes influencing the chemotherapy resistance by altering the stemness of OSCs have been described (Lee et al, 2017;F. Liu et al, 2018;Qi et al, 2019;Shang et al, 2017;Shi et al, 2021;L. Xu et al, 2020;.…”