MicroRNA‐519d‐3p antagonizes osteosarcoma resistance against cisplatin by targeting PD‐L1

Abstract

Accumulating evidence indicates that a ligand of programmed cell death receptor‐1 (PD‐L1) participates in the progression and recurrence of multiple malignancies, including osteosarcoma. Nevertheless, the role of PD‐L1 in chemoresistance development is not fully understood. In the current study, we aim to clarify the interaction of miR‐519d‐3p and PD‐L1 in the development of cisplatin resistance. Immunohistochemistry, quantitative reverse‐transcription polymerase reaction, and Western blot were used to evaluate PD‐L1 expression. MTT and transwell migration assays were used to measure cell growth and motility, respectively. ENCORI, miRCode, and miRDB databases were recruited to predict candidate miRNAs targeting PD‐L1. The binding sequences of miR‐519d‐3p and PD‐L1 3ʹ untranslated region were identified by dual‐luciferase reporter and RNA immunoprecipitation assays. Flow cytometric analysis was conducted to measure the cycle distribution and cell apoptosis. Metastatic mouse models were generated with cisplatin‐resistant sublines by intravenous injection. We found that PD‐L1 expression was positively correlated to cisplatin resistance and metastasis, whereas miR‐519d‐3p expression was reduced in cisplatin‐resistant specimens and was negatively correlated to cisplatin resistance and metastasis of osteosarcoma. We demonstrated that miR‐519d‐3p overexpression reversed cisplatin resistance, induced G1/S phase arrest and apoptosis. In addition, we proved that miR‐519d‐3p inhibited lung metastasis by establishing cisplatin‐resistant MG63 metastatic xenograft models. The present findings suggest that miR‐519d‐3p/PD‐L1 axis is a novel signaling pathway contributing to cisplatin resistance. Our study provides new clues for curing refractory osteosarcoma beyond immune checkpoint inhibitors.

Targeted Delivery of PD‐L1‐Derived Phosphorylation‐Mimicking Peptides by Engineered Biomimetic Nanovesicles to Enhance Osteosarcoma Treatment

“…PD‐L1 also reportedly regulates cisplatin resistance in osteosarcoma. [ 23 ] Notably, intercellular PD‐L1 functions as an RNA binding protein to protect the mRNAs of NBS1 and BRCA1 from degradation and regulate DNA damage response, [ 11 ] possibly providing one explanation for how PD‐L1 leads to cisplatin resistance. Similarly, we have demonstrated that NPM PD‐L1 activates mTOR signaling to regulate osteosarcoma growth by binding with IGFBP3.…”

Deciphering chemoresistance in osteosarcoma: Unveiling regulatory mechanisms and function through the lens of noncoding RNA

“…However, the downstream factor JUN interacts with the promoter of miR‐223 to upregulate its transcription, forming a miR‐223/Hsp70/JNK/JUN/miR‐223 feedback loop (Tang et al, 2018). A high level of miR‐340, miR‐340‐5p, miR‐138, miR‐203, miR‐519d‐3p, and miR‐217 shows drug sensitivity to DDP by stimulating cell death (Huang et al, 2021; Song, Duan, et al, 2017; Wang, Zhang, et al, 2022; Yan et al, 2018; Zhang, Guo, et al, 2015; Zhu et al, 2016). miRNAs can promote drug sensitivity by turning on the PI3K/AKT signaling pathway, which is a crucial strategy for overcoming chemotherapy resistance.…”

CJ2: A Novel Potent Platinum(IV) Prodrug Enhances Chemo-Immunotherapy by Facilitating PD-L1 Degradation in the Cytoplasm and Cytomembrane

“…Membrane-localized PD-L1 can combine with the PD-1 ligand on the T cell surface to inhibit immune cell proliferation and activity, thus helping tumor cells avoid immune monitoring. , Unlike that of the PD-L1 protein on the membrane, the role of PD-L1 in the cytoplasm is often neglected. In fact, recent research has shown that intracellular PD-L1 could promote tumor growth via a non-immune pathway. , Lou et al found that intracellular PD-L1 can act as an RNA-binding protein to regulate the mRNA stability of DNA damage repair (DDR) . In addition, high expression of PD-L1 can promote cisplatin or radiotherapy resistance. , …”

“…In fact, recent research has shown that intracellular PD-L1 could promote tumor growth via a non-immune pathway. 35,36 Lou et al found that intracellular PD-L1 can act as an RNA-binding protein to regulate the mRNA stability of DNA damage repair (DDR). 37 In addition, high expression of PD-L1 can promote cisplatin or radiotherapy resistance.…”