Cisplatin-induced PANDAR-Chemo-EVs contribute to a more aggressive and chemoresistant ovarian cancer phenotype through the SRSF9-SIRT4/ SIRT6 axis

다국어 초록 (Multilingual Abstract)

Objective: We previously elucidated that long non-coding RNA Promoter of CDKN1A AntisenseDNA damage Activated RNA (PANDAR) as a p53-dependent oncogene to promote cisplatinresistance in ovarian cancer (OC). Intriguingly, high level of p53-independent PANDAR wasfound in cisplatin-resistant patients with p53 mutation. Here, our study probed the new rolesand the underlying mechanisms of PANDAR in p53-mutant OC cisplatin-resistance.
Methods: A2780 and A2780-DDP cells were ser ved as OC cisplatin-sensitive and cisplatin-resistant cells. HO-8910PM cells were subjected to construct chemotherapy-inducedextracellular vesicles (Chemo-EVs). Transmission electron microscopy (TEM) and nanoparticletracking analysis were employed to evaluate Chemo-EVs. Cell viability was assessed using cellcounting kit-8 and colony formation assays. Cell apoptosis was assessed using Annexin V andpropidium iodide staining. The relationships between PANDAR, serine and arginine-rich pre-mRNA splicing factor 9 (SRSF9) were verified by RNA immunoprecipitation and fluorescencein situ hybridization. Tumor xenograft experiment was employed to evaluate the effects ofPANDAR-Chemo-EVs on OC cisplatin-resistance in vivo. Immunofluorescent staining andimmunohistochemistr y were performed in tumor tissue.
Results: PANDAR level increased in OC patients with p53-mutation. PANDAR efflux enactedvia exosomes under cisplatin conditions. Additionally, exosomes from OC cell lines carriedPANDAR, which significantly increased cell sur vival and chemoresistance in vitro and tumorprogression and metastasis in vivo. During cisplatin-induced stress, SRSF9 was recruited tonuclear bodies by increased PANDAR and muted apoptosis in response to cisplatin. Besides,SRSF9 significantly increased the ratio of SIRT4/SIRT6 mRNA in OC.
Conclusion: Cisplatin-induced exosomes transfer PANDAR and lead to a rapid adaptation ofOC cell sur vival through accumulating SRSF9 following cisplatin stress exposure.