Abstract
Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2–specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.
Highlights
Licensee MDPI, Basel, Switzerland.Ovarian cancer (OC) is the most fatal gynecologic tumor in women, accounting for approximately 14,000 deaths annually worldwide [1,2]
PRKAR1B-AS2 Long noncoding RNAs (lncRNAs) Is Overexpressed in ovarian cancer (OC) and Associated with Poor Survival
The fact that various lncRNAs are implicated in tumorigenesis and chemoresistance given their differential overexpression in cancer has prompted us to investigate the role of lncRNAs in OC
Summary
Ovarian cancer (OC) is the most fatal gynecologic tumor in women, accounting for approximately 14,000 deaths annually worldwide [1,2]. The standard treatment modality for OC relies on tumor debulking followed by a combination of platinum- and taxane-based chemotherapy [3,4,5,6]. Among these regimens, platinum is the most commonly used antineoplastic agent in OC. Most patients with OC experience relapse due to the emergence of platinum resistance [6].
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