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PRKAR1B-AS2 长非编码 RNA 通过 PI3K/AKT/mTOR 通路促进肿瘤发生、存活和化疗耐药性。

PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis, Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway.

机构信息

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11675, Egypt.

出版信息

Int J Mol Sci. 2021 Feb 13;22(4):1882. doi: 10.3390/ijms22041882.

DOI:10.3390/ijms22041882
PMID:33668685
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7918312/
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.

摘要

许多长链非编码 RNA 被认为与肿瘤发生和化疗耐药有关；然而，其潜在机制尚不清楚。我们研究了 PRKAR1B-AS2 长链非编码 RNA 在卵巢癌 (OC) 和化疗耐药中的作用，并确定了其作用的潜在下游分子机制。我们进行了癌症基因组图谱 OC 数据集分析、体外实验、蛋白质组学分析和卵巢癌荷瘤小鼠模型实验。我们的研究结果表明，PRKAR1B-AS2 的过表达与 OC 患者的总生存期呈负相关。此外，PRKAR1B-AS2 敲低减弱了 OC 细胞的增殖、迁移和侵袭，并改善了体外顺铂和 alpelisib 的耐药性。在蛋白质组学分析中，沉默 PRKAR1B-AS2 显著抑制了 PI3K-110α 的蛋白表达，并阻断了 PDK1、AKT 和 mTOR 的磷酸化，而对 PTEN 没有明显影响。RNA 免疫沉淀检测到 PRKAR1B-AS2 与 PI3K-110α 之间存在物理相互作用。此外，通过系统给予载有 PRKAR1B-AS2 特异性小干扰 RNA 的 1,2-二油酰基-sn-甘油-3-磷酸胆碱纳米粒进行 PRKAR1B-AS2 敲低，增强了卵巢癌荷瘤小鼠模型中顺铂的敏感性。总之，PRKAR1B-AS2 通过调节 PI3K/AKT/mTOR 通路促进肿瘤生长并赋予化疗耐药性。因此，靶向 PRKAR1B-AS2 可能代表治疗 OC 患者的一种新的治疗方法。

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