Therapeutic targeting using tumor specific peptides inhibits long non-coding RNA HOTAIR activity in ovarian and breast cancer.
Therapeutic targeting using tumor specific peptides inhibits long non-coding RNA HOTAIR activity in ovarian and breast cancer.
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DOI：
10.1038/s41598-017-00966-3
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发表时间：
2017-04-18
影响因子：
4.6
通讯作者：
Nephew KP
中科院分区：
文献类型：
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作者：
Özeş AR;Wang Y;Zong X;Fang F;Pilrose J;Nephew KP
长链非编码RNA（lncRNA）在包括癌症在内的人类疾病中发挥关键作用。lncRNA HOTAIR（HOX转录反义RNA）的功能研究为HOTAIR在癌症中的治疗靶向提供了令人信服的证据，但体内靶向lncRNA已被证明是困难的。在目前的研究中，我们描述了一种基于肽核酸（PNA）的方法来阻断HOTAIR与EZH 2相互作用的能力，随后抑制HOTAIR-EZH 2活性并使耐药卵巢肿瘤对铂重新敏感。用PNA治疗HOTAIR过表达的卵巢癌和乳腺癌细胞系可降低侵袭性并增加化疗敏感性。此外，其作用机制与核因子-κ B（NF-κB）活化降低和NF-κB靶基因基质金属蛋白酶9和白细胞介素6表达降低相关。为了将抗lncRNA递送至酸性（pH约6）肿瘤微环境，将PNA缀合至pH低插入肽（pHLIP）。用pHLIP-PNA构建体治疗携带铂抗性卵巢肿瘤异种移植物的小鼠抑制HOTAIR活性，减少肿瘤形成并提高存活率。关于体内靶向实体肿瘤的pHLIP-PNA lncRNA的这一首次报道提出了一种新的癌症治疗方法。
Long non-coding RNAs (lncRNAs) play key roles in human diseases, including cancer. Functional studies of the lncRNA HOTAIR (HOX transcript antisense RNA) provide compelling evidence for therapeutic targeting of HOTAIR in cancer, but targeting lncRNAs in vivo has proven to be difficult. In the current study, we describe a peptide nucleic acids (PNA)-based approach to block the ability of HOTAIR to interact with EZH2 and subsequently inhibit HOTAIR-EZH2 activity and resensitize resistant ovarian tumors to platinum. Treatment of HOTAIR-overexpressing ovarian and breast cancer cell lines with PNAs decreased invasion and increased chemotherapy sensitivity. Furthermore, the mechanism of action correlated with reduced nuclear factor-kappaB (NF-κB) activation and decreased expression of NF-κB target genes matrix metalloprotease 9 and interleukin 6. To deliver the anti-lncRNA to the acidic (pH approximately 6) tumor microenvironment, PNAs were conjugated to pH-low insertion peptide (pHLIP). Treatment of mice harboring platinum-resistant ovarian tumor xenografts with pHLIP-PNA constructs suppressed HOTAIR activity, reduced tumor formation and improved survival. This first report on pHLIP-PNA lncRNA targeting solid tumors in vivo suggests a novel cancer therapeutic approach.