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Aptamer-guided targeting of the intracellular long-noncoding RNA HOTAIR.

ABSTRACT: Long non-coding RNAs (lncRNAs) are increasingly recognized as promising targets in cancer treatment. However, compared to targeting the ordinary protein-coding genes, suppressing non-coding RNAs expressed in cancer cells has been a more challenging task. The major hurdles lay on the requirement of a tumor-specific delivery system for the designated inhibitor to suppress the target transcripts within the cellular compartment. EGFR is a cancer driver gene which is frequently associated with the triple-negative phenotype of breast cancer. Prior studies have shown that expression of the tumor-promoting lncRNA HOTAIR (HOX antisense intergenic RNA) is positively regulated by the epithelial growth factor receptor (EGFR) in triple-negative breast cancer (TNBC), and consistently the expression of both genes is closely correlated in breast cancer. Here we show that a chimeric aptamer recognizing the epithelial growth factor receptor (EGFR) coupled with a siRNA against HOTAIR (EGFR aptamer-coupled siHOTAIR) preferentially and effectively down-regulated HOTAIR in EGFR-expressing cancer cells. Functionally, the EGFR aptamer-coupled siHOTAIR more potently inhibited the growth, migration, and invasion of EGFR-expressing TNBC cells as well as cells with reconstituted EGFR compared to cancer cells with low EGFR expression. Our results demonstrate a novel strategy of targeting cancer progression by aptamer-directed delivery of anti-lncRNA RNA interference that can be applicable to other cellular contexts and cancer types.

SUBMITTER: Wang YL

PROVIDER: S-EPMC7994153 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHOTAIR, a newly discovered long intergenic noncoding RNA (lincRNA), has been reported to be aberrantly expressed in many types of cancers. This meta-analysis summarizes its potential role as a biomarker in malignancy.MethodsA quantitative meta-analysis was performed through a systematic search in Pubmed, Medline and Web of Science for eligible papers on the prognostic impact of HOTAIR in cancer from inception to Feb. 28, 2014. Pooled hazard ratios (HRs) with 95% confidence interval (95% CI) were calculated to summarize the effect.ResultsNineteen studies were included in the study, with a total of 2033 patients. A significant association was observed between high HOTAIR expression and poor overall survival (OS) in patients with cancer (pooled HR 2.22, 95% CI: 1.68-2.93). Place of residence (Asian or Western countries), type of cancer (digestive or non-digestive disease), sample size (more or less than 100), and paper quality (score more or less than 85%) did not alter the significant predictive value of HOTAIR in OS from various kinds of cancer but preoperative status did. By combining HRs from Cox multivariate analyses, we found that HOTAIR expression was an independent prognostic factor for cancer patients (pooled HR 2.26, 95% CI: 1.62-3.15). Subgroup analysis showed that HOTAIR abundance was an independent prognostic factor for cancer metastasis (HR 3.90, 95% CI: 2.25-6.74). For esophageal carcinoma, high HOTAIR expression was significantly associated with TNM stage (III/IV vs. I/II: OR 6.90, 95% CI: 2.81-16.9) without heterogeneity. In gastric cancer, HOTAIR expression was found to be significantly associated with lymph node metastases (present vs. absent: OR 4.47, 95% CI: 1.88-10.63) and vessel invasion (positive vs. negative: OR 2.88, 95% CI: 1.38-6.04) without obvious heterogeneity.ConclusionsHOTAIR abundance may serve as a novel predictive factor for poor prognosis in different types of cancers in both Asian and Western countries.

Project description:Glioblastoma multiforme (GBM) is the most common and aggressive malignant adult primary brain tumor. Despite surgical resection followed by radiotherapy and chemotherapy, the median survival rate is approximately 14 months. Although experimental therapies are in clinical trials for GBM, there is an urgent need for a peripheral GBM biomarker for measuring treatment response. As we have previously demonstrated that the long noncoding RNA HOX Transcript Antisense Intergenic RNA, or HOTAIR, is dysregulated in GBM and required for GBM cell proliferation, we hypothesized that HOTAIR expression may be utilized as a peripheral biomarker for GBM. HOTAIR expression was measured in serum from 43 GBM and 40 controls using quantitative real-time PCR (qRT-PCR). The PCR products were subsequently subcloned into pCR™4-TOPO®TA vectors for DNA sequencing. A ROC curve was also generated to examine HOTAIR's prognostic value. The amount of HOTAIR in serum exosomes and exosome-depleted supernatant was calculated by qRT-PCR. The relative HOTAIR expression was also investigated in 15 pairs of GBM serum and tumors. We detected HOTAIR in serum from GBM patients. HOTAIR levels in serum samples from GBM patients was significantly higher than in the corresponding controls (P <?0.0001). The area under the ROC curve distinguishing GBM patients from controls was 0.913 (95% CI: 0.845-0.982, P <?0.0001), with 86.1% sensitivity and 87.5% specificity at the cut-off value of 10.8. HOTAIR expression was significantly correlated with high grade brain tumors. In addition, Pearson correlation analysis indicated a medium correlation of serum HOTAIR levels and the corresponding tumor HOTAIR levels (r =?0.734, P <?0.01). We confirmed via sequencing that the amplified HOTAIR from serum contained the HOTAIR sequence and maps to the known HOTAIR locus at 12q13. The serum-derived exosomes contain HOTAIR and the purified exosomes were validated by western blot and nanoparticle tracking analysis. Importantly, our results demonstrate that serum HOTAIR can be used as a novel prognostic and diagnostic biomarker for GBM.

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Aptamer-guided targeting of the intracellular long-noncoding RNA HOTAIR.

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