Department of Pediatric Hematology and Oncology, Children's Research Center, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
Research Unit Protein Science, Helmholtz Zentrum Munich (GmbH), German Research Center for Environmental Health, Munich, Germany.
Liver Int. 2018 Jul;38(7):1280-1291. doi: 10.1111/liv.13687. Epub 2018 Jan 25.
BACKGROUND & AIMS: MicroRNAs are important genetic regulators of physiological and pathophysiological processes including cancer initiation and progression of hepatoblastoma, the most common liver tumour in childhood. We aimed to identify malignant and metastasis promoting effects of miR-492, a miRNA, previously reported to be overexpressed in metastatic hepatoblastoma. Furthermore, we intended to evaluate its diagnostic and prognostic potential.
Stable and transient overexpression of miR-492 in two liver tumour cell lines HepT1 and HUH7 was used to analyse features of metastatic tumour progression such as proliferation, anchorage-independent growth, migration and invasion. Via a mass spectrometry based proteomic screen, we investigated miRNA-492-dependent effects on proteome level and explored the underlying biology. One of the predicted target genes, CD44, was experimentally validated via luciferase assays. Diagnostic and prognostic properties of miR-492 were studied in hepatoblastoma tumour samples.
We show that miR-492 significantly enhances cell proliferation, anchorage-independent growth, migration and invasion of hepatoblastoma cells. We also identified and validated CD44, a transmembrane adhesion receptor for hyaluronan, as direct and functional target of miR-492. This miRNA has a strong direct impact on two CD44 isoforms (standard and v10). High miR-492 expression correlates with high-risk or aggressive tumours and further bears potential for predicting reduced event-free survival.
We identified miR-492 and its target CD44 as regulators of a number of biological features important for malignancy and metastasis. Furthermore, we demonstrated the diagnostic and prognostic potential of miR-492, a promising novel therapeutic target and biomarker for hepatoblastoma.
microRNAs 是生理和病理生理过程（包括肝癌的发生和肝母细胞瘤的进展）的重要遗传调节剂，肝母细胞瘤是儿童中最常见的肝脏肿瘤。我们旨在确定 microRNA-492 的恶性和转移促进作用，miR-492 先前被报道在转移性肝母细胞瘤中过度表达。此外，我们还旨在评估其诊断和预后潜力。
使用两种肝癌细胞系 HepT1 和 HUH7 的稳定和瞬时过表达 miR-492 来分析转移性肿瘤进展的特征，如增殖、非锚定依赖性生长、迁移和侵袭。通过基于质谱的蛋白质组筛选，我们研究了 miRNA-492 对蛋白质组水平的依赖性影响，并探索了潜在的生物学机制。预测的靶基因之一 CD44 通过荧光素酶测定实验进行了验证。研究了 miR-492 在肝母细胞瘤肿瘤样本中的诊断和预后特性。
我们表明，miR-492 显著增强了肝癌细胞的增殖、非锚定依赖性生长、迁移和侵袭。我们还鉴定并验证了 CD44，一种透明质酸的跨膜粘附受体，是 miR-492 的直接和功能靶标。该 miRNA 对两种 CD44 异构体（标准型和 v10）具有强烈的直接影响。高 miR-492 表达与高危或侵袭性肿瘤相关，并且具有预测无事件生存时间减少的潜力。
我们确定了 miR-492 和其靶标 CD44 作为调节恶性和转移的多个生物学特征的调节剂。此外，我们证明了 miR-492 的诊断和预后潜力，miR-492 是一种有前途的新型治疗靶点和肝母细胞瘤的生物标志物。
