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PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma.
Oncogene ( IF 6.9 ) Pub Date : 2018-Apr-01 , DOI: 10.1038/s41388-017-0081-3
Jason A. Hanna , Matthew R. Garcia , Alicia Lardennois , Patrick J. Leavey , Dino Maglic , Alexandre Fagnan , Jonathan C. Go , Jordan Roach , Yong-Dong Wang , David Finkelstein , Mark E. Hatley

Rhabdomyosarcoma is the most common soft-tissue sarcoma in childhood and histologically resembles developing skeletal muscle. Alveolar rhabdomyosarcoma (ARMS) is an aggressive subtype with a higher rate of metastasis and poorer prognosis. The majority of ARMS tumors (80%) harbor a PAX3-FOXO1 or less commonly a PAX7-FOXO1 fusion gene. The presence of either the PAX3-FOXO1 or PAX7-FOXO1 fusion gene foretells a poorer prognosis resulting in clinical re-classification as either fusion-positive (FP-RMS) or fusion-negative RMS (FN-RMS). The PAX3/7-FOXO1 fusion genes result in the production of a rogue transcription factors that drive FP-RMS pathogenesis and block myogenic differentiation. Despite knowing the molecular driver of FP-RMS, targeted therapies have yet to make an impact for patients, highlighting the need for a greater understanding of the molecular consequences of PAX3-FOXO1 and its target genes including microRNAs. Here we show FP-RMS patient-derived xenografts and cell lines display a distinct microRNA expression pattern. We utilized both loss- and gain-of function approaches in human cell lines with knockdown of PAX3-FOXO1 in FP-RMS cell lines and expression of PAX3-FOXO1 in human myoblasts and identified microRNAs both positively and negatively regulated by the PAX3-FOXO1 fusion protein. We demonstrate PAX3-FOXO1 represses miR-221/222 that functions as a tumor suppressing microRNA through the negative regulation of CCND2, CDK6, and ERBB3. In contrast, miR-486-5p is transcriptionally activated by PAX3-FOXO1 and promotes FP-RMS proliferation, invasion, and clonogenic growth. Inhibition of miR-486-5p in FP-RMS xenografts decreased tumor growth, illustrating a proof of principle for future therapeutic intervention. Therefore, PAX3-FOXO1 regulates key microRNAs that may represent novel therapeutic vulnerabilities in FP-RMS.

中文翻译:

PAX3-FOXO1驱动miR-486-5p并抑制miR-221,从而促进了肺泡横纹肌肉瘤的发病。

横纹肌肉瘤是儿童时期最常见的软组织肉瘤,在组织学上类似于发育中的骨骼肌。肺泡横纹肌肉瘤(ARMS)是一种侵袭性亚型,具有较高的转移率和较差的预后。大多数ARMS肿瘤(80%)都带有PAX3-FOXO1或更不常见的PAX7-FOXO1融合基因。PAX3-FOXO1或PAX7-FOXO1融合基因的存在预示了较差的预后,导致临床重新分类为融合阳性(FP-RMS)或融合阴性RMS(FN-RMS)。PAX3 / 7-FOXO1融合基因导致流氓转录因子的产生,该转录因子驱动FP-RMS发病机理并阻止肌原性分化。尽管了解FP-RMS的分子驱动因素,但靶向疗法尚未对患者产生影响,强调需要进一步了解PAX3-FOXO1及其靶基因(包括microRNA)的分子后果。在这里,我们显示FP-RMS患者来源的异种移植物和细胞系显示出不同的microRNA表达模式。我们在人细胞系中利用了功能丧失和获得功能的方法,在FP-RMS细胞系中敲低了PAX3-FOXO1,并在人成肌细胞中表达了PAX3-FOXO1,并鉴定了受PAX3-FOXO1融合蛋白正向和负向调控的microRNA。蛋白质。我们证明PAX3-FOXO1抑制miR-221 / 222,其通过CCND2,CDK6和ERBB3的负调控来抑制肿瘤的microRNA。相反,miR-486-5p被PAX3-FOXO1转录激活,并促进FP-RMS增殖,侵袭和克隆形成生长。FP-RMS异种移植物中miR-486-5p的抑制作用降低了肿瘤的生长,说明了未来治疗干预的原理证明。因此,PAX3-FOXO1调节可能代表FP-RMS中新型治疗漏洞的关键microRNA。
更新日期:2018-01-25
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