Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma
Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma
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染色体易位衍生的异常 Rab22a 驱动骨肉瘤转移
DOI：
10.1038/s41556-020-0522-z
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发表时间：
2020-06-01
影响因子：
21.3
通讯作者：
Kang, Tiebang
中科院分区：
文献类型：
--
作者：
Liao, Dan;Zhong, Li;Kang, Tiebang
骨肉瘤是一种侵袭性恶性骨肿瘤，常转移至肺部，导致预后不良。然而，骨肉瘤肺转移的分子机制仍未完全明晰。在此，我们在骨肉瘤细胞系和组织中鉴定出了外显子 - 内含子融合基因。这些融合基因源于染色体易位，使得Rab22a第1 - 38位氨基酸的编码区（Rab22a(1 - 38)）与20号染色体的多个反向内含子及非翻译区并列。由此产生的翻译产物，命名为Rab22a - NeoFs，获得了驱动骨肉瘤肺转移的能力。Rab22a(1 - 38)部分通过与RhoA的鸟苷三磷酸 - 鸟苷二磷酸交换因子SmgGDS - 607结合，来调控Rab22a - NeoFs的功能。这种结合促进了与鸟苷三磷酸（GTP）结合的RhoA从SmgGDS - 607上释放，从而诱导RhoA活性增强并促进转移。在骨肉瘤原位模型中，用合成肽破坏Rab22a - NeoF1与SmgGDS - 607之间的相互作用，可防止肺转移。我们的研究结果可能为部分发生肺转移的骨肉瘤患者提供一种有前景的治疗策略。外显子 - 内含子融合的RAB22A调控骨肉瘤转移。廖等人表明，由涉及RAB22A的染色体易位产生的蛋白质产物介导与GTP结合的RhoA的释放，诱导其激活并促进骨肉瘤的肺转移。
Osteosarcoma is a type of aggressive malignant bone tumour that frequently metastasizes to lungs, resulting in poor prognosis. However, the molecular mechanisms of lung metastasis of osteosarcoma remain poorly understood. Here we identify exon-intron fusion genes in osteosarcoma cell lines and tissues. These fusion genes are derived from chromosomal translocations that juxtapose the coding region for amino acids 1-38 of Rab22a (Rab22a(1-38)) with multiple inverted introns and untranslated regions of chromosome 20. The resulting translation products, designated Rab22a-NeoFs, acquire the ability to drive lung metastasis of osteosarcoma. The Rab22a(1-38) moiety governs the function of Rab22a-NeoFs by binding to SmgGDS-607, a GTP-GDP exchange factor of RhoA. This association facilitates the release of GTP-bound RhoA from SmgGDS-607, which induces increased activity of RhoA and promotes metastasis. Disrupting the interaction between Rab22a-NeoF1 and SmgGDS-607 with a synthetic peptide prevents lung metastasis in an orthotopic model of osteosarcoma. Our findings may provide a promising strategy for a subset of osteosarcoma patients with lung metastases.Exon-intron-fused RAB22A regulates metastasis of osteosarcoma. Liao et al. show that protein products resulting from chromosomal translocations involving RAB22A mediate release of GTP-bound RhoA, induce its activation and promote lung metastasis of osteosarcoma.