FMRP ligand circZNF609 destabilizes RAC1 mRNA to reduce metastasis in acral melanoma and cutaneous melanoma.
FMRP ligand circZNF609 destabilizes RAC1 mRNA to reduce metastasis in acral melanoma and cutaneous melanoma.
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DOI：
10.1186/s13046-022-02357-7
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发表时间：
2022-05-10
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黑色素瘤是一种侵袭性强、预后差的恶性肿瘤。目前，黑色素瘤的转移仍然是导致黑色素瘤患者死亡的重要原因。然而，大多数环状RNA(CircRNAs)在黑色素瘤转移中的潜在功能和分子机制仍不清楚。根据基于重复Transwell分析的筛选模型，利用CircRNA阵列鉴定具有不同转移能力的黑色素瘤细胞亚群中的CircRNAs。采用定量逆转录聚合酶链式反应(qRT-PCR)、核质分离分析和荧光原位杂交等方法，检测皮肤黑色素瘤和肢端黑色素瘤细胞及组织中CircZNF609的表达及预后意义。用体外伤口愈合、Transwell和3D侵袭实验分析黑色素瘤细胞的转移能力。分别采用尾静脉注射和脾内注射进行体内肺转移和肝转移的研究。通过RNA免疫沉淀、RNA下拉、银染和免疫荧光共定位实验进一步探讨了CircZNF609的作用机制。CircZNF609在黑色素瘤组织和细胞中低水平稳定表达，与肿瘤深度、临床分期及预后呈负相关。CircZNF609在体内和体外均能抑制肢端和皮肤黑色素瘤的转移。从机制上讲，CircZNF609促进了FMRP蛋白与RAC1mRNA的结合，从而增强了FMRP蛋白对RAC1mRNA稳定性的抑制作用，最终抑制了黑色素瘤的转移。我们的研究结果表明，CircZNF609通过CircRNF609-FMRP-RAC1轴在肢端和皮肤黑色素瘤的转移中发挥重要作用，并提示CircZNF609通过与FMRP结合来调节RAC1mRNA的稳定性，这可能为深入了解黑色素瘤的发病机制和治疗黑色素瘤提供一个新的潜在靶点。网上版载有补充材料，可在10.1186/s13046-022-02357-7查阅。
Melanoma is a type of malignant tumor with high aggressiveness and poor prognosis. At present, metastasis of melanoma is still an important cause of death in melanoma patients. However, the potential functions and molecular mechanisms of most circular RNAs (circRNAs) in melanoma metastasis remain unknown. circRNAs dysregulated in melanoma cell subgroups with different metastatic abilities according to a screening model based on repeated Transwell assays were identified with a circRNA array. The expression and prognostic significance of circZNF609 in skin cutaneous melanoma and acral melanoma cells and tissues were determined by qRT–PCR, nucleoplasmic separation assays and fluorescence in situ hybridization. In vitro wound healing, Transwell and 3D invasion assays were used to analyse melanoma cell metastasis ability. Tail vein injection and intrasplenic injection were used to study in vivo lung metastasis and liver metastasis, respectively. The mechanism of circZNF609 was further evaluated via RNA immunoprecipitation, RNA pull-down, silver staining, and immunofluorescence colocalization assays. circZNF609 was stably expressed at low levels in melanoma tissues and cells and was negatively correlated with Breslow depth, clinical stage and prognosis of melanoma patients. circZNF609 inhibited metastasis of acral and cutaneous melanoma in vivo and in vitro. Mechanistically, circZNF609 promoted the binding of FMRP protein and RAC1 mRNA, thereby enhancing the inhibitory effect of FMRP protein on the stability of RAC1 mRNA and ultimately inhibiting melanoma metastasis. Our findings revealed that circZNF609 plays a vital role in the metastasis of acral and cutaneous melanoma through the circRNF609-FMRP-RAC1 axis and indicated that circZNF609 regulates the stability of RAC1 mRNA by combining with FMRP, which might provide insight into melanoma pathogenesis and a new potential target for treatment of melanoma. The online version contains supplementary material available at 10.1186/s13046-022-02357-7.
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