Yeh Da-Wei, Zhao Xuyao, Siddique Hifzur R, Zheng Mengmei, Choi Hye Yeon, Machida Tatsuya, Narayanan Padmini, Kou Yi, Punj Vasu, Tahara Stanley M, Feldman Douglas E, Chen Lin, Machida Keigo
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, 90033, USA.
Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, 202002, India.
Cell Death Discov. 2023 Apr 28;9(1):141. doi: 10.1038/s41420-023-01427-9.
RNA-binding protein Musashi 2 (MSI2) is elevated in several cancers and is linked to poor prognosis. Here, we tested if MSI2 promotes MYC and viral mRNA translation to induce self-renewal via an internal ribosome entry sequence (IRES). We performed RIP-seq using anti-MSI2 antibody in tumor-initiating stem-like cells (TICs). MSI2 binds the internal ribosome entry site (IRES)-containing oncogene mRNAs including MYC, JUN and VEGFA as well as HCV IRES to increase their synthesis and promote self-renewal and tumor-initiation at the post-transcriptional level. MSI2 binds a lncRNA to interfere with processing of a miRNA that reduced MYC translation in basal conditions. Deregulation of this integrated MSI2-lncRNA-MYC regulatory loop drives self-renewal and tumorigenesis through increased IRES-dependent translation of MYC mRNA. Overexpression of MSI2 in TICs promoted their self-renewal and tumor-initiation properties. Inhibition of MSI2-RNA binding reduced HCV IRES activity, viral replication and liver hyperplasia in humanized mice predisposed by virus infection and alcohol high-cholesterol high-fat diet. Together MSI2, integrating the MYC oncogenic pathway, can be employed as a therapeutic target in the treatment of HCC patients. A hypothetical model shows that MSI2 binds and activates cap-independent translation of MYC, c-JUN mRNA and HCV through MSI2-binding to Internal Ribosome Entry Sites (IRES) resulting in upregulated MYC, c-JUN and viral protein synthesis and subsequent liver oncogenesis. Inhibitor of the interaction between MYC IRES and MSI2 reduces liver hyperplasia, viral mRNA translation and tumor formation.
RNA结合蛋白Musashi 2（MSI2）在多种癌症中表达升高，且与预后不良相关。在此，我们测试了MSI2是否通过内部核糖体进入序列（IRES）促进MYC和病毒mRNA翻译以诱导自我更新。我们在肿瘤起始干细胞样细胞（TICs）中使用抗MSI2抗体进行了RIP-seq。MSI2结合含内部核糖体进入位点（IRES）的癌基因mRNA，包括MYC、JUN和VEGFA以及HCV IRES，以增加它们的合成，并在转录后水平促进自我更新和肿瘤起始。MSI2结合一种长链非编码RNA（lncRNA），干扰一种在基础条件下降低MYC翻译的微小RNA（miRNA）的加工。这种整合的MSI2-lncRNA-MYC调节环的失调通过增加MYC mRNA的IRES依赖性翻译来驱动自我更新和肿瘤发生。TICs中MSI2的过表达促进了它们的自我更新和肿瘤起始特性。在病毒感染和酒精高胆固醇高脂肪饮食诱导的人源化小鼠中，抑制MSI2与RNA的结合降低了HCV IRES活性、病毒复制和肝脏增生。总之，整合MYC致癌途径的MSI2可作为治疗肝癌患者的治疗靶点。一个假设模型表明，MSI2通过与内部核糖体进入位点（IRES）结合，结合并激活MYC、c-JUN mRNA和HCV的不依赖帽的翻译，导致MYC、c-JUN和病毒蛋白合成上调以及随后的肝脏肿瘤发生。MYC IRES与MSI2之间相互作用的抑制剂可减少肝脏增生、病毒mRNA翻译和肿瘤形成。
