Mishima Keishiro, Obika Satoshi, Shimojo Masahito
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka 565-0871, Japan.
Mol Ther Nucleic Acids. 2024 Jul 2;35(3):102250. doi: 10.1016/j.omtn.2024.102250. eCollection 2024 Sep 10.
RNA splicing regulation has revolutionized the treatment of challenging diseases. Neuroendocrine cancers, including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (PCa), are highly aggressive, with metastatic neuroendocrine phenotypes, leading to poor patient outcomes. We investigated amido-bridged nucleic acid (AmNA)-based splice-switching oligonucleotides (SSOs) targeting RE1-silencing transcription factor (REST) splicing as a novel therapy. We designed AmNA-based SSOs to alter REST splicing. Tumor xenografts were generated by subcutaneously implanting SCLC or PCa cells into mice. SSOs or saline were intraperitoneally administered and tumor growth was monitored. Blood samples were collected from mice after SSO administration, and serum alanine aminotransferase and aspartate aminotransferase levels were measured to assess hepatotoxicity using a biochemical analyser. , REST_SSO reduced cancer cell viability. In a tumor xenograft model, it exhibited significant antitumor effects. It repressed REST-controlled RE1-harboring genes and upregulated miR-4516, an SCLC biomarker. Our findings suggest that REST_SSO suppresses tumorigenesis in neuroendocrine cancers by restoring REST function. This novel therapeutic approach holds promise for intractable neuroendocrine cancers such as SCLC and neuroendocrine PCa.
RNA剪接调控彻底改变了对疑难疾病的治疗方式。神经内分泌癌，包括小细胞肺癌（SCLC）和神经内分泌前列腺癌（PCa），具有高度侵袭性，伴有转移性神经内分泌表型，导致患者预后不良。我们研究了靶向RE1沉默转录因子（REST）剪接的基于酰胺桥连核酸（AmNA）的剪接转换寡核苷酸（SSO）作为一种新型疗法。我们设计了基于AmNA的SSO来改变REST剪接。通过将SCLC或PCa细胞皮下植入小鼠体内生成肿瘤异种移植模型。腹腔注射SSO或生理盐水，并监测肿瘤生长情况。在给予SSO后从小鼠采集血样，使用生化分析仪测量血清丙氨酸转氨酶和天冬氨酸转氨酶水平以评估肝毒性。REST_SSO降低了癌细胞活力。在肿瘤异种移植模型中，它表现出显著的抗肿瘤作用。它抑制了REST控制的含有RE1的基因，并上调了SCLC生物标志物miR-4516。我们的研究结果表明，REST_SSO通过恢复REST功能抑制神经内分泌癌的肿瘤发生。这种新型治疗方法有望用于治疗诸如SCLC和神经内分泌PCa等难治性神经内分泌癌。
