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Gut:浙江大学来茂德课题组揭示SRSF6作为结直肠癌治疗靶点调控RNA可变剪接的分子机制

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摘要 : 2017年11月10日,国际著名的胃肠道学杂志《Gut》上在线发表浙江大学基础医学院免疫学研究所来茂德教授研究组题为SRSF6-Regulated Alternative Splicing that Promotes Tumor Progression Offers a Therapy Target for Colorectal Cancer的研究论文,研究揭示了SRSF6作为结直肠癌治疗靶点调控RNA可变剪接的分子机制。
2017年11月10日,国际著名的胃肠道学杂志《Gut》上在线发表浙江大学基础医学院免疫学研究所来茂德教授研究组题为SRSF6-Regulated Alternative Splicing that Promotes Tumor Progression Offers a Therapy Target for Colorectal Cancer的研究论文,研究揭示了SRSF6作为结直肠癌治疗靶点调控RNA可变剪接的分子机制。论文第一作者为博士生万乐栋,来茂德教授和张红河副教授为通讯作者。 课题组前期研究lncRNA LINC01133通过结合可变剪接因子SRSF6,抑制结直肠癌EMT和转移(Kong J, Sun W, Li C, Wan L, Wang S, Wu Y, Xu E, Zhang H*, Lai M*. Long non-coding RNA LINC01133 inhibits epithelial-mesenchymal transition and metastasis in colorectal cancer by interacting with SRSF6. Cancer Lett. 2016,380:476-84)的工作基础上,发现SRSF6在结直肠中异常高表达并且与病人的预后相关。体外研究发现,SRSF6能够促进结直肠癌细胞的增殖与迁移侵袭。RNA测序和生物信息学鉴定了SRSF6下游的可变剪接靶点及作用机制,其中紧密连接蛋白ZO-1第23号外显子的可变剪接是SRSF6的重要靶点之一。体内动物实验也发现异常表达的SRSF6通过调控ZO-1 RNA第23号外显子异常剪接促进结直肠癌的发生和转移。最后课题组通过对SRSF6蛋白同源建模发现治疗慢性阻塞性肺疾病的药物茚达特罗能够在较低剂量下结合并抑制SRSF6的剪接调控功能。在动物模型中,茚达特罗治疗结直肠癌实验显示较好的疗效。该研究通过全新的角度研究肿瘤发病机理,在详细阐明了结直肠癌中异常可变剪接机制,秉承“老药新用”的理念,通过交叉学科进行药物虚拟筛选发现了慢性阻塞性肺疾病药物具有抗结直肠癌作用。 Gut:浙江大学来茂德课题组揭示SRSF6作为结直肠癌治疗靶点调控RNA可变剪接的分子机制
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SRSF6-regulated alteRNAtive splicing that promotes tumour progression offers a therapy target for colorectal cancer 原文摘要: Objective To investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6. Design We performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed in vitro and in vivo. SRSF6-regulated alternative splicing (AS) and its binding motif were identified by next-generation RNA-sequencing and RNA immunoprecipitation sequencing (RIP-seq), which was validated by gel shift and minigene reporter assay. ZO-1 exon23 AS was investigated to mediate the function of SRSF6 in vitro and in vivo. Based on the analysis of domain-specific role, SRSF6-targeted inhibitor was discovered de novoby virtual screening in 4855 FDA-approved drugs and its antitumour effects were evaluated in vitroand in vivo. Results SRSF6 was frequently upregulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis in vitro and in vivo. We identified SRSF6-regulated AS targets and discovered the SRSF6 binding motif. Particularly, SRSF6 regulates ZO-1 aberrant splicing to function as an oncogene by binding directly to its motif in the exon23. Based on the result that SRSF6 RRM2 domain plays key roles in regulating AS and biological function, indacaterol, a β2-adrenergic receptor agonist approved for chronic obstructive pulmonary disease treatment, is identified as the inhibitor of SRSF6 to suppress CRC tumourigenicity. Conclusions SRSF6 functions the important roles in mediating CRC progression through regulating AS, and indacaterol is repositioned as an antitumour drug through targeting SRSF6. doi:10.1136/gutjnl-2017-314983 作者:来茂德 点击:
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