Cell Death Dis:SF3B1调节KSR2 mRNA的成熟促进子宫内膜癌的发生发展

2020-10-20 星云 MedSci原创

2020年美国预计约有65,620名患者新确诊子宫内膜癌,预计有12,590名妇女死于该疾病,这也使得该疾病成为最常见的妇科恶性肿瘤之一。随着肥胖症(子宫内膜癌的关键危险因素)的增加,预计到2030年

2020年美国预计约有65,620名患者新确诊子宫内膜癌,预计有12,590名妇女死于该疾病,这也使得该疾病成为最常见的妇科恶性肿瘤之一。随着肥胖症(子宫内膜癌的关键危险因素)的增加,预计到2030年,病例数将增加一倍。

该疾病得主要治疗选择包括内分泌治疗、化疗、免疫疗法、放疗和子宫切除术。但由于内分泌疗法的疗效有限,而子宫切除术对于希望保留生育能力的女性而言并不是最合适的选择。因此,更深入的了解子宫内膜癌发生发展相关基因有利于开发新型的疾病治疗策略。


为了鉴定新型的预后和治疗靶标,研究人员将重点放在该癌症的新领域:mRNA可变剪接,并研究剪接因子SF3B1在子宫内膜癌的发病机制中的重要作用。

SF3B1在子宫内膜癌细胞中过表达

通过组织芯片分析,研究人员发现,相比于非癌组织,人子宫内膜癌中SF3B1蛋白的表达水平更高。此外,敲低SF3B1能够减少子宫内膜癌细胞系Ishikawa和AN3CA的增殖、迁移和侵袭作用。同样的,SF3B1抑制剂PLAD-B(Pladienolide-B)可减少两个细胞系的增殖和侵袭作用。此外,PLAD-B能抑制原位子宫内膜癌小鼠模型中肿瘤的生长。

PLAD-B抑制子宫内膜癌的生长

研究人员通过RNA-Seq方法,在子宫内膜癌细胞中鉴定出约2000个与SF3B1敲低相关的差异表达基因(DEG)。此外,可变剪接(AS)事件分析显示,敲除SF3B1会引起多类别的AS事件的发生,包括外显子跳跃(ES)、转录起始位点可变剪接(TSS)和转录终止位点可变剪接(TTS)。

SF3B1调节KSR2 mRNA的成熟,而KSR2介导SF3B1驱动的细胞增殖作用

生物信息学分析显示,KSR2是SF3B1介导的子宫内膜癌功能的潜在候选因子。进一步研究显示,敲除SF3B1能够下调KSR2的表达水平,该作用是由于KSR2的pre-mRNA前体到成熟RNA的过程减少。重要的是,研究人员发现,敲低SF3B1能够挽救KSR2的表达并部分恢复子宫内膜癌细胞的生长。


总而言之,该研究结果揭示,在子宫内膜癌的发生发展过程中,SF3B1起着至关重要的致癌作用,因此,SF3B1相关抑制剂或可用于治疗该疾病。


原始出处:

Popli, P., Richters, M.M., Chadchan, S.B. et al. Splicing factor SF3B1 promotes endometrial cancer progression via regulating KSR2 RNA maturation. Cell Death Dis 11, 842 (10 October 2020).

 

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    2021-08-25 zhaojie88
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    2021-01-01 维他命
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    2020-10-22 紫砂壶
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    2020-10-22 cy0328

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