Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
IIS Fundación Jiménez Díaz, Madrid, Spain.
Oncogene. 2019 Jun;38(23):4620-4636. doi: 10.1038/s41388-019-0746-1. Epub 2019 Feb 11.
FBXW7 is a driver gene in T-cell lymphoblastic neoplasia acting through proteasome degradation of key proto-oncogenes. FBXW7 encodes three isoforms, α, β and γ, which differ only in the N-terminus. In this work, massive sequencing revealed significant downregulation of FBXW7 in a panel of primary T-cell lymphoblastic lymphomas characterised by the absence of mutations in its sequence. We observed that decreased expression mainly affected the FBXW7β isoform and to a lesser extent FBXW7α and may be attributed to the combined effect of epigenetic changes, alteration of upstream factors and upregulation of miRNAs. Transient transfections with miRNA mimics in selected cell lines resulted in a significant decrease of total FBXW7 expression and its different isoforms separately, with the consequent increment of critical substrates and the stimulation of cell proliferation. Transient inhibition of endogenous miRNAs in a T-cell lymphoblastic-derived cell line (SUP-T1) was capable of reversing these proliferative effects. Finally, we show how FBXW7 isoforms display different roles within the cell. Simultaneous downregulation of the α and γ isoforms modulates the amount of CCNE1, whilst the β-isoform alone was found to have a prominent role in modulating the amount of c-MYC. Our data also revealed that downregulation of all isoforms is a sine qua non condition to induce a proliferative pattern in our cell model system. Taking these data into account, potential new treatments to reverse downregulation of all or a specific FBXW7 isoform may be an effective strategy to counteract the proliferative capacity of these tumour cells.
FBXW7 是 T 细胞淋巴母细胞性白血病中的驱动基因，通过蛋白酶体降解关键原癌基因发挥作用。FBXW7 编码三种异构体，α、β 和 γ，它们仅在 N 端不同。在这项工作中，大量测序揭示了在一组缺乏其序列突变的原发性 T 细胞淋巴母细胞淋巴瘤中，FBXW7 显著下调。我们观察到表达减少主要影响 FBXW7β 异构体，其次是 FBXW7α，这可能归因于表观遗传改变、上游因子改变和 miRNA 上调的综合作用。在选定的细胞系中用 miRNA 模拟物进行瞬时转染导致总 FBXW7 表达及其不同异构体分别显著下降，随之而来的是关键底物的增加和细胞增殖的刺激。在 T 细胞淋巴母细胞衍生的细胞系（SUP-T1）中短暂抑制内源性 miRNA 能够逆转这些增殖效应。最后，我们展示了 FBXW7 异构体在细胞内的不同作用。α 和 γ 异构体的同时下调调节 CCNE1 的数量，而单独的 β-异构体被发现在调节 c-MYC 的数量方面起着重要作用。我们的数据还表明，所有异构体的下调都是在我们的细胞模型系统中诱导增殖模式的必要条件。考虑到这些数据，逆转所有或特定 FBXW7 异构体下调的潜在新治疗方法可能是对抗这些肿瘤细胞增殖能力的有效策略。
