Format

Send to

Choose Destination
Oncogene. 2019 Feb 11. doi: 10.1038/s41388-019-0746-1. [Epub ahead of print]

Downregulation of specific FBXW7 isoforms with differential effects in T-cell lymphoblastic lymphoma.

Author information

1
Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
2
IIS Fundación Jiménez Díaz, Madrid, Spain.
3
Consorcio de Investigación Biomédica de Enfermedades Raras (CIBERER), Madrid, Spain.
4
Unidad de Epidemiología Ambiental y Cáncer, Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain.
5
Consorcio de Investigación Biomédica de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
6
Centro de Investigación en Nanomateriales y Nanotecnología (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Oviedo, Spain.
7
Unidad de Epigenética del Cáncer, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Fundación para la Investigación Biosanitaria de Asturias (FINBA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA-HUCA), Oviedo, Spain.
8
Grupo de División Celular y Cáncer, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
9
Unidad de Bioinformática, Biología Estructural y Biocomputación, Centro Nacional de Investigaciones Ocológicas (CNIO), Madrid, Spain.
10
Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain. jfpiqueras@cbm.csic.es.
11
IIS Fundación Jiménez Díaz, Madrid, Spain. jfpiqueras@cbm.csic.es.
12
Consorcio de Investigación Biomédica de Enfermedades Raras (CIBERER), Madrid, Spain. jfpiqueras@cbm.csic.es.

Abstract

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.

PMID:
30742097
DOI:
10.1038/s41388-019-0746-1

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center