4 research outputs found
Pathogenesis and targeted therapy of T-cell lymphoma
Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 26-04-201
The role of LKB1 in the pathogenesis of Osteosarcoma
Osteosarcoma (OS) is a rare malignant mesenchymal neoplasm, but the third most
common cancer in adolescents. Understanding the molecular pathogenesis of this disease is
essential to design new, effective therapeutic strategies to improve patient survival. The recent
report that LKB1-deficient mice develop bone-forming tumours begs the question whether loss
of this tumour suppressor gene plays a role in human OS pathogenesis.
We found that LKB1 protein expression was reduced in 20 of 26 (77%) human OS cases
by Western blot and 153 of 259 (59%) by immunohistochemistry. Downstream, the mTOR
pathway was activated in 137 of 158 cases (87%) and this activation was correlated to LKB1
loss, providing new insights into potential treatments.
No copy number loss of the LKB1 region was identified in 93 OS cases by interphase
fluorescent in situ hybridization. Four of 12 informative cases had concomitant loss of one
parental allele at the locus of one single nucleotide polymorphism and reduced protein
expression; one of them possessed only one LKB1 copy by qPCR. Direct sequencing of 21 cases
failed to detect LKB1 mutations and all these cases expressed similarly high levels of LKB1
mRNA by qRT-PCR, irrespective of their protein expression. It suggested that LKB1 is regulated
post-transcriptionally in OS.
In silico analysis of our OS microRNA data showed that this cannot be accounted for by
microRNA directly targeting LKB1 mRNA and a preliminary study could not exclude the
involvement of SIRT1.
The knock-down of LKB1 by shRNA in the osteoblast cell line HOB had only subtle
effects on cell proliferation and survival. Its role in OS pathogenesis was confirmed by knock-in
in LKB1-deficient OS cell lines, which induced reduced cell proliferation.
To conclude, LKB1 protein expression is reduced in a subset of OS by a post-transcriptional
mechanism, leading to increased cell proliferation in the tumour