Duhamel, L.A.E.; (2011) The role of LKB1 in the pathogenesis of Osteosarcoma. Doctoral thesis , UCL (University College London).

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Abstract

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.

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