P46 Meiotic proteins – liver cancer specific drug targets

Résumé fourni par la source

Introduction Cell division by meiosis involves an extraordinary chromosome choreography including pairing, synapsis and crossing over between homologous chromosomes to facilitate the creation of gametes. The many meiosis-specific genes involved in these processes constitute a latent toolbox of oncogenes that may be exploited through aberrant expression in cancer. Results Here, we report that all eight members of synaptonemal complex involved in meiotic chromosome synapsis, are aberrantly expressed in liver cancer patients at both mRNA and protein level. Furthermore, high levels of synaptonemal protein re-activation in cancer correlate with poor prognosis. We find that silencing these meiotic proteins causes proliferative failure in multiple cancer cell lines. Furthermore, we confirm the role of one of these meiotic proteins, TEX12, in the early stages of oncogenesis. We detected Tex12 expression in a diethylnitrosamine (DEN)-induced mouse model of hepatocellular carcinoma. Importantly, Tex12 expression was detected as early as five weeks following DEN treatment, with peak levels observed at 40 weeks. Its detection at the five week-stage indicates that Tex12 is already expressed at the very early stages of oncogenesis, prior to the formation of an overt tumour. This observation raises the possibility that TEX12 is a driver of early oncogenesis and highlights its potential as an early diagnostic marker. Discussion In meiosis, TEX12 was observed at the chromosomes. Remarkably, we find that somatically expressed TEX12 localises to the centrosomes, leading to altered centrosome number and structure, features associated with cancer development. In cancer cells TEX12 promotes rosette centrosomes and centrosome amplification. Thus, we propose that cancer cells aberrantly express TEX12, and other synaptonemal complex proteins, promoting oncogenesis and cellular proliferation in cancer. Consequently, synaptonemal complex proteins could be targeted for novel liver cancer therapeutics and diagnostics as they are absent in all normal somatic cells.

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