Role of retinoblastoma protein in the development of liver cancer

Abstract

Hepatocellular carcinoma is the sixth most common cancer worldwide with a diverse aetiology. Dysregulation of the Rb pathway can occur in as high as 92% of liver cancers implicating Rb as an important factor in the progression of the disease. The impact Rb loss has on the development of liver cancer was determined using an in vitro system, with Cre-lox technology. The Cre-lox technology enables the lethality of Rb loss in the embryo to be overcome. The regulation of p53, extent of DNA damage and cell cycle control were investigated in Rb-/- hepatocytes. The tumor suppressor p19ᴬᴿᶠ, previously reported to induce stabilisation of p53 was found upregulated. This combined with the localisation of MDM2 in the nucleolus implicates p19ᴬᴿᶠ as an important factor in the stabilisation of p53 in the Rb-/- hepatocytes. The elevated levels of ROS were found to be sufficient to induce DNA damage as measured by an increase in 8-oxo-dG and apurinic and apyrimdinic sites. The regulation of three cyclins, cyclin A, cyclin B and cyclin E is found to lack governance. Analysis of the G2/M checkpoint proteins such as Gadd45a, MAD2 and CDC25a all show a dysregulation in their activities. In conclusion Rb loss leads to aberrant regulation of p53 and induces DNA damage, this superimposed on a background of a lack of cell cycle control predisposes the hepatocyte to becoming a cancerous cell.