AbstractHepatocellular carcinoma (HCC) is the most common type of liver cancer globally
but ranks third in mortality. Occludin expression analysis shows a low occludin
expression in 83.5 % of HCCs and this is associated with increased metastasis and
a low prognosis.
In a high proportion of hepatocellular carcinomas, there is a low expression of
occludin and ZO1. The ZO2 expression has not been investigated in detail in
hepatocellular carcinoma. Screening studies have shown there is reduced ZO2
expression in chronic liver disease and liver cancer. The loss of these proteins are
seldom investigated together in respects to HCC.
Using a 2D cell migration and 3D invasion assay it was observed that ZO1 and ZO2 expression knockdown in HepG2 cells increased migration and invasion. This was shown to be associated with reduced occludin phosphorylation reducing its function. Silencing of HepG2 cells with combined occludin and ZO1 knockdown resulted in a further increase of migration and invasion rates. Occludin overexpression in HepG2 cells is partially protective and reduces migration and invasion rates with ZO1 and ZO2 knockdown and partially maintained it phosphorylation state.
The increased migration in occludin knockdown is due to the HepG2 cells losing their contact inhibition and show greater signs of proliferation and migration. Occludin silencing with ZO1 and ZO2 knockdown increases the migration and invasion rates due to ZO1 and ZO2 having anti-proliferative functions through YBX3 sequestration and ZO2 oncogenic transcription inhibition. Occludin overexpression reduces the migration and invasion rates as intracellular aggregates of occludin sensitise cells to apoptosis and maintain tight junction function.
|Date of Award
|Christopher Mee (Supervisor)