Crosstalk of LKB1-Regulated and PTEN-Regulated Signals in Liver Morphogenesis and Tumor Development in Mice

Liver kinase B 1 (LKB1 or STK11) and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) are two tumor suppressors that regulate the mammalian target of rapamycin signaling pathway. Deletion studies show that loss of either Lkb1 (Lkb(+1/-)) or Pten (Pten(loxP)/(loxP); Alb-Cre(+)) leads to liver injury and development of hepatocarcinoma. In this study, we investigated the crosstalk of LKB1 and PTEN loss during tumorigenesis and liver development. We show that haplo-insufficiency of Lkb1 in the liver leads to advanced tumor development in Pten-null mice (Pten(loxP)/(loxP); Lkb(loxP)/(+); Alb-Cre(+)). Our analysis shows that LKB1 and PTEN interact with each other in their regulation of fatty acid synthase as well as p(21) expression. The combined loss of LKB1 and PTEN (Pten(loxP)/(loxP); Lkb(loxP)/(loxP); Alb-Cre(+)) also leads to the inability to form zonal structures in the liver. The lack of metabolic zonal structures is consistent with the inability of the livers to store glycogen as well as elevated plasma bilirubin and alanine aminotransferase, indicative of liver dysfunction. These structural and functional defects are associated with cytoplasm distribution of a canalicular membrane protein multidrug resistant protein 2, which is responsible for clearing bilirubin. This observed regulation of multidrug resistant protein 2 by LKB1 likely contributes to the lack of cellular polarity and the early lethality phenotype associated with the homozygous loss of Lkb1 alone or in combination with Pten. Finally, Pten deletion does not rescue the precocious ductal plate formation reported for Lkb1-deleted livers. Conclusion: Our study dissected the functional and molecular crosstalk of PTEN and LKB1 and elucidated key molecular targets for such interactions.