LKB1 Haploinsufficiency Cooperates With Kras to Promote Pancreatic Cancer Through Suppression of p21-Dependent Growth Arrest

作者：Morton Jennifer P; Jamieson Nigel B; Karim Saadia A; Athineos Dimitris; Ridgway Rachel A; Nixon Colin; Mckay Colin J; Carter Ross; Brunton Valerie G; Frame Margaret C; Ashworth Alan; Oien Karin A; Evans T R Jeffry; Sansom Owen J^*

来源：Gastroenterology, 2010, 139(2): 586-597.

DOI：10.1053/j.gastro.2010.04.055

• Pancreatic Cancer
• Kras
• LKb1
• p21

BACKGROUND & AIMS: Patients carrying germline mutations of LKB1 have an increased risk of pancreatic cancer; however, it is unclear whether down-regulation of LKB1 is an important event in sporadic pancreatic cancer. In this study, we aimed to investigate the impact of LKB1 down-regulation for pancreatic cancer in mouse and human and to elucidate the mechanism by which Lkb1 deregulation contributes to this disease. METHODS: We first investigated the consequences of Lkb1 deficiency in a genetically modified mouse model of pancreatic cancer, both in terms of disease progression and at the molecular level. To test the relevance of our findings to human pancreatic cancer, we investigated levels of LKB1 and its potential targets in human pancreatic cancer. RESULTS: We definitively show that Lkb1 haploinsufficiency can cooperate with oncogenic Kras(G12D) to cause pancreatic ductal adenocarcinoma (PDAC) in the mouse. Mechanistically, this was associated with decreased p53/p21-dependent growth arrest. Haploinsufficiency for p21 (Cdkn1a) also synergizes with Kras(G12D) to drive PDAC in the mouse. We also found that levels of LKB1 expression were decreased in around 20% of human PDAC and significantly correlated with low levels of p21 and a poor prognosis. Remarkably, all tumors that had low levels of LKB1 had low levels of p21, and these tumors did not express mutant p53. CONCLUSIONS: We have identified a novel LIKB1-p21 axis that suppresses PDAC following Kras mutation in vivo. Down-regulation of LKB1 may therefore serve as an alternative to p53 mutation to drive pancreatic cancer in vivo.

• 出版日期2010-8