2009 Fiscal Year Final Research Report

The mechanisms of hepatocarcinogenesis by loss of LKB1

Research Project

Project/Area Number	20790304
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Single-year Grants
Research Field	Experimental pathology
Research Institution	Kyoto University
Principal Investigator	DEGUCHI Atsuko Kyoto University, 医学研究科, 研究員 (10422932)
Project Period (FY)	2008 – 2009
Keywords	腫瘍 / 肝細胞癌 / シグナル伝達 / LKB1 / キナーゼ
Research Abstract	The serine/threonine protein kinase LKB1 is a tumor suppressor gene mutated in the Peutz-Jeghers syndrome patients. The mutations are found also in several types of spDradic cancer. We have previously shown that the heterozygous Lkbl mutations in mice cause gastrointestinal hamartomas after 20 weeks of age, and hepatocellular carcinomas (HCC) after 50 weeks. However, the mechanisms of hepatocaricinogenesis by LKB1 loss have not been elucidated. In this study, we found that expression of c-Jun was increased by LKB1 loss. In addition, we investigated the effect of LKB1 on cell motility whose acquisition occurs in early metastasis. We found that knockdown of LKB1 enhanced cell migration and PAK1 activity in human colon cancer HCT116 cells. Furthermore, we found that PAK1 was activated in the hepatocellular carcinomas and the precancerous liver lesions of Lkbl (+/-) mice. Taken together, these results suggest that PAK1 is a direct downstream target of LKB1 and plays an essential role in LKB1-induced suppression of cell migration.