Peutz-Jeghers polyposis and the LKB1 tumor suppressor

Lina Viveca Udd

Forskningsoutput: AvhandlingDoktorsavhandling


The Peutz-Jeghers Syndrome is a rare cancer predisposition condition, caused by mutations inactivating the LKB1 tumor suppressor kinase. This study aimed to further the understanding of this disease, provide potential means of treatment to Peutz-Jeghers patients, and to add to our understanding of cancer formation in general. These aims were pursued through exploring the molecular functions of the LKB1 kinase, studying the tumor formation upon loss of LKB1 function, and through intervening with this tumor formation process. The study was mainly performed in the Lkb1 knockout mouse or derived tissues and cells, but partly also with Peutz-Jeghers patients and patient materials.

We found that the LKB1 kinase phosphorylates and thereby activates 13 kinases in the AMP-activated kinase family, any of which could putatively relay the tumor suppressor functions of LKB1. We also found that Cyclooxygenase-2 participates in tumorigenesis in Peutz-Jeghers syndrome by promoting the growth of gastric polyps, and that inhibitor treatment suppresses the polyp formation. We also observed that these Peutz-Jeghers polyps are less differentiated than previously thought, and that signs of poor differentiation can be seen in the gastric epithelium already prior to polyp formation. In addition, we found that the polyp formation process is likely to be enhanced by other genes in addition to LKB1 and Cycloxygenase-2, as alkylating mutagenesis increased polyp formation independently of the activity of the latter.

Taken together, these results point to a wide array of molecules and processes interplaying in Peutz-Jeghers tumorigenesis beyond the LKB1 kinase. Both straight molecular targets of LKB1 activity, indirect mediators of LKB1-regulated tumorigenesis, and cooperating processes have been identified. One may expect that these findings will be of use for future studies both characterizing the Peutz-Jeghers syndrome and targeting treatments for this and related tumor diseases.
Tryckta ISBN978-952-10-8354-9
Elektroniska ISBN978-952-10-8355-6
StatusPublicerad - 2012
MoE-publikationstypG5 Doktorsavhandling (artikel)


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