Ph.D Thesis

Ph.D StudentWorms-Bitton Keren
SubjectThe Role of AP-1 in Inflammation Dependent Hepatocellular
Carcinoma Animal Models
DepartmentDepartment of Medicine
Supervisor PROF. Ami Aronheim
Full Thesis textFull thesis text - English Version


The c-Jun dimerization protein 2, JDP2, is a member of the bZIP family. JDP2 represses AP-1 dependent transcription by multiple mechanisms. JDP2 is involved in cellular differentiation processes, proliferation and transformation.  The role of JDP2 in carcinogenesis is a matter of debate. On the one hand, JDP2 counteracts AP-1 transcription. AP-1 transcription is typically correlated with cell proliferation and transformation. However, on the other hand, JDP2 was identified as a potential cooperating oncogene in T-cell lymphoma.

To examine the potential oncogenic activity of JDP2 in vivo, we have generated a tetracycline inducible transgenic mouse expressing JDP2 specifically in the liver.  Although JDP2 is highly expressed in the liver, mice displayed normal liver function.

To reveal the role of JDP2 in oncogenesis, we used two distinct protocols to induce liver cancer. The first, involves a single injection of diethylnitrosamine (DEN) at four weeks of age followed by tumor promoter Phenobarbital since eight weeks of age..  Using this protocol, JDP2-transgenic mice displayed a significantly lower survival rate. Liver damage parameters were significantly higher in JDP2-transgenic mice compared with wild type mice. Moreover, 90% of JDP2-mice displayed numerous visible macroscopic tumors while only one out of sixteen livers derived from control wild type mice displayed one macroscopic tumor.

In the second DEN protocol mice were injected by a single injection of DEN at 14 days postnatal without promotion. Using  this model  100 %  of  injected mice  developed macroscopic  liver  tumors  at  eleven months  of  age. To  identify  the  importance  of  the  time  of  JDP2  expression  at  the  different  stages  of   liver  cancer,  we  took  advantage  of  the  ability  to  shut-off  the  transgene  expression  using doxycycline provided in the drinking water. We studied three groups of mice in which JDP2 expression was shut-off during different stages of liver cancer development. In JDP2-transgenic mice that were either not treated or treated with doxycycline during the initiation stage the number of macroscopic tumors was doubled as compared with the wild type mice. Interestingly, JDP2-trangenic mice treated with doxycycline during the initiation and promotion time displayed comparable number of tumors as compared with wild type mice. Collectively, using the DEN protocols, JDP2-transgenic displayed a significantly lower survival rate and increased severity of liver cancer disease, and the expression of JDP2 at the promotion stage was found to be the most critical for enhancing liver cancer severity by JDP2.