Z Gastroenterol 2015; 53 - A4_13
DOI: 10.1055/s-0035-1568072

Different oncogenic potential in the mouse liver of mutant forms of the p110alpha catalytic subunit of phosphoinositide-3-kinase (PIK3CA)

K Annweiler 1, K Evert 2, A Cigliano 1, M Sini 1, G Latte 3, M Frau 3, RM Pascale 3, F Dombrowski 1, DF Calvisi 1, M Evert 2, K Utpatel 2
  • 1University Medicine Greifswald, Institute of Pathology, Greifswald, Germany
  • 2University of Regensburg, Institute of Pathology, Regensburg, Germany
  • 3University of Sassari, Department of Clinical and Experimental Medicine, Sassari, Italy

Background:

PIK3CA, encoding the catalytic subunit p110α of class I phosphoinositide-3-kinase (PI3K), is mutated or overexpressed in many tumors, including hepatocellular carcinoma (HCC), where it is supposed to act as an oncogene. Here, we developed new mouse models to investigate the oncogenic effects of gain-of-function PIK3CA mutations and identified downstream PI3K signaling components in the mouse liver.

Methods:

PIK3CA mutants G1633A:E545K and A1340G:H1047R were overexpressed in the liver of 129/Sv-C57BL/6 mice via hydrodynamic gene delivery (HGD). Three, six, nine and twelve months after HGD, preneoplastic lesions and liver tumors were analyzed and compared histomorphologically. Putative PIK3CA targets were examined via Western Blot analysis and immunhistochemistry. In addition, microarray analysis was performed in order to identify novel targets of PIK3CA in HCC.

Results:

Three and six months after HGD, the overexpression of different PIK3CA mutant forms in 129/Sv-C57BL/6 mice resulted in the development of multiple liver preneoplastic lesions and liver tumors. However, overexpression of PIK3CA-E545K exhibited a much more pronounced oncogenic potential than PIK3CA-H1047R. Indeed, all mice injected with PIK3CA-E545K developed liver tumors by six months post HGD, whereas only 10%, 10%, and 30% of mice injected with PIK3CA-H1047R developed liver tumors by six, nine, and twelve months after HGD, respectively. Furthermore, overexpression of key enzymes of lipid metabolism and proteins involved in cell growth or survival were identified as downstream targets of oncogenic PIK3CA in mice.

Conclusion:

Our investigation indicates that PIK3CA mutant forms, G1633A:E545K and A1340G:H1047R, are oncogenic in the mouse liver albeit with a different oncogenic potential. In addition, we identified a number of PIK3CA targets in the liver, whose investigation might be helpful both for a better understanding of the molecular pathogenesis of HCC and the development of new therapeutic strategies against this deadly disease.

Corresponding author: Utpatel, Kirsten

E-Mail: kirsten.utpatel@klinik.uni-regensburg.de