Enhanced expression of a proto-oncogene, Pim-3, with serine/threonine kinase activity, in various types of tumors

To recapitulate hepatitis-induced hepatocarcinogenesis, we have developed the mouse model of hepatocellular carcinoma using hepatitis B virus surface antigen transgenic mice. In order to identify the genes associated with hepatocarcinogenesis in this model, we compared the gene expression patterns between pre-malignant lesions surrounded by hepatocellular carcinoma tissues and control liver tissues by using a fluorescent differential display analysis.
Among the genes which were expressed differentially in the pre-malignant lesions, we focused on Pim-3, a member of a proto-oncogene Pim family. Due to the unavailability of the nucleotide sequence of full-length human Pim-3 cDNA, we cloned full-length Pim-3 cDNA, consisting of 2,392 bp, which encodes a predicted open reading frame consisting of 326 amino acids (Human Pim-3).
Pim-3 mRNA was selectively expressed in human hepatoma cell lines, but not in normal liver tissues. Moreover, Pim-3 protein was detected in human hepatocellular carcinoma tissues and cell lines but not in normal hepatocytes. Furthermore, cell proliferation was attenuated and apoptosis was enhanced in human hepatoma cell lines by the ablation of Pim-3 gene with RNA interference (Fujii et al., 2004).

Pim-3 gene expression was enhanced similarly in human pancreatci cancer tissues, but not normal human pancreatic tissues. A detailed molecular analysis further demonstrated that aberrantly-expressed Pim-3 inactivated a pro-apoptotic molecule, Bad, by phosphorylating its Ser 112 and eventually prevented apoptosis (see below figure, Li et al., 2006). These observations would indicate that Pim-3 may be a good molecular target for several types of cancer, for example, pancreatic cancer, a representative intractable cancer.

Moreover, we demonstrated that mice expressing human Pim-3 transgene in liver exhibited accelerated hepatocellular carcinoma develpoment and progression when these mice were administered with a hepatocarcinogen, diethylnitrosamine (Wu et al., 2010)

　These observations would indicate that Pim-3 acts as a promoter but not an initiator of carcinogenessis (Mukaida et al., 2011)..

Based on this assumption, we screened various low-molecule compounds by examining their inhibitory activities against Pim-3 kinase activity. Until present, we identified several types of compounds, which can inhibit in vitro and in vivo proliferation of human cancer cell lines and filed patents on these chemicals.