oa Overexpression Of Human S100a4 Gene In Drosophila Melanogaster Can Promote Metastasis

The major problem with cancer is the ability of cancer cells to infiltrate surrounding tissue (invasion) or to spread to distant organs (metastasis), decreasing patient survival. One of the Ca2+ binding proteins of the S100 family, S100A4, is expressed at elevated level in several forms of cancer and has the ability to induce metastasis and invasion in benign mammary cells. In order to generate a genetically tractable experimental model of S100A4-mediated metastasis, we have expressed the human S100A4 in the fruit fly Drosophila melanogaster to uncover players in tumour progression, invasion and metastasis. Here we demonstrate that the expression of full open reading frame of human S100A4 wild type protein in cooperation with RasVal12 into Drosophila, developed metastatic phenotypes. Fly larvae expressing the human S100A4 as determined by Western blot exhibit metastasis in the ventral nerve cord when crossed with Drosophila strains expressing oncogenic RasVal12 targeted to the optic lobes by the UAS-GAL4 system. However, the mutant of S100A4 (S100A4/∆2) missing the last two lysine reduced the tumour dissemination into the ventral nerve cord in Drosophila flies expressing RasVal12 oncogene. Downstream genes associated with the metastatic behaviour including JNK and MMPs (metalloproteinase) proteins are also investigated. We showed that the MMPs and the JNK are also activated in the flies with S100A4/ RasVal12 genotype. Loss this activation in flies with S100A4∆2/RasVal12 genotype indicated that MMPs and JNK proteins are essential in tumour progression and metastasis pathways. Therefore, MMPs and JNK are excellent targets for cancer therapy.