In renal cell carcinoma the PTEN splice variant PTEN-Δ shows similar function as the tumor suppressor PTEN itself

Background: Loss of PTEN is involved in tumor progression of several tumor entities including renal cell carcinoma (RCC). During the translation process PTEN generates a number of splice variants, including PTEN-Delta. We analyzed the impact of PTEN-Delta in RCC progression. Methods: In specimens of RCC patients the expression of PTEN-Delta and PTEN was quantified. The PTEN expressing RCC cell line A498 and the PTEN deficient 786-0 cell line were stably transfected with the PTEN-Delta or PTEN transcript In Caki-1 cells that highly express PTEN-Delta, this isoform was knocked down by siRN Delta. Cell migration, adhesion, apoptosis and signaling pathways activities were consequently analyzed in vitro. Results: Patients with a higher PTEN-Delta expression had a longer lymph node metastasis free and overall survival. In RCC specimens, the PTEN-Delta expression correlated with the PTEN expression. PTEN-Delta as well as PTEN induced a reduced migration when using extracellular matrix (ECM) compounds as chemotaxins. This effect was confirmed by knockdown of PTEN-Delta, inducing an enhanced migration. Likewise a decreased adhesion on these ECM components could be shown in PTEN-Delta and PTEN transfected cells. The apoptosis rate was slightly increased by PTEN-Delta. In a phospho-kinase array and Western blot analyses a consequently reduced activity of AKT, p38 and JNK could be shown. Conclusions: We could show that the PTEN splice variant PTEN-Delta acts similar to PTEN in a tumor suppressive manner, suggesting synergistic effects of the two isoforms. The impact of PTEN-Delta in context of tumor progression should thus be taken into account when generating new therapeutic options targeting PTEN signaling in RCC.