Periodic Reporting for period 1 - EMBRACE (Elucidating Mechanisms of Bladder Cancer Metastasis)
Reporting period: 2018-09-01 to 2020-08-31
We have also identified and validated another E3 ubiquitin ligase TRAF4 (TNF receptor associated factor 4) as biomarker for advanced stages of bladder cancer progression. TRAF4 has been largely implicated as a tumour promoting element in a wide range of cancers. Over-expression and amplification of this gene product has been a common observation in breast , lung, prostate and other metastatic tumours. In contrast, we observed that expression of TRAF4 negatively correlated with overall (bladder cancer) patient survival. We also performed transcriptomic data analysis, which revealed the changes in the intracellular signaling pathways upon TRAF4 mis-expression in bladder cancer cells. BMP (Bone morphogenetic protein) signaling and the NF-B signaling pathways were the most affected by TRAF4 mis-expression in bladder cancer cells. Furthermore, we identified and validated an ERK kinase phosphorylation site on TRAF4 which not only affects the stability but also its ability to localize to the plasma membrane. Our findings were further validated using bladder cancer patient material.
The next step of the project would be to test the combinatorial drug treatment strategies on human trials. Also, further testing the efficacy of SMURF2 as a potential biomarker is warranted. These studies will lead to precise and personalized treatment strategies for bladder cancer patients. The TRAF4 project also has a lot of potential as a novel biomarker for bladder cancer progression. We observed that TRAF4 expression is epigenetically silenced in advanced stages of bladder cancer patients and also observed a negative trend of its expression across the advancing stages of bladder cancer progression. We also uncovered an important link between TRAF4 and the BMP signaling pathway. TRAF4 is able to degrade SMURF1, which is a negative regulator of BMP signaling pathway. A positive correlation between BMP signaling pathway’s effector molecule pSMAD1/5/8 and TRAF4 expression was observed. Also, we observed a negative correlation between NF-KappaB signaling pathway and TRAF4 expression.