Die Biologische und Klinische Bedeutung der EVI1-Expression in der Prostatakarzinogenese
Zusammenfassung der Projektergebnisse
Prostate cancer (PCa) is the most commonly diagnosed cancer noncutaneous cancer and the second most common cancer-related cause of death in men in the western world. Although mutations in tumor suppressor genes and oncogenes have been shown to be important for PCa progression, the involvement of cancer stem cells (CSC) in prostate carcinogenesis has not been thoroughly investigated. Cancer stem cells (CSCs) are considered to be essential regulators of tumor initiation, progression and therapy resistance in cancer patients, so it is crucial to identify the CSCs markers implicated in PCa progression. EVI1 is a stem cell transcriptional regulator that plays an essential role in the regulation of hematopoietic stem cell renewal, it is shown to be overexpressed in myeloid leukemia and epithelial cancers and is associated with poor patient survival. However, the role of EVI1 in PCa progression has not been by now investigated. The overall aims of these study were to investigate the expression status of EVI1 and to correlate its expression with other stem cell markers on PCa tissues as well as to elucidate its functional role in PCa in vitro. The results performed on our PCa tissue have showed that the EVI1 expression is restricted to the prostate stem cell compartment located at the basal layer and EVI1 expression correlated with the stem cell marker CD44. Furthemore, EVI1 protein was shown to be heterogeneously distributed within primary PCa while more homogenous expression was observed in lymph node and distant metastases while high EVI1 expression was shown to be associated with tumor progression. These results suggest that EVI1 is implicated in PCa progression and that the induction of EVI1 expression is a PCa driver event. Functionally, EVI1 knockdown reduced cell growth and proliferation, interfered with cell cycle progression, reduced migratory capacity and anchorage-independent growth as well as inhibited tumor sphere formation of PCa cells. Interestingly, EVI1 was shown to regulate stem cell properties influencing in vivo tumor initiation capacity in zebrafish model emphasizing a correlation between EVI1 expression and tumor progression. Furthermore, our results have also shown that EVI1 mediates docetaxel resistance. Using PCa cells we were able to show increased EVI1 expression in docetaxel-resistant PCa cells in comparison to docetaxel nonresistant PCa cells. In addition, knockdown of EVI1 in these cells restored sensitivity to docetaxel, in part by downregulating anti-apoptotic marker BCL2. To conclude, our results demonstrate EVI1 as a novel molecular regulator of PCa progression and chemotherapy resistance, and could be exploited as a potential drug target in aggressive PCa. The results of our unpublished study performed on HNSCC cohort, showed differential EVI1 expression in different HNSCC origin sites, as well as the correlation of increased EVI1 expression with HPV positivity and lymph node metastatic disease pointing to the role of EVI1 in HNSCC progression. In summary, both of these studies illustrate the important role of EVI1 in the PCa and HNSCC progression and provide new insights into molecular regulation of EVI1 in PCa.
Projektbezogene Publikationen (Auswahl)
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Ecotropic viral integration site 1, a novel oncogene in prostate cancer. Oncogene. 2017 Mar;36(11):1573-1584
Queisser A, Hagedorn S, Wang H, Schaefer T, Konantz M, Alavi S, Deng M, Vogel W, von Mässenhausen A, Kristiansen G, Duensing S, Kirfel J, Lengerke C, Perner S
