Physiological role of Nox4 in the prevention of tumor developement

• Applicant: Professorin Dr. Katrin Schröder, Ph.D.
• Subject Area: Anatomy and Physiology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 265299203

Nox4 is a member of the NADPH oxidase family whose only known function is the production of reactive oxygen species. While most NADPH oxidases are acutely activated and produce O2-, Nox4 is constitutively active and continuously produces small amounts of H2O2. Another special feature of Nox4 is that it is ubiquitously expressed and is found mainly in differentiated cells. We could show that Nox4 is involved in the differentiation of mesenchymal cells, such as adipocytes and osteoclasts. Mediated by the permanent production of H2O2, Nox4 is also an essential component of cellular redox homeostasis and prevents the inflammatory activation of cells.Inflammation and dedifferentiation are essential characteristics of malignant transformation. The aim of proposed project is to identify the role of Nox4 in the development of fibrosarcomas and carcinogenesis using knockout mice and pharmacological inhibition of NADPH oxidases. The proposed work includes the analysis of human samples for an association of Nox4 and malignancies, as well as two inflammation-driven tumor models in transgenic mice (metyhlcholantren- and azoxymethan/dextran-sodium-sulfat- model) and cell culture experiments. The objectives are divided into a tumor biological and a molecular part. The aim of the tumor biological part is to identify a cell-specific role of Nox4 in the sarcoma development and carcinogenesis as well as to uncover its role in the formation and growth of tumors in mice and patient samples. The molecular part is devoted to unraveling the mechanistic contribution of Nox4 to malignant transformation and proliferation of tumor cells.

• DFG Programme: Research Grants