Mechanisms of therapy resistance in colorectal carcinomas: regulation of apoptosis by microRNA-mediated oxidative-metabolic effects

• Applicant: Professor Dr. Wilfried Roth
• Subject Area: Pathology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 244751722

Defects in the apoptotic signaling cascades essentially contribute to the therapy resistance of malignant tumors. The poor treatment response in many patients with colorectal cancer results from a primary or acquired radio- and chemoresistance of the tumor tissue. However, reliable molecular markers for therapy-resistant carcinomas have not been identified so far, and effective therapeutic approaches to overcome radiochemoresistance in colorectal carcinomas are still missing. Thus, a better understanding of the cellular and molecular basis of therapy resistance is a central requirement for the development of improved diagnostic and therapeutic tools. Increased resistance to apoptosis of tumor cells is frequently characterized by a diminished expression of the pro-apoptotic members of the Bcl-2 protein family. In our preliminary experiments we found that the microRNA-210 (miR-210) is regulated by ionizing irradiation and that an increased expression of miR-210 plays an important role in the initiation of apoptosis in colon cancer cells. Our findings indicate that the cytotoxic effect of miR-210 is exerted by the pro-apoptotic Bim protein, and that Bim expression is induced by a miR-210-mediated increase in ROS with subsequent activation of the CHOP and FOXO transcription factors. In the proposed project we aim at demonstrating that the miR-210 dependent induction of Bim expression is mediated by suppression of NDUFA4 and SDHD (both subunits of the complexes of the respiratory chain) with consecutive inhibition of the corresponding respiratory chain complex and by increased ROS generation. Furthermore, we will investigate (both in cell culture and in animal experiments) to which extent this particular mechanism as well as a general modulation of the oxidative metabolic activity regulates the cellular resistance to apoptosis. Besides, our preliminary experiments demonstrate a radiation dependent regulation of miR-210. In this context, we will analyze which transcription factors are involved in this modulation. Additionally, the effects of radiation on miR-210 expression in non-tumorigenic tissue will be investigated. Moreover, we will analyze the prognostic and predictive value of the expression of miR-210 and Bim in a large collection of human colorectal cancer samples (n = 1250).

• DFG Programme: Research Grants