Impact of extracellular acidosis on microRNA expression in tumors and analysis of their role for functional cell properties

• Applicant: Professor Dr. Oliver Thews
• Subject Area: Anatomy and Physiology ; Hematology, Oncology ; Cell Biology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388523742

Compared to normal tissues solid growing tumors often show an acidic extracellular pH which results primarily from a glycolytic metabolism due to severe hypoxia, but also from aerobic glycolysis (Warburg effect). In previous studies we could demonstrate that the extracellular acidosis affects different functional properties of tumor cells such as migration, formation of far-distance metastases or p-glycoprotein-mediated chemoresistance. The functional analysis revealed that especially the MAP kinases p38 and ERK1/2 were activated by the low pH and blocking of these signaling pathways was able to antagonize the acidosis-induced functional changes. We could also demonstrate that p38 phosphorylation at low pH was found in various normal tissue cells (fibroblasts, monocytes, macrophages) which could indicate a general cellular response to acidosis.In recent experiments we could show that different microRNAs (miRNA: small non-coding RNA with regulatory function) are controlled by the acidic extracellular pH (e.g. miR-203). In silico analyses on the function of these acidosis-dependent miRNAs indicated that they are involved in regulation of metabolism, cell cycle control, cell communication as well as in proliferation and migration. On the basis of these results the present projects aims to analyze the role of miRNAs for the observed pH-dependent functional changes of metastasis formation and tumor progression. For this the role of these miRNAs on functional properties of tumor cells (in vitro) as well as of experimental rat tumors (in vivo) will be studied. Functional properties analyzed will be cell proliferation and migration, metastasis formation and the expression of inflammatory mediators. Since the tumor tissue consists also of normal fibroblasts, which are also affected by the low tissue pH, the acidosis-dependent miRNA expression in these cells will be studied as well, in order to determine whether changes in miRNA are a general cell biological reaction or a tumor-specific effect. In order to get an insight in the mechanism by which low extracellular pH may affect the miRNA levels, the expression of miRNA precursors (pri- and pre-miRNA) will be studied, which could give an indication whether acidosis affects the transcription or induces pH-dependent posttranscriptional modifications of miRNAs. From these results general cell biological aspects on the role of miRNA regulation and function can be derived, but they can also lead to new therapeutic interventions in clinical oncology.

• DFG Programme: Research Grants