Lämmerhirt, Felix
[VerfasserIn]
;
Lerch, Markus M.
[AkademischeR BetreuerIn];
Gress, Thomas Mathias
[AkademischeR BetreuerIn];
Weiß, Frank Ulrich
[AkademischeR BetreuerIn]Universität Greifswald
Die Rolle von microRNAs in der Chemotherapie-Resistenz des Pankreaskarzinoms
BACKGROUND: With a 5-year survival rate of only 9% pancreatic cancer ranks on the top of cancer related deaths in Germany. The poor prognosis is often associated with an early chemoresistance to 5FU or gemcitabine. MicroRNAs are small, non-coding RNAs with an important influence on gene regulation and tumour cell biology. This study reveals microRNAs aberrantly regulated in chemoresistant pancreatic cancer to find new strategies for an improved antitumour therapy. MATERIALS AND METHODS: Four pancreatic cancer cell lines (BXPC-3, COLO 357, PATU-S, PATU-T) with an intrinsic sensitivity to 5FU or gemcitabine were propagated with increasing drug concentrations over a period of nine month until an acquired chemoresistance was established. MicroRNA transcriptome analysis was performed. MicroRNAs were transiently inhibited by lipid-based transfection. Cell viability, metabolism, apoptosis or proliferation were measured by spectrophotometric, fluorogenic or luminescent assays. RESULTS: A cell culture model containing eleven cell lines with different grades of chemoresistance was established. MicroRNA expression profiling could highlighted miR-100 and miR-125b overexpressed in all resistant cell lines. Cell function assays revealed a reduced viability, an increased apoptosis and a dose dependent restoration of chemosensitivity in resistant cells after knock-down of miR-100 or miR-125b. CONCLUSION: This is the first study revealing miR-100 and miR-125b as potential new targets of an ...