Investigation on tissue specific effects of pro-apoptotic micro RNAs revealed miR-147b as a potential biomarker in ovarian cancer prognosis.
The development and progression of cancer can be ascribed to imbalances in gene regulation leading to aberrant cellular behavior. The loss of micro RNAs (miRNAs) exhibiting tumor-suppressive function has been demonstrated to be often causative for uncontrolled cell proliferation, migration or tissue infiltration. The installation of de novo tumor suppressive function by using pro-apoptotic miRNAs might be a promising therapeutic approach. In addition, there is a great demand for novel biomarkers for the prognosis of cancer, which prompted us to transfer a high content miRNA screening initially performed to identify bioprocess relevant miRNAs in Chinese hamster ovary (CHO) cells to human cancer cell lines . Analysis of screened miRNAs exhibiting strongest pro-apoptotic effects discovered globally and cross-species active candidates. The recovery rate of apoptosis inducing miRNAs was highest in the human ovarian carcinoma cell line SKOV3. Focusing on ovarian cell lines miR-1912, miR-147b and miR-3073a showed significant apoptosis induction in cell lines with different genetic background (SKOV3p53null, OVCAR3p53R248Q, TOV21G, TOV112Dp53R175H, A2780, A2780-cisp53K351N) alone and additive effects in combination with carboplatin. While expression analysis revealed a low endogenous expression of miR-1912 and miR-147b in SKOV3, miRNA expression was highly upregulated upon apoptosis induction using chemotherapeutics. Ectopic introduction of these miRNAs lead to enhanced activation of caspase-dependent death signaling and an induction of the pro-apoptotic proteins Bak1 and Bax and a reduced expression of Bcl2 and Bcl-xL. Finally, analysis of The Cancer Genome Atlas data revealed the expression of hsa-miR-147b-5p to show a positive influence on the median survival of ovarian cancer patients.
Institute of Applied Biotechnology, University of Applied Sciences Biberach, 88400 Biberach, Germany.|University of Ulm, Faculty of Medicine, 89079 Ulm, Germany.
Michael
M
Kleemann
Institute of Applied Biotechnology, University of Applied Sciences Biberach, 88400 Biberach, Germany.
Jeremias
J
Bereuther
Boehringer Ingelheim Pharma GmbH and Co.KG, BP Process Development Germany, 88400 Biberach, Germany.
Simon
S
Fischer
Institute of Applied Biotechnology, University of Applied Sciences Biberach, 88400 Biberach, Germany.
Kim
K
Marquart
Institute of Applied Biotechnology, University of Applied Sciences Biberach, 88400 Biberach, Germany.
Simon
S
Hänle
Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Kristian
K
Unger
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, 45122 Essen, Germany.
Verena
V
Jendrossek
University of Ulm, Faculty of Medicine, 89079 Ulm, Germany.
Christian U
CU
Riedel
Institute of Applied Biotechnology, University of Applied Sciences Biberach, 88400 Biberach, Germany.
René
R
Handrick
Institute of Applied Biotechnology, University of Applied Sciences Biberach, 88400 Biberach, Germany.
Kerstin
K
Otte
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality; D016133:Polymerase Chain Reaction; D011379:Prognosis
D014408:Biomarkers, Tumor; C572377:MIRN147 microRNA, human; D035683:MicroRNAs
apoptosis; biomarker; miR-147b; ovarian cancer; prognosis