Oncotarget

Research Papers:

Investigation on tissue specific effects of pro-apoptotic micro RNAs revealed miR-147b as a potential biomarker in ovarian cancer prognosis

Michael Kleemann _, Jeremias Bereuther, Simon Fischer, Kim Marquart, Simon Hänle, Kristian Unger, Verena Jendrossek, Christian U. Riedel, René Handrick and Kerstin Otte

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Oncotarget. 2017; 8:18773-18791. https://doi.org/10.18632/oncotarget.13095

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Abstract

Michael Kleemann1,2, Jeremias Bereuther1, Simon Fischer3, Kim Marquart1, Simon Hänle1, Kristian Unger4, Verena Jendrossek5, Christian U. Riedel2, René Handrick1, Kerstin Otte1

1Institute of Applied Biotechnology, University of Applied Sciences Biberach, 88400 Biberach, Germany

2University of Ulm, Faculty of Medicine, 89079 Ulm, Germany

3Boehringer Ingelheim Pharma GmbH and Co.KG, BP Process Development Germany, 88400 Biberach, Germany

4Research Unit Radiation Cytogenetics, Helmholtz Zentrum München , 85764 Neuherberg, Germany

5Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, 45122 Essen, Germany

Correspondence to:

Michael Kleemann, email: [email protected]

Keywords: miR-147b, biomarker, ovarian cancer, apoptosis, prognosis

Received: May 04, 2016     Accepted: October 27, 2016     Published: November 04, 2016

ABSTRACT

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.


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