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.
Highlights
Ovarian cancer is a common human cancer with dismal prognosis. 2012 the World Health Organization dated 239,000 new cases and 152,000 deaths from ovarian CA
The loss of micro RNAs exhibiting tumor-suppressive function has been demonstrated to be often causative for uncontrolled cell proliferation, migration or tissue infiltration
After successful adaptation of the previously developed transient micro RNAs (miRNAs) mimics transfection protocol employing ScreenFect®A [25], www.impactjournals.com/oncotarget cell type specific screening controls were established by transfecting functional control siRNAs including a non-targeting siRNA (NT), a human cell death inducing siRNA (DT) as well as the two already known proapoptotic miRNAs miR-137-3p (T98G, SKOV3, SGBS) and miR-28-5p ( HCT 116 ) as positive controls
Summary
Ovarian cancer (ovarian CA) is a common human cancer with dismal prognosis. 2012 the World Health Organization dated 239,000 new cases and 152,000 deaths from ovarian CA. 2012 the World Health Organization dated 239,000 new cases and 152,000 deaths from ovarian CA. Ovarian CA is the seventh most common cancer in women worldwide and the eighth most common cause of death from cancer [1]. The most frequently used biomarker for ovarian CA diagnosis is Carbohydrate antigen-125 (CA-125) [2]. Chemotherapy most commonly employs carboplatin and paclitaxel for 3 to 6 cycles. Paclitaxel inhibits the cell division by binding to α-tubulin and thereby stabilizing the microtubules whereas carboplatin leads to apoptosis induction by DNA cross linking [5] [6]. In recurrent or persistent ovarian CA Bevacizumab (Avastin®) can be administered in combination with these first-line drugs to inhibit tumor angiogenesis by binding to vascular epidermal growth factor A (VEGFA) [7]
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