Abstract
Accumulating evidence has indicated that microRNAs play a critical role in the pathogenesis of human cancers. microRNA-34a (miR-34a) has been shown to be a key regulator of tumor suppression by targeting several cancer-related signals, including the interleukin-6 receptor (IL-6R)/Signal Transducers and Activator of Transcription 3 (STAT3) signaling pathway. Previously, we determined that miR-34a expression was frequently reduced in high-grade serous carcinoma (HGSC), the major subtype of epithelial ovarian cancer (EOC). Considering that the IL-6R/STAT3 signaling pathway is upregulated and believed to be a potential therapeutic target in EOC, we investigated the biological significance of reduced miR-34a expression in HGSC with regard to IL-6R signaling. Additionally, we evaluated the viability of miR-34a as a therapeutic application for HGSC both in vitro and in vivo. Accordingly, we found that the ectopic expression of miR-34a significantly reduced tumor proliferation and invasion through downregulation of IL-6R expression, suggesting that reduced miR-34a expression might play an important role in the malignant potential of HGSC through upregulation of the IL-6R/STAT3 signaling pathway. Moreover, we demonstrated that replacement of miR-34a reduced tumorigenicity of HGSC in vivo. Therefore, this study may provide the rationale for miR-34a replacement as a promising therapeutic strategy for HGSC.
Highlights
Ovarian cancer is a lethal gynecological malignancy that accounts for 5%–6% of all cancerrelated deaths
We addressed whether miR-34a in high-grade serous carcinoma (HGSC) could target interleukin-6 receptor (IL-6R), which has been shown to be highly expressed in Epithelial ovarian cancer (EOC) [16, 18]
In the HGSC cell lines used ectopic expression of miR-34a significantly reduced proliferation and invasion abilities through the downregulation of IL-6R expression and downstream Signal Transducers and Activator of Transcription 3 (STAT3) signaling, suggesting that reduced miR-34a expression might play an important role in the malignant potential of HGSC cells
Summary
Ovarian cancer is a lethal gynecological malignancy that accounts for 5%–6% of all cancerrelated deaths. Given that EOC generally develops with few specific symptoms, majority of the patients are diagnosed at advanced stages [2]. Molecular targeted therapies, including bevacizumab, poly ADP-ribose polymerase (PARP) inhibitors, and antiprogrammed cell death (PD)-1 antibodies, have been helping to overcome the poor prognosis of EOC [4, 5]. In the SOLO2/ENGOT-Ov21 www.oncotarget.com trial, which aimed to investigate the efficacy of PARP inhibitor, clinical benefits were found in patients bearing germline BRCA1/2 mutations, indicating that mutation testing for BRCA1/2 should be considered in part of clinical practice [4, 6]. The development of these molecular targeted therapies has shed light on novel treatment options for EOC, their efficacy is still limited and mortality in EOC cases with advanced stages remains substantially problematic
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