Dysregulation of miR-375/AEG-1 Axis by Human Papillomavirus 16/18-E6/E7 Promotes Cellular Proliferation, Migration, and Invasion in Cervical Cancer

Abstract

Cervical Cancer (CC) is a highly aggressive tumor and is one of the leading causes of cancer-related deaths in women. miR-375 was shown to be significantly down-regulated in cervical cancer cells. However, the precise biological functions of miR-375 and the molecular mechanisms underlying its action in CC are largely unknown. miR-375 targets were predicted by bioinformatics target prediction tools and validated using luciferase reporter assay. Herein, we investigated the functional significance of miR-375 and its target gene in CC to identify potential new therapeutic targets. We found that miR-375 expression was significantly downregulated in CC, and astrocyte elevated gene-1 (AEG-1) was identified as a target of miR-375. Our results also showed that ectopic expression of miR-375 suppressed CC cell proliferation, migration, invasion and angiogenesis, and increased the 5-fluorouracil-induced apoptosis and cell cycle arrest in vitro. In contrast, inhibition of miR-375 expression significantly enhanced these functions. Furthermore, HPV - 16 E6/E7 and HPV - 18 E6/E7 significantly down-regulates miR-375 expression in CC. HPV 16/18-E6/E7/miR-375/AEG-1 axis plays an important role in the regulation of cell proliferation, migration, and invasion in CC. Therefore, targeting miR-375/AEG-1 mediated axis could serve as a potential therapeutic target for CC.

RETRACTED ARTICLE: microRNA-375 released from extracellular vesicles of bone marrow mesenchymal stem cells exerts anti-oncogenic effects against cervical cancer

“…The downregulation of miR-375 has been commonly found in multiple cancers, including colorectal cancer [ 21 ], ovarian cancer [ 22 ], and breast cancer [ 23 ]. Moreover, miR-375 expression was shown to be significantly reduced in cervical cancer cells, while its ectopic expression suppressed cervical cancer cell proliferation, migration, invasion, and angiogenesis and increased the 5-fluorouracil-induced apoptosis [ 24 ].…”

RETRACTED: AEG-1/miR-221 Axis Cooperatively Regulates the Progression of Hepatocellular Carcinoma by Targeting PTEN/PI3K/AKT Signaling Pathway

“…MicroRNAs (miRNAs) are a class of short endogenous noncoding RNAs (18–25 nucleotides in length), and it acts as oncogenes or tumor suppressors that dysregulate target gene expression at the post-transcription level [8,9]. It is considered as a key mediator in the various biological processes, including differentiation, proliferation, apoptosis, and angiogenesis via degradation of specific target mRNA [10,11] or signaling pathways, such as PTEN/PI3K/AKT [12] signaling targeted by several miRNAs, especially miR-221/222 [13], miR-181a/b-1 [14], miR-146b [15], and miR-543 [16] through binding at their 3′ UTR (untranslated region). Besides, miRNAs are involved in the progression of NAFLD in different cell types and considered as some of the potential biomarkers [4].…”

<p>Interfering Human Papillomavirus E6/E7 Oncogenes in Cervical Cancer Cells Inhibits the Angiogenesis of Vascular Endothelial Cells via Increasing miR-377 in Cervical Cancer Cell-Derived Microvesicles</p>

“…HPV-negative CC cell lines were transfected with HPV18 E6/E7 lentivirus to overexpress E6/E7, and HPV-positive CC cell lines were transfected with siHPV18 E6/E7 to interfere E6/E7 using Lipofectamine 2000 (Thermo Fisher Scientific, Waltham, MA, USA). 9 To investigate the impact of miR-377 on CC-MVs, HeLa cells were transfected with miR-377 inhibitor or NC (negative controls) using Lipofectamine 2000 (Thermo Fisher Scientific). Moreover, HUVECs were transfected with miR-377 inhibitor or miR-377 mimic using Lipofectamine 2000 to analysis the influence of miR-377 on HUVECs.…”

“…The qRT-PCR was done as previously described. 9 RNA samples of CC-MVs were prepared via RNA lysis buffer supplied in a NucleoSpin miRNA isolation kit (TaKaRa, Otsu, Japan) added to an MV pellet. NucleoSpin miRNA isolation kit (TaKaRa) was also used to isolate total RNA from cultured CC cells and HUVECs.…”

“…6,7 The previous study showed that the aberrant expression of HPV18 E6 and E7 oncogenes is the major cause for the CC angiogenesis, which inhibits the activities of tumor suppressor gene p53 and pRb and leads to the immune escape of cancer cells. 8,9 Importantly, researchers have found that microvesicles (MVs) which are derived from CC cells play an important role in E6/E7-mediated carcinogenesis, as silencing E6/E7 oncogenes enhanced the contents and numbers of extracellular MVs which were secreted by HPV-positive CC cells. 10 However, the mechanism of E6/E7 oncogenes in the CC angiogenesis remains largely unknown.…”