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

Sridharan Jayamohan,Rajesh Kannan Moorthy,Hun Soon Jung,Antony Joseph Velanganni Arockiam,Young Kee Shin,Nirmal Rajasekaran,Maheshkumar Kannan

doi:10.3389/fonc.2019.00847

Sridharan Jayamohan, Rajesh Kannan Moorthy + Show 5 more

Open Access

https://doi.org/10.3389/fonc.2019.00847

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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.

Highlights

Cervical Cancer (CC) significantly affects the health of women worldwide, especially in developing countries like India, and currently ranks as the second leading cancer in women following breast cancer [1]
The results showed that the expression of miR-375 was significantly decreased in all CC cell lines when compared to HEK-293
We revealed that miR-375 expression is downregulated in CC cells and that it is correlated with tumorigenesis. miR-375 suppressed cell proliferation, migration, invasion, and angiogenesis; enhanced chemosensitivity toward 5-fluorouracil, arrested cell cycle in sub G0G1 phase, and induced apoptosis by targeting astrocyte elevated gene-1 (AEG-1)

Summary

Introduction

Cervical Cancer (CC) significantly affects the health of women worldwide, especially in developing countries like India, and currently ranks as the second leading cancer in women following breast cancer [1]. Human Papillomavirus (HPV) is the major risk factor for the development of CC and HPV DNA has been found in almost all cases of CC [2]. High-Risk HPV (HR-HPV) types 16 and 18 strains are associated with more than 70% of CC [3, 4]. HR-HPV encodes E6 and E7 which are two key oncogenes that induce a series of signals that eventually target the tumor suppressor genes TP53 and retinoblastoma (Rb). This alters the HPV16/18-E6/E7 Deregulates miR-375/AEG-1 Axis in CC genomic stability and cell cycle regulatory pathways, prevents apoptosis, and potentially induces cellular transformation [5, 6]. It has been reported that epigenetic alterations are needed for triggering the multi-step carcinogenesis process [7, 8]

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