Abstract
Prolonged infection of uterine cervix epithelium with human papillomavirus (HPV) and constitutive expression of viral oncogenes have been recognized as the main cause of the complex molecular changes leading to transformation of cervical epithelial cells. Deregulated expression of microRNAs (miRNA), long non-coding RNAs (lncRNA), and circular RNAs (circRNA) is involved in the initiation and promotion processes of cervical cancer development. Expression profiling of small RNAs in cervical neoplasia revealed up-regulated “oncogenic” miRNAs, such as miR-10a, miR-21, miR-19, and miR-146a, and down regulated “tumor suppressive” miRNAs, including miR-29a, miR-372, miR-214, and miR-218, associated with cell growth, malignant transformation, cell migration, and invasion. Also several lncRNAs, comprising among others HOTAIR, MALAT1, GAS5, and MEG3, have shown to be associated with various pathogenic processes such as tumor progression, invasion as well as therapeutic resistance and emerged as new diagnostic and prognostic biomarkers in cervical cancer. Moreover, human genes encoded circular RNAs, such as has_circ-0018289, have shown to sponge specific miRNAs and to concur to the deregulation of target genes. Viral encoded circE7 has also demonstrated to overexpress E7 oncoprotein thus contributing to cell transformation. In this review, we summarize current literature on the complex interplay between miRNAs, lncRNAs, and circRNAs and their role in cervical neoplasia.
Highlights
Cervical cancer is the fourth most frequently diagnosed tumor and the fourth leading cause of cancer death in women in the world with ∼570,000 cases and 311,000 deaths in 2018 [1]
Cervical squamous cell carcinoma (SCC) is generally preceded by persistent squamous intraepithelial lesions (SIL) caused by human papillomaviruses (HPV) infection, the detection of viral nucleic acids has shown to be valuable for the effective prevention of cervical cancer development in oncologic screening programs [3]
The HPV E5 protein has a relevant role in tumor cell invasion and metastasis for its ability to increase the expression of the epidermal growth factor receptor (EGFR) and c-MET, the latter being critical for viral gene expression [6, 7]
Summary
Cervical cancer is the fourth most frequently diagnosed tumor and the fourth leading cause of cancer death in women in the world with ∼570,000 cases and 311,000 deaths in 2018 [1]. Epigenetic modifications, including deregulation of microRNA (miRNA), long non-protein coding RNA (lncRNA) and circular RNA (circRNA) levels, have shown to play important roles in cell transformation during distinct stages of cervical intraepithelial neoplasia and cervical carcinoma development [Figure 1; [15,16,17]]. The aim of this review is to summarize the recent studies on the role of miRNAs, lncRNAs, and circRNAs as well as their reciprocal regulation in different stages of cervical neoplasia. It provides an overview of the potential impact of non-coding RNAs in the diagnosis and therapy of cervical cancer. Many research groups reported the identification of specific miRNA signatures during the transition from SIL to cervical cancer with variable results mainly due to the small sample size, the type of specimens (i.e., formalin fixed paraffin embedded vs. fresh biopsies), the number of miRNAs included in each panel (ranging from one to 7788 miRNAs) as well as the diverse methods used to quantify [37, 96, 111, 112]
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