Abstract
Heterogeneity in cervical cancers (CaCx) in terms of HPV16 physical status prompted us to investigate the mRNA and miRNA signatures among the different categories of CaCx samples. We performed microarray-based mRNA expression profiling and quantitative real-time PCR-based expression analysis of some prioritised miRNAs implicated in cancer-related pathways among various categories of cervical samples. Such samples included HPV16-positive CaCx cases that harboured either purely integrated HPV16 genomes (integrated) and those that harboured episomal viral genomes, either pure or concomitant with integrated viral genomes (episomal), which were compared with normal cervical samples that were either HPV negative or positive for HPV16. The mRNA expression profile differed characteristically between integrated and episomal CaCx cases for enriched biological pathways. miRNA expression profiles also differed among CaCx cases compared with controls (upregulation—miR-21, miR-16, miR-205, miR-323; downregulation—miR-143, miR-196b, miR-203, miR-34a; progressive upregulation—miR-21 and progressive downregulation—miR-143, miR-34a, miR-196b and miR-203) in the order of HPV-negative controls, HPV16-positive non-malignant samples and HPV16-positive CaCx cases. miR-200a was upregulated in HPV16-positive cervical tissues irrespective of histopathological status. Expression of majority of the predicted target genes was negatively correlated with their corresponding miRNAs, irrespective of the CaCx subtypes. E7 mRNA expression correlated positively with miR-323 expression among episomal cases and miR-203, among integrated cases. miR-181c expression was downregulated only among the episomal CaCx cases and negatively correlated with protein coding transcript of the proliferative target gene, CKS1B of the significantly enriched “G2/M DNA Damage Checkpoint Regulation” pathway among CaCx cases. Thus, the two CaCx subtypes are distinct entities at the molecular level, which could be differentially targeted for therapy. In fact, availability of a small molecule inhibitor of CKS1B, suggests that drugging CKS1B could be a potential avenue of treating the large majority of CaCx cases harbouring episomal HPV16.
Highlights
Cervical cancer (CaCx) appears to be the most common malignancy in Indian women, characterised by high incidence and mortality rates that are attributable to late detection and lack of access to affordable health care.Official journal of the Cell Death Differentiation AssociationMandal et al Cell Death Discovery (2019)5:81Oncogenic human papillomavirus (HPV) infections are the major aetiological factors, with a predominance of HPV16 that accounts for over 50% of such cancers[1]
Ingenuity pathway analysis (IPA) revealed that biological processes such as cell proliferation, retroviridae infection, and viral Infections were the most significantly enriched among the episomal CaCx cases
The most important pathways identified for CaCx pathogenesis, irrespective of HPV physical status were the cell cycle regulatory pathways such as “Cell Cycle: G2/M DNA Damage Checkpoint
Summary
Cervical cancer (CaCx) appears to be the most common malignancy in Indian women, characterised by high incidence and mortality rates that are attributable to late detection and lack of access to affordable health care.Official journal of the Cell Death Differentiation AssociationMandal et al Cell Death Discovery (2019)5:81Oncogenic human papillomavirus (HPV) infections are the major aetiological factors, with a predominance of HPV16 that accounts for over 50% of such cancers[1]. Under the impact of oncogenic HPV infections, could be influenced by several epigenetic mechanisms like DNA methylation, histone modifications, by microRNAs, etc., through perturbations of gene expression profiles. In this communication, we chose to focus on the expression of host mRNAs and miRNAs in various categories of cervical samples spanning the discrete stages of CaCx development. We chose to focus on the expression of host mRNAs and miRNAs in various categories of cervical samples spanning the discrete stages of CaCx development These small non-coding RNAs, through recognition of sequence-complementary target elements, can either translationally suppress or catalytically degrade both cellular and viral RNAs5,6. A glimpse of the deregulated expression of mRNAs and miRNAs in CaCx cases might offer some insights into the mechanisms of CaCx pathogenesis among the two subtypes that bear integrated HPV16 and episomal HPV16 in presence or absence of integration, subsequently referred to as integrated and episomal CaCx cases, respectively
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