Bridging Links between Long Noncoding RNA HOTAIR and HPV Oncoprotein E7 in Cervical Cancer Pathogenesis.

Sweta Sharma,Rahul Roy Chowdhury,Sudipta Roy,Tamal Sadhukhan,Sharmila Sengupta,Nidhu Ranjan Mondal,Tanmay Chatterjee,Paramita Mandal,Biman Chakravarty

doi:10.1038/srep11724

Abstract

Human Papillomavirus (HPV) type 16 oncoprotein E7 plays a major role in cervical carcinogenesis by interacting with and functionally inactivating various host regulatory molecules. Long noncoding RNA (lncRNA) HOTAIR is one such regulator that recruits chromatin remodelling complex PRC2, creating gene silencing H3K27 me3 marks. Hence, we hypothesized that HOTAIR could be a potential target of E7, in HPV16 related cervical cancers (CaCx). We identified significant linear trend of progressive HOTAIR down-regulation through HPV negative controls, HPV16 positive non-malignants and CaCx samples. Majority of CaCx cases portrayed HOTAIR down-regulation in comparison to HPV negative controls, with corresponding up-regulation of HOTAIR target, HOXD10, and enrichment of cancer related pathways. However, a small subset had significantly higher HOTAIR expression, concomitant with high E7 expression and enrichment of metastatic pathways. Expression of HOTAIR and PRC2-complex members (EZH2 and SUZ12), showed significant positive correlation with E7 expression in CaCx cases and E7 transfected C33A cell line, suggestive of interplay between E7 and HOTAIR. Functional inactivation of HOTAIR by direct interaction with E7 could also be predicted by in silico analysis and confirmed by RNA-Immunoprecipitation. Our study depicts one of the causal mechanisms of cervical carcinogenesis by HPV16 E7, through modulation of HOTAIR expression and function.

Highlights

Transformation by interacting with the PDZ domain of cellular proteins and pRb, thereby contributing to neoplastic progression[8]
HOX transcript antisense intergenic RNA (HOTAIR) is deregulated in Human Papillomavirus (HPV) 16 positive cases as compared to the healthy HPV negative controls
We identified a positive correlation of EZH2 and SUZ12 mRNA expression, with HPV16 E7 mRNA expression among the CaCx cases (Supplementary Fig. S5)

Summary

Introduction

Transformation by interacting with the PDZ domain of cellular proteins and pRb, thereby contributing to neoplastic progression[8]. HPV16 positive CaCx cases portray a characteristic E7-dependent global reduction in the chromatin repressive H3K27 me[3] mark[14,31,32], indicative of probable impairment of HOTAIR function Based on this rationale, we hypothesized that one of the mechanisms by which HPV16 E7 mediates its causal effect of activation of cancer-related pathway genes in CaCx pathogenesis, is through interplay with lncRNA HOTAIR. We hypothesized that one of the mechanisms by which HPV16 E7 mediates its causal effect of activation of cancer-related pathway genes in CaCx pathogenesis, is through interplay with lncRNA HOTAIR This affects the function of PRC2-complex recruitment by HOTAIR, which otherwise would normally act by creating chromatin repressive H3K27 me[3] marks. This helped us to propose that HOTAIR could serve as one of the targets of the HPV16 oncoprotein E7 in the process of cervical carcinogenesis

Methods

Results

Conclusion