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Cellular Oncology
Published in: Cellular Oncology 6/2016

01-12-2016 | Original Paper

Identification of genetic variation in the lncRNA HOTAIR associated with HPV16-related cervical cancer pathogenesis

Authors: Sweta Sharma Saha, Rahul Roy Chowdhury, Nidhu Ranjan Mondal, Biman Chakravarty, Tanmay Chatterjee, Sudipta Roy, Sharmila Sengupta

Published in: Cellular Oncology | Issue 6/2016

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Abstract

Purpose

Previously, over-expression of the long noncoding RNA (lncRNA) HOTAIR has been found to be associated with the invasive and metastatic capacities of several epithelial cancers, including cervical cancer (CaCx). Here, we aimed at identifying functionally relevant genetic variants that may be employed to differentiate between clinically distinct CaCx subtypes, i.e., those exhibiting high HOTAIR levels and molecular signatures of metastasis and those lacking such signatures in the presence of low HOTAIR expression levels.

Methods

Genomic DNA isolated from various cervical tissue samples (characterized by histopathology and HPV status) was used for HOTAIR amplicon sequencing, followed by validation of the findings by Sanger sequencing. The impact of the genetic variants found on the secondary structure of HOTAIR and the concomitant alterations in miRNA binding sites were determined through in silico analysis, followed by miRNA expression analysis by quantitative real-time PCR and confirmation of miRNA binding using a luciferase reporter assay.

Results

We found that rs2366152C was over-represented [ORage-adjusted = 2.58 (1.23–5.57); p = 0.014] in low HOTAIR expressing HPV positive CaCx cases compared to HPV negative controls. This genetic variant showed the propensity of a secondary structure alteration and gain of a miR-22 binding site in HOTAIR, which was found to be concordant with miR-22 over-expression in low HOTAIR CaCx cases compared to controls. We found that miR-22 expression negatively correlated with HOTAIR and E7 expression in HPV16 positive cases and in an E7 transfected HPV negative CaCx-derived cell line (C33A), but was not altered in high HOTAIR cases compared to controls. Reduced luciferase activity of a HOTAIR rs2366152C expression plasmid in C33A cells through miR-22 co-transfection confirmed the ability of miR-22 to specifically target rs2366152C-harbouring HOTAIR lncRNA in CaCx cells, ultimately leading to its down-regulation.

Conclusions

Our data indicate that rs2366152C not only has the potential to serve as a marker for singling out CaCx cases lacking metastatic molecular signatures, but also to explain the functional inactivation of HOTAIR in these cases, including the mechanism of its down-regulation.
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Metadata
Title
Identification of genetic variation in the lncRNA HOTAIR associated with HPV16-related cervical cancer pathogenesis
Authors
Sweta Sharma Saha
Rahul Roy Chowdhury
Nidhu Ranjan Mondal
Biman Chakravarty
Tanmay Chatterjee
Sudipta Roy
Sharmila Sengupta
Publication date
01-12-2016
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 6/2016
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-016-0298-0

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