Deregulation of Long Noncoding RNA HOTTIP/HOXA13 expression associates with poor prognosis in cervical squamous cell carcinomas


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Sweta Sharma Saha1,Sharmila Sengupta2,Rahul Roy Chowdhury2,Nidhu Ranjan Mondal2,Sudipta Roy3
1Tata Medical Center,2Saroj Gupta Cancer Centre and Research Institute,3Sri Aurobindo Seva Kendra

Abstract

Background

Long noncoding RNAs (lncRNAs) are frequently found to be deregulated in a variety of cancers including cervical cancer. Our previous reports highlight the deregulation of lncRNA HOTAIR in cervical cancer (CaCx) and its role in regulating global gene expression, specifically the HOX cluster, through epigenetic reprogramming. In this study, we tested the hypothesis that expression of lncRNA HOTTIP and its physically contiguous gene HOXA13 show altered expression in HPV16 positive CaCx cases and this deregulation associates with poor disease prognosis.

Method

Expression analysis of HOTTIP and HOXA13 was done using SYBR Green based quantitative Real-Time PCR employing 107 CaCx cases (63 with episomal and 44 with integrated HPV16 genomes) and 37 HPV negative histopathologically normal controls. GAPDH was used as a normalization control. Statistical significance of expression differences were determined based on Mann-Whitney U test/t-Test. Integration status of the HPV genome was determined by APOT-assay. To assess the association of HOXA13 with disease progression, The Cancer Genome Atlas (TCGA) cervical cancer data was analysed (HOTTIP expression data was not available).

Results

Both HOTTIP and HOXA13 showed a statistically significant up-regulation in CaCx by 12.88-folds (p = 0.02) and 10.32-folds (p = 0.006), respectively, in comparison to HPV negative controls, irrespective of the HPV16 integration status. HOTTIP expression positively correlated with HOXA13 (Pearson’s Correlation Coefficient = 0.467, p=0.006). TCGA cervical cancer data analysis revealed that the average HOXA13 expression value was significantly higher (1.74-fold; p=0.029) in CaCx with progressive disease as compared to patients with complete remission, specifically in late stage cancers (IIB onwards).

Conclusion

The study demonstrated a significant and correlated up-regulation of HOTTIP and HOXA13 expression highlighting the strong co-occurrence/co-expression of these genes in CaCx. TCGA data analysis revealed that such up-regulation of HOXA13 could serve as a prognostic marker for progression in CaCx patients.