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

Sharma S, Mandal P, Sadhukhan T, Roy Chowdhury R, Ranjan Mondal N, Chakravarty B, Chatterjee T, Roy S, Sengupta S - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Biomedical Genomics, Netaji Subhas Sanatorium, 2nd Floor, P.O. N.S.S, Kalyani 741251, West Bengal, India.

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.

No MeSH data available.


Related in: MedlinePlus

HOTAIR expression correlates positively with HPV16 E7 expression.(a–c) Correlation analysis between HOTAIR and HPV16 E7 expression among CaCx cases, episomal and integrated CaCx cases, respectively. (d,e) Box plots representing distribution of HPV16 E7 and HOTAIR expression levels respectively, in C33A cell line at various time points post-transfection (p. t.) of pcDNA3.1-HPV16 E7 vector. (f,g) Box plots representing distribution of expression levels of HPV16 E7 and HOTAIR among SiHa and Caski cell lines respectively.
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f2: HOTAIR expression correlates positively with HPV16 E7 expression.(a–c) Correlation analysis between HOTAIR and HPV16 E7 expression among CaCx cases, episomal and integrated CaCx cases, respectively. (d,e) Box plots representing distribution of HPV16 E7 and HOTAIR expression levels respectively, in C33A cell line at various time points post-transfection (p. t.) of pcDNA3.1-HPV16 E7 vector. (f,g) Box plots representing distribution of expression levels of HPV16 E7 and HOTAIR among SiHa and Caski cell lines respectively.

Mentions: We employed two approaches, to confirm the correlation between E7 and HOTAIR expression, based on both clinical samples and CaCx cell lines. HOTAIR expression was positively and significantly correlated with HPV16 E7 expression among the CaCx samples harbouring episomal or integrated HPV16 (Fig. 2a–c). Expression of HOTAIR and E7 correlated with viral load only among episomal CaCx cases (Supplementary Fig. S4). This was in concordance with an earlier report from our laboratory36 that identified similar correlation between E7 expression and viral load among CaCx cases with episomal HPV16, ensuring the expression of E7 from all episomal viral genomes. Taken together the observations point towards a possible dependence between HOTAIR and E7 expression.


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

Sharma S, Mandal P, Sadhukhan T, Roy Chowdhury R, Ranjan Mondal N, Chakravarty B, Chatterjee T, Roy S, Sengupta S - Sci Rep (2015)

HOTAIR expression correlates positively with HPV16 E7 expression.(a–c) Correlation analysis between HOTAIR and HPV16 E7 expression among CaCx cases, episomal and integrated CaCx cases, respectively. (d,e) Box plots representing distribution of HPV16 E7 and HOTAIR expression levels respectively, in C33A cell line at various time points post-transfection (p. t.) of pcDNA3.1-HPV16 E7 vector. (f,g) Box plots representing distribution of expression levels of HPV16 E7 and HOTAIR among SiHa and Caski cell lines respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495428&req=5

f2: HOTAIR expression correlates positively with HPV16 E7 expression.(a–c) Correlation analysis between HOTAIR and HPV16 E7 expression among CaCx cases, episomal and integrated CaCx cases, respectively. (d,e) Box plots representing distribution of HPV16 E7 and HOTAIR expression levels respectively, in C33A cell line at various time points post-transfection (p. t.) of pcDNA3.1-HPV16 E7 vector. (f,g) Box plots representing distribution of expression levels of HPV16 E7 and HOTAIR among SiHa and Caski cell lines respectively.
Mentions: We employed two approaches, to confirm the correlation between E7 and HOTAIR expression, based on both clinical samples and CaCx cell lines. HOTAIR expression was positively and significantly correlated with HPV16 E7 expression among the CaCx samples harbouring episomal or integrated HPV16 (Fig. 2a–c). Expression of HOTAIR and E7 correlated with viral load only among episomal CaCx cases (Supplementary Fig. S4). This was in concordance with an earlier report from our laboratory36 that identified similar correlation between E7 expression and viral load among CaCx cases with episomal HPV16, ensuring the expression of E7 from all episomal viral genomes. Taken together the observations point towards a possible dependence between HOTAIR and E7 expression.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: National Institute of Biomedical Genomics, Netaji Subhas Sanatorium, 2nd Floor, P.O. N.S.S, Kalyani 741251, West Bengal, India.

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.

No MeSH data available.


Related in: MedlinePlus