Deregulation of microRNAs Let-7a and miR-21 mediate aberrant STAT3 signaling during human papillomavirus-induced cervical carcinogenesis: role of E6 oncoprotein

BMC Cancer

Alok Chandra Bharti²  Bhudev Chandra Das¹  Ravi Mehrotra²  Yogesh Srivastava²  Gaurav Verma²  Gauri Shishodia¹ 

[1]Dr. BR. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India

[2]Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I-7, Sector-39, Noida, Uttar Pradesh 201301, India

关键词: Let-7a;    miR-21;    STAT3;    microRNAs;    Cervical cancer;    HPV;   

Others  :  1106774
DOI  :  10.1186/1471-2407-14-996

 received in 2014-07-23, accepted in 2014-12-10,  发布年份 2014

【 摘 要 】

Background

Aberrantly expressed and constitutively active STAT3 signaling plays a pivotal role in initiation and progression of human papillomavirus-induced cervical carcinogenesis. However, the underlying mechanism(s) responsible for pleiotropic effects of STAT3 signaling is poorly understood. In view of emerging regulatory role of microRNAs, Let-7a and miR-21 that may interact with STAT3 signaling and/or its downstream effectors, present study was designed in HPV16-positive cervical cancer cells to assess the functional contribution of these miRs in STAT3 signaling in cervical cancer.

Methods

Functional silencing of STAT3 signaling and HPV16 oncoprotein expression in SiHa cells was done by STAT3-specific and 16 E6 siRNAs. Pharmacological intervention of STAT3 was done using specific inhibitors like curcumin and stattic. Loss-of-function study of miR-21 using miR-21 inhibitor and gain-of-function study of let-7a was done using let-7a mimic in SiHa cells.

Results

Functional silencing of STAT3 signaling in SiHa cells by STAT3-specific siRNA resulted in a dose-dependent decrease in cellular miR-21 level. Pharmacological intervention of STAT3 using specific inhibitors like curcumin and Stattic that abrogated STAT3 activation resulted in loss of cellular miR-21 pool. Contrary to this, specific targeting of miR-21 using miR-21 inhibitor resulted in an increased level of PTEN, a negative regulator of STAT3, and reduced active pSTAT3 level. Besides miR-21, restoration of cellular Let-7a using chemically synthesized Let-7a mimic reduced overall STAT3 level. Abrogation of HPV oncoprotein E6 by specific siRNA resulted in increased Let-7a but loss of miR-21 and a correspondingly reduced pSTAT3/STAT3 and elevated the level of cellular PTEN.

Conclusions

Our results demonstrate existence of a functional loop involving Let-7a, STAT3 and miR-21 which were found potentially regulated by viral oncoprotein E6. Implications: miR-21 and Let-7a along with STAT3 may prove useful targets for pharmacological intervention for management of cervical cancer.

【 授权许可】

   
2014 Shishodia et al.; licensee BioMed Central.

【 图 表 】

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