Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep34377
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Funding
- Department of Science and Technology (DST) [DST-PURSE Phase II/RC/2016/944]
- Department of Biotechnology, Government of India [BT/PR10347, 102/IFD/SAN/PR-1612/2007, 6242-P34/RGCB/PMD/DBT/ALCB/2015]
- INSA (India)
- University of Delhi, Government of India, India
- Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India, India
- UGC-Junior Research Fellowship [F.2-2/2009 (SA-I)]
- ICMR [3/1/13/PDF(2)/2011-HRD, 81/3/2009/BMS/Stem Cell, 3/2/2/11/2010/NCD-III, 3/2/2/278/2014-NCD III]
- UGC [F.2-2/2009 (SA-I), 2061430699 22/06/2014 (i) EU-V]
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Viral oncoproteins E6/E7 play key oncogenic role in human papillomavirus (HPV)-mediated cervical carcinogenesis in conjunction with aberrant activation of cellular signaling events. GLI-signaling has been implicated in metastasis and tumor recurrence of cervical cancer. However, the interaction of GLI-signaling with HPV oncogenes is unknown. We examined this relationship in established HPV-positive and HPV-negative cervical cancer cell lines using specific GLI inhibitor, cyclopamine and HPVE6/E7 siRNAs. Cervical cancer cell lines showed variable expression of GLI-signaling components. HPV16-positive SiHa cells, overexpressed GLI1, Smo and Patch. Inhibition by cyclopamine resulted in dose-dependent reduction of Smo and GLI1 and loss of cell viability with a higher magnitude in HPV-positive cells. Cyclopamine selectively downregulated HPVE6 expression and resulted in p53 accumulation, whereas HPVE7 and pRb level remained unaffected. siRNA-mediated silencing of HPV16E6 demonstrated reduced GLI1 transcripts in SiHa cells. Cervical cancer stem-like cells isolated by side population analysis, displayed retention of E6 and GLI1 expression. Fraction of SP cells was reduced in cyclopamine-treated cultures. When combined with E6-silencing cyclopamine resulted in loss of SP cell's sphere-forming ability. Co-inhibition of GLI1 and E6 in cervical cancer cells showed additive anticancer effects. Overall, our data show existence of a cooperative interaction between GLI signaling and HPVE6.
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