Cross-talk between Human Papillomavirus Oncoproteins and Hedgehog Signaling Synergistically Promotes Stemness in Cervical Cancer Cells.
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 anti-cancer effects. Overall, our data show existence of a cooperative interaction between GLI signaling and HPVE6.
Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.|Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.|School of Biotechnology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Kanchan
K
Vishnoi
Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.
Sutapa
S
Mahata
Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.|Molecular Oncology Laboratory, B.R. Ambedkar Center for Biomedical Research (ACBR), University of Delhi, New Delhi, India.
Abhishek
A
Tyagi
Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.
Arvind
A
Pandey
Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.|Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.|School of Biotechnology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Gaurav
G
Verma
Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.|Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.
Mohit
M
Jadli
Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.|Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.
Tejveer
T
Singh
School of Biotechnology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Sukh Mahendra
SM
Singh
Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.|Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.
Alok C
AC
Bharti
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