Cross-talk between Human Papillomavirus Oncoproteins and Hedgehog Signaling Synergistically Promotes Stemness in Cervical Cancer Cells
Open Access
- 28 September 2016
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 6 (1), 34377
- https://doi.org/10.1038/srep34377
Abstract
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.This publication has 46 references indexed in Scilit:
- Annual Report to the Nation on the Status of Cancer, 1975–2009, Featuring the Burden and Trends in Human Papillomavirus (HPV)–Associated Cancers and HPV Vaccination Coverage LevelsJNCI Journal of the National Cancer Institute, 2013
- Stem Cell Pathways Contribute to Clinical Chemoresistance in Ovarian CancerClinical Cancer Research, 2012
- Sonic Hedgehog Pathway Is Essential for Maintenance of Cancer Stem-Like Cells in Human Gastric CancerPLOS ONE, 2011
- Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinomaLaboratory Investigation, 2010
- Context-dependent Regulation of the GLI Code in Cancer by HEDGEHOG and Non-HEDGEHOG SignalsJournal of Molecular Cell Biology, 2010
- A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbersThe EMBO Journal, 2009
- Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2Proceedings of the National Academy of Sciences of the United States of America, 2008
- The Gli code: an information nexus regulating cell fate, stemness and cancerTrends in Cell Biology, 2007
- HEDGEHOG-GLI1 Signaling Regulates Human Glioma Growth, Cancer Stem Cell Self-Renewal, and TumorigenicityCurrent Biology, 2007
- Papillomaviruses and cancer: from basic studies to clinical applicationNature Reviews Cancer, 2002