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Differential effects of GLI2 and GLI3 in regulating cervical cancer malignancy in vitro and in vivo


Advanced, recurrent, or persistent cervical cancer is often incurable. Therefore, in-depth insights into the molecular mechanisms are needed for the development of novel therapeutic targets and the improvement of current therapeutic strategies. In this study, we investigated the role of GLI2 and GLI3 in the regulation of the malignant properties of cervical cancer. We showed that down-regulation of GLI2, but not GLI3, with an inducible GLI2 shRNA inhibited the growth and migration of cervical cancer cell lines, which could be rescued by ectopic expression of GLI2. GLI2 appeared to support cell growth by regulating the mitosis, but not the apoptosis, of the cervical cancer cells. Mechanistically, these functions of GLI2 were in part mediated by the activation of AKT pathway. Knockdown of GLI2, but not GLI3, also inhibited xenograft growth of cervical cancer cells in vivo. Finally, analysis of TCGA data showed that high levels of GLI2, but not GLI3, conferred a poor prognosis in cervical cancer patients. These observations for the first time suggest that GLI2, but not GLI3, exerts a tumor-promoting role in cervical cancer and may be targeted as a novel therapeutic strategy.

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  1. 1.

    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.

  2. 2.

    Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell. 2008;15:801–12.

  3. 3.

    Robbins DJ, Fei DL, Riobo NA. The Hedgehog signal transduction network. Sci Signal. 2012;5:re6.

  4. 4.

    Briscoe J, Therond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013;14:416–29.

  5. 5.

    Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R. The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins. Genes Dev. 2010;24:670–82.

  6. 6.

    Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol. 2011;27:513–37.

  7. 7.

    Chaudary N, Pintilie M, Hedley D, et al. Hedgehog pathway signaling in cervical carcinoma and outcome after chemoradiation. Cancer. 2012;118:3105–15.

  8. 8.

    Chen H, Wang J, Yang H, Chen D, Li P. Association between FOXM1 and hedgehog signaling pathway in human cervical carcinoma by tissue microarray analysis. Oncol Lett. 2016;12:2664–73.

  9. 9.

    Xuan YH, Jung HS, Choi YL, et al. Enhanced expression of hedgehog signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions. Mod Pathol. 2006;19:1139–47.

  10. 10.

    Vishnoi K, Mahata S, Tyagi A, et al. Cross-talk between human Papillomavirus oncoproteins and hedgehog signaling synergistically promotes stemness in cervical cancer cells. Sci Rep. 2016;6:34377.

  11. 11.

    Roessler E, Ermilov AN, Grange DK, et al. A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. Hum Mol Genet. 2005;14:2181–8.

  12. 12.

    Du CX, Wang Y. Expression of P-Akt, NFkappaB and their correlation with human papillomavirus infection in cervical carcinoma. Eur J Gynaecol Oncol. 2012;33:274–7.

  13. 13.

    Cho H, Noh KH, Chung JY, et al. Synaptonemal complex protein 3 is a prognostic marker in cervical cancer. PLoS ONE. 2014;9:e98712.

  14. 14.

    Choi SK, Hong YO, Lee WM, et al. Overexpression of PI3K-p110alpha in the progression of uterine cervical neoplasia and its correlation with pAkt and DJ-1. Eur J Gynaecol Oncol. 2015;36:389–93.

  15. 15.

    Bumrungthai S, Munjal K, Nandekar S, et al. Epidermal growth factor receptor pathway mutation and expression profiles in cervical squamous cell carcinoma: therapeutic implications. J Transl Med. 2015;13:244.

  16. 16.

    Chan DW, Liu VW, Leung LY, et al. Zic2 synergistically enhances Hedgehog signalling through nuclear retention of Gli1 in cervical cancer cells. J Pathol. 2011;225:525–34.

  17. 17.

    Thiyagarajan S, Bhatia N, Reagan-Shaw S, et al. Role of GLI2 transcription factor in growth and tumorigenicity of prostate cells. Cancer Res. 2007;67:10642–6.

  18. 18.

    Zhang DW, Li HY, Lau WY, et al. Gli2 silencing enhances TRAIL-induced apoptosis and reduces tumor growth in human hepatoma cells in vivo. Cancer Biol Ther. 2014;15:1667–76.

  19. 19.

    Zhang D, Liu J, Wang Y, Chen J, Chen T. shRNA-mediated silencing of Gli2 gene inhibits proliferation and sensitizes human hepatocellular carcinoma cells towards TRAIL-induced apoptosis. J Cell Biochem. 2011;112:3140–50.

  20. 20.

    Nagao H, Ijiri K, Hirotsu M, et al. Role of GLI2 in the growth of human osteosarcoma. J Pathol. 2011;224:169–79.

  21. 21.

    Li F, Duman-Scheel M, Yang D, et al. Sonic hedgehog signaling induces vascular smooth muscle cell proliferation via induction of the G1 cyclin-retinoblastoma axis. Arterioscler Thromb Vasc Biol. 2010;30:1787–94.

  22. 22.

    Kramann R, Fleig SV, Schneider RK, et al. Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis. J Clin Invest. 2015;125:2935–51.

  23. 23.

    Kump E, Ji J, Wernli M, Hausermann P, Erb P. Gli2 upregulates cFlip and renders basal cell carcinoma cells resistant to death ligand-mediated apoptosis. Oncogene. 2008;27:3856–64.

  24. 24.

    Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30:193–204.

  25. 25.

    Mundi PS, Sachdev J, McCourt C, Kalinsky K. AKT in cancer: new molecular insights and advances in drug development. Br J Clin Pharmacol. 2016;82:943–56.

  26. 26.

    Wen SY, Lin Y, Yu YQ, et al. miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer. Oncogene. 2015;34:717–25.

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This study was in part supported by grants from NIH R01CA172886 and R01CA196214 to L. -Z. S., and from Key Lab of Wenzhou city-Gynecological Oncology to X. Q. Z. Additional support was provided by the Flow Cytometry Shared Resource of the Cancer Therapy and Research Center, which is supported by the NIH NCI Cancer Center Support Grant P30 CA054174-17. H. -Y. Z. and Qi Shen were supported by a fellowship from the Second Affiliated Hospital of Wenzhou Medical University and Key Lab of Wenzhou city-Gynecological Oncology. L. X. and B. W. were in part supported by a fellowship from Xiangya School of Medicine, Central South University, Hunan, China. X. G. was supported by the CPRIT Research Training Award RP140105 and RP170345.

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Ethics statement

All animal experiments were conducted following appropriate guidelines. They were approved by the Institutional Animal Care and Use Committee and monitored by the Department of Laboratory Animal Resources at the University of Texas Health Science Center at San Antonio.

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Lu-Zhe Sun or Xueqiong Zhu.

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