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

Abstract

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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Acknowledgements

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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