Downregulation of Sonic Hedgehog Signaling Induces G2-arrest in Genital Warts

Overview

Journal Skin Res Technol

Specialty Biomedical Engineering

Date 2023 Jan 27

PMID 36704875

Authors

XiangXi Du

Shan Li

Kun Yang

Yuchun Cao

Affiliations

Soon will be listed here.

Abstract

Background: Human papillomavirus (HPV) infected keratinocyte dysfunction results in the formation of genital warts, and the specific role of Sonic hedgehog (SHh) signaling in genital warts remains elusive. Thus, this study aimed to identify the correlation between wart formation and SHh signaling.

Materials And Methods: In this study, nine male patients with genital warts were recruited, and the expression of SHh and its downstream signal molecules Patched-1 and GLI family zinc finger 1 (Ptch1 and Gli1) was detected. Moreover, G2-phase cells in the collected genital warts samples were assessed with normal foreskin samples as a comparison. HPV6/11 were detected via in situ hybridization (ISH), and SHh expression of the corresponding paraffin sections was determined via immunohistochemical staining (IHC). In addition, an in vitro down-regulated SHh model was constructed by siRNA transfection of the HaCaT cell line, and the cell cycle was detected at 36 h by flow cytometry with propidium iodide staining.

Results: SHh, Ptch1, and Gli1 in warts were significantly downregulated in the condyloma acuminatum (CA) group compared to the normal foreskin group. G2-phase cells in the middle section of the spinous layer of CA wart tissues were significantly increased. Moreover, the expression of HPV-DNA was amplified and negatively correlated with SHh activity in CA wart tissues. Lastly, the downregulation of SHh-induced G2 arrest in vitro.

Conclusions: The downregulation of the SHh signaling promotes HPV replication and the formation of warts by inducing G2/M arrest in the keratinocytes of CA.

Citing Articles

Emodin combined with 5-aminolevulinic acid photodynamic therapy inhibits condyloma acuminate angiogenesis by targeting SerRS.

Lu H, Peng Z, Luo Y, Zheng Z, Li C, Wang Q J Cell Mol Med. 2024; 28(19):e70122.

PMID: 39351642 PMC: 11443161. DOI: 10.1111/jcmm.70122.

ZNT1 Regulates the Proliferation, Migration and Invasion of HaCaT Cells Infected with HPV Through the PI3K/Akt Pathway.

Jiang L, Yi Q, Sun Z, Lin Y Indian J Dermatol. 2024; 69(2):201.

PMID: 38841228 PMC: 11149793. DOI: 10.4103/ijd.ijd_775_23.

Downregulation of Sonic hedgehog signaling induces G2-arrest in genital warts.

Du X, Li S, Yang K, Cao Y Skin Res Technol. 2023; 29(1):e13265.

PMID: 36704875 PMC: 9838784. DOI: 10.1111/srt.13265.

References

Nguyen H, Ramirez-Fort M, Rady P . The biology of human papillomaviruses. Curr Probl Dermatol. 2014; 45:19-32. DOI: 10.1159/000355959. View

Barnes E, Kong M, Ollendorff V, Donoghue D . Patched1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J. 2001; 20(9):2214-23. PMC: 125436. DOI: 10.1093/emboj/20.9.2214. View

Nusslein-Volhard C, Wieschaus E . Mutations affecting segment number and polarity in Drosophila. Nature. 1980; 287(5785):795-801. DOI: 10.1038/287795a0. View

Papaioannou E, Yanez D, Ross S, Lau C, Solanki A, Chawda M . Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation. J Clin Invest. 2019; 129(8):3153-3170. PMC: 6668675. DOI: 10.1172/JCI125170. View

Ockenfels H . Therapeutic management of cutaneous and genital warts. J Dtsch Dermatol Ges. 2016; 14(9):892-9. DOI: 10.1111/ddg.12838. View

Doorbar J . The E4 protein; structure, function and patterns of expression. Virology. 2013; 445(1-2):80-98. DOI: 10.1016/j.virol.2013.07.008. View

Chang C, Yu M, Wu P, Jiang T, Yu H, Widelitz R . Sculpting skin appendages out of epidermal layers via temporally and spatially regulated apoptotic events. J Invest Dermatol. 2004; 122(6):1348-55. PMC: 4386661. DOI: 10.1111/j.0022-202X.2004.22611.x. View

Doorbar J, Quint W, Banks L, Bravo I, Stoler M, Broker T . The biology and life-cycle of human papillomaviruses. Vaccine. 2012; 30 Suppl 5:F55-70. DOI: 10.1016/j.vaccine.2012.06.083. View

Ding J, Doorbar J, Li B, Zhou F, Gu W, Zhao L . Expression of papillomavirus L1 proteins regulated by authentic gene codon usage is favoured in G2/M-like cells in differentiating keratinocytes. Virology. 2010; 399(1):46-58. DOI: 10.1016/j.virol.2009.12.021. View

10.

Du X, Li S, Yang K, Cao Y . Downregulation of Sonic hedgehog signaling induces G2-arrest in genital warts. Skin Res Technol. 2023; 29(1):e13265. PMC: 9838784. DOI: 10.1111/srt.13265. View

11.

Adolphe C, Narang M, Ellis T, Wicking C, Kaur P, Wainwright B . An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development. 2004; 131(20):5009-19. DOI: 10.1242/dev.01367. View

12.

Knight G, Turnell A, Roberts S . Role for Wee1 in inhibition of G2-to-M transition through the cooperation of distinct human papillomavirus type 1 E4 proteins. J Virol. 2006; 80(15):7416-26. PMC: 1563741. DOI: 10.1128/JVI.00196-06. View

13.

Longworth M, Laimins L . Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiol Mol Biol Rev. 2004; 68(2):362-72. PMC: 419925. DOI: 10.1128/MMBR.68.2.362-372.2004. View

14.

Moody C . Mechanisms by which HPV Induces a Replication Competent Environment in Differentiating Keratinocytes. Viruses. 2017; 9(9). PMC: 5618027. DOI: 10.3390/v9090261. View

15.

Jung Y, Vermeer P, Vermeer D, Lee S, Goh A, Ahn H . CD200: association with cancer stem cell features and response to chemoradiation in head and neck squamous cell carcinoma. Head Neck. 2014; 37(3):327-35. PMC: 4557697. DOI: 10.1002/hed.23608. View

16.

Laukkanen M, Gutkind J, Castellone M . Sonic Hedgehog in SCLC. Aging (Albany NY). 2015; 7(9):605-6. PMC: 4600616. DOI: 10.18632/aging.100817. View

17.

Reinson T, Henno L, Toots M, Ustav Jr M, Ustav M . The Cell Cycle Timing of Human Papillomavirus DNA Replication. PLoS One. 2015; 10(7):e0131675. PMC: 4489393. DOI: 10.1371/journal.pone.0131675. View

18.

Reinson T, Toots M, Kadaja M, Pipitch R, Allik M, Ustav E . Engagement of the ATR-dependent DNA damage response at the human papillomavirus 18 replication centers during the initial amplification. J Virol. 2012; 87(2):951-64. PMC: 3554080. DOI: 10.1128/JVI.01943-12. View

19.

Milla L, Arros A, Espinoza N, Remke M, Kool M, Taylor M . Neogenin1 is a Sonic Hedgehog target in medulloblastoma and is necessary for cell cycle progression. Int J Cancer. 2013; 134(1):21-31. DOI: 10.1002/ijc.28330. View

20.

Samarzija I, Beard P . Hedgehog pathway regulators influence cervical cancer cell proliferation, survival and migration. Biochem Biophys Res Commun. 2012; 425(1):64-9. DOI: 10.1016/j.bbrc.2012.07.051. View