Persistent infection with Porphyromonas gingivalis increases the tumorigenic potential of human immortalised oral epithelial cells through ZFP36 inhibition

  • Ze Lu ,
  • Ruoyan Cao ,
  • Fengxue Geng ,
  • Yaping Pan
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  • Department of Periodontics, School of Stomatology, China Medical University, Shenyang, China
gfx1989_@126.com
yppan@cmu.edu.cn

Received date: 16 Nov 2023

Revised date: 16 Jan 2024

Accepted date: 27 Jan 2024

Copyright

2024 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.

Abstract

The association between Porphyromonas gingivalis infection and oral squamous cell carcinoma (OSCC) has been established by numerous epidemiological studies. However, the underlying mechanism specific to this connection remains unclear. By bioinformatical analysis, we identified ZFP36 as a potentially significant co-expressed gene in both the OSCC gene database and the persistent infection model of P. gingivalis. To further investigate the role of ZFP36, we established a cell model that human immortalized oral epithelial cells (HIOECs) that were sustainedly infected by P. gingivalis (MOI = 1) for a duration of 30 weeks. Our findings indicated that sustained infection with P. gingivalis inhibited the expression of ZFP36 protein and induced changes in the biological behaviour of HIOECs. The mechanism investigation demonstrated the potential role of ZFP36 in regulating the cancer-related biological behaviour of HIOECs. Subsequent studies revealed that highly expressed CCAT1 could serve as a molecular scaffold in the formation of the ZFP36/CCAT1/MK2 complex. This complex formation enhanced the binding abundance of MK2 and ZFP36, thereby promoting the inhibition of ZFP36 protein phosphorylation. To summarize, low expression of ZFP36 protein under persistent P. gingivalis infection enhances the cancer-related biological behaviour of HIOECs.

Cite this article

Ze Lu , Ruoyan Cao , Fengxue Geng , Yaping Pan . Persistent infection with Porphyromonas gingivalis increases the tumorigenic potential of human immortalised oral epithelial cells through ZFP36 inhibition[J]. Cell Proliferation, 2024 , 57(6) : e13609 . DOI: 10.1111/cpr.13609

1
Gasner NS, Schure RS. Periodontal disease. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023.

2
Bodet C, Chandad F, Grenier D. Potentiel pathogénique de Porphyromonas gingivalis, Treponema denticola et Tannerella forsythia, le complexe bactérien rouge associé à la parodontite [pathogenic potential of Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, the red bacterial complex associated with periodontitis]. Pathol Biol (Paris). 2007;55(3–4):154-162.

DOI

3
Xu W, Zhou W, Wang H, Liang S. Roles of Porphyromonas gingivalis and its virulence factors in periodontitis. Adv Protein Chem Struct Biol. 2020;120:45-84.

DOI

4
Zheng S, Yu S, Fan X, et al. Porphyromonas gingivalis survival skills: Immune evasion. J Periodontal Res. 2021;56(6):1007-1018.

DOI

5
Sakanaka A, Takeuchi H, Kuboniwa M, Amano A. Dual lifestyle of Porphyromonas gingivalis in biofilm and gingival cells. Microb Pathog. 2016;94:42-47.

DOI

6
Singh S, Singh AK. Porphyromonas gingivalis in oral squamous cell carcinoma: a review. Microbes Infect.2022;24(3):104925.

DOI

7
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249.

DOI

8
Nagy K, Szöke I, Sonkodi I, et al. Inhibition of microflora associated with oral malignancy. Oral Oncol. 2000;36(1):32-36.

DOI

9
Katz J, Onate MD, Pauley KM, Bhattacharyya I, Cha S. Presence of Porphyromonas gingivalis in gingival squamous cell carcinoma. Int J Oral Sci. 2011;3(4):209-215.

DOI

10
Sayehmiri F, Sayehmiri K, Asadollahi K, et al. The prevalence rate of Porphyromonas gingivalis and its association with cancer: a systematic review and meta-analysis. Int J Immunopathol Pharmacol. 2015;28(2):160-167.

DOI

11
Xie M, Tang Q, Yu S, et al. Porphyromonas gingivalis disrupts vascular endothelial homeostasis in a TLR-NF-κB axis dependent manner. Int J Oral Sci. 2020;12(1):28.

DOI

12
Kleinstein SE, Nelson KE, Freire M. Inflammatory networks linking Oral microbiome with systemic health and disease. J Dent Res. 2020;99(10):1131-1139.

DOI

13
Li C, Yu R, Ding Y. Association between Porphyromonas Gingivalis and systemic diseases: focus on T cells-mediated adaptive immunity. Front Cell Infect Microbiol. 2022;17(12):1026457.

DOI

14
Groeger S, Domann E, Gonzales JR, Chakraborty T, Meyle J. B7-H1 and B7-DC receptors of oral squamous carcinoma cells are upregulated by Porphyromonas gingivalis. Immunobiology. 2011;216(12):1302-1310.

DOI

15
Antonyuk SV, Siemińska K, Śmiga M, et al. Bacteroides fragilis expresses three proteins similar to Porphyromonas gingivalis HmuY: Hemophore-like proteins differentially evolved to participate in heme acquisition in oral and gut microbiomes. FASEB J. 2023;37(7):e22981.

DOI

16
Settem RP, Honma K, Chinthamani S, Kawai T, Sharma A. B-cell RANKL contributes to pathogen-induced alveolar bone loss in an experimental periodontitis mouse model. Front Physiol. 2021;14(12):722859.

DOI

17
Han YK, Jin Y, Miao YB, Shi T, Lin XP. CD8+ Foxp3+ T cells affect alveolar bone homeostasis via modulating Tregs/Th17 during induced periodontitis: an adoptive transfer experiment. Inflammation. 2018;41(5):1791-1803.

DOI

18
Cicchetto AC, Jacobson EC, Sunshine H, et al. ZFP36-mediated mRNA decay regulates metabolism. Cell Rep. 2023;42(5):112411.

DOI

19
Tiedje C, Diaz-Muñoz MD, Trulley P, et al. The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation. Nucleic Acids Res. 2016;44(15):7418-7440.

DOI

20
Taylor GA, Carballo E, Lee DM, et al. A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity. 1996;4(5):445-454.

DOI

21
Makita S, Takatori H, Nakajima H. Post-transcriptional regulation of immune responses and inflammatory diseases by RNA-binding ZFP36 family proteins. Front Immunol. 2021;1(12):711633.

DOI

22
Nelson EV, Ross SJ, Olejnik J, et al. The 3′ untranslated regions of Ebola virus mRNAs contain AU-rich elements involved in post-transcriptional stabilization and decay. J Infect Dis. 2023;8:jiad312.

DOI

23
Saini Y, Chen J, Patial S. The Tristetraprolin family of RNA-binding proteins in cancer: Progress and future prospects. Cancers (Basel). 2020;12(6):1539.

DOI

24
Lee WH, Kim SH, An JH, et al. Tristetraprolin regulates phagocytosis through interaction with CD47 in head and neck cancer. Exp Ther Med. 2022;24(3):541.

DOI

25
Van Tubergen EA, Banerjee R, Liu M, et al. Inactivation or loss of TTP promotes invasion in head and neck cancer via transcript stabilization and secretion of MMP9, MMP2, and IL-6. Clin Cancer Res. 2013;19(5):1169-1179.

DOI

26
Zhang D, Zhou Z, Yang R, et al. Tristetraprolin, a potential safeguard against carcinoma: role in the tumor microenvironment. Front Oncol. 2021;7(11):632189.

DOI

27
Feng Y, Fang Z, Liu B, Zheng X. p38MAPK plays a pivotal role in the development of acute respiratory distress syndrome. Clinics (Sao Paulo). 2019;74:e509.

DOI

28
Beamer E, Corrêa SAL. The p38MAPK-MK2 signaling Axis as a critical link between inflammation and synaptic transmission. Front Cell Dev Biol. 2021;28(9):635636.

DOI

29
Nie Y, Wang Z, Chai G, et al. Dehydrocostus lactone suppresses LPS-induced acute lung injury and macrophage activation through NF-κB signaling pathway mediated by p38 MAPK and Akt. Molecules. 2019;24(8):1510.

DOI

30
Ronkina N, Shushakova N, Tiedje C, et al. The role of TTP phosphorylation in the regulation of inflammatory cytokine production by MK2/3. J Immunol. 2019;203(8):2291-2300.

DOI

31
Zhang T, Qiu L, Cao J, et al. ZFP36 loss-mediated BARX1 stabilization promotes malignant phenotypes by transactivating master oncogenes in NSCLC. Cell Death Dis. 2023;14(8):527.

DOI

32
Neininger A, Kontoyiannis D, Kotlyarov A, et al. MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels. J Biol Chem. 2002;277(5):3065-3068.

DOI

33
Qi MY, Song JW, Zhang Z, Huang S, Jing Q. P38 activation induces the dissociation of tristetraprolin from Argonaute 2 to increase ARE-mRNA stabilization. Mol Biol Cell. 2018;29(8):988-1002.

DOI

34
Franz C, Wuehrl M, Hartmann S, Klupp F, Schmidt T, Schneider M. Long non-coding RNAs CCAT1 and CCAT2 in colorectal liver metastases are tumor-suppressive via MYC interaction and might predict patient outcomes. PloS One. 2023;18(6):e0286486.

DOI

35
Liau XL, Salvamani S, Gunasekaran B, et al. CCAT 1- a pivotal oncogenic long non-coding RNA in colorectal cancer. Br J Biomed Sci. 2023;21(80):11103.

DOI

36
Jiang Y, Jiang YY, Xie JJ, et al. Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression. Nat Commun. 2018;9(1):3619.

DOI

37
Zhao J, Jia X, Li Q, et al. Genomic and transcriptional characterization of early esophageal squamous cell carcinoma. BMC Med Genomics. 2023;16(1):153.

DOI

38
Statement of Retraction: Long non-coding RNA CCAT1 promotes multiple myeloma progression by acting as a molecular sponge of miR-181a-5p to modulate HOXA1 expression. Cell Cycle. 2023;22:1798.

DOI

39
Al-Souhibani N, Al-Ahmadi W, Hesketh JE, Blackshear PJ, Khabar KS. The RNA-binding zinc-finger protein tristetraprolin regulates AU-rich mRNAs involved in breast cancer-related processes. Oncogene. 2010;29(29):4205-4215.

DOI

40
Bourcier C, Griseri P, Grépin R, Bertolotto C, Mazure N, Pagès G. Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells. Am J Physiol Cell Physiol. 2011;301(3):C609-18.

DOI

41
Geng F, Liu J, Guo Y, et al. Persistent exposure to Porphyromonas gingivalis promotes proliferative and invasion capabilities, and tumorigenic properties of human immortalized Oral epithelial cells. Front Cell Infect Microbiol. 2017;24(7):57.

DOI

42
Irfan M, Delgado RZR, Frias-Lopez J. The Oral microbiome and cancer. Front Immunol. 2020;23(11):591088.

DOI

43
Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB. Inflammation and cancer. Ann Afr Med. 2019;18(3):121-126.

DOI

44
Molle C, Zhang T, Ysebrant de Lendonck L, et al. Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease. J Exp Med. 2013;210(9):1675-1684.

DOI

45
Suswam E, Li Y, Zhang X, et al. Tristetraprolin down-regulates interleukin-8 and vascular endothelial growth factor in malignant glioma cells. Cancer Res. 2008;68(3):674-682.

DOI

46
Kim TW, Yim S, Choi BJ, et al. Tristetraprolin regulates the stability of HIF-1alpha mRNA during prolonged hypoxia. Biochem Biophys Res Commun. 2010;391(1):963-968.

DOI

47
Wang Q, Ning H, Peng H, et al. Tristetraprolin inhibits macrophage IL-27-induced activation of antitumour cytotoxic T cell responses. Nat Commun. 2017;8(1):867.

DOI

48
Kratochvill F, Gratz N, Qualls JE, et al. Tristetraprolin limits inflammatory cytokine production in tumor-associated macrophages in an mRNA decay-independent manner. Cancer Res. 2015;75(15):3054-3064.

DOI

49
Hibino S, Kawazoe T, Kasahara H, et al. Inflammation-induced tumorigenesis and metastasis. Int J Mol Sci. 2021;22(11):5421.

DOI

50
Kinane JA, Benakanakere MR, Zhao J, Hosur KB, Kinane DF. Porphyromonas gingivalis influences Actin degradation within epithelial cells during invasion and apoptosis. Cell Microbiol. 2012;14(7):1085-1096.

DOI

51
Stasiewicz M, Karpiński TM. The oral microbiota and its role in carcinogenesis. Semin Cancer Biol. 2022;86(Pt 3):633-642.

DOI

52
French PW. Unfolded p53 in non-neuronal cells supports bacterial etiology of Alzheimer's disease. Neural Regen Res. 2022;17(12):2619-2622.

DOI

53
Marderosian M, Sharma A, Funk AP, et al. Tristetraprolin regulates cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling. Oncogene. 2006;25(47):6277-6290.

DOI

54
Dang CV. MYC on the path to cancer. Cell. 2012;149(1):22-35.

DOI

55
Lee HH, Lee SR, Leem SH. Tristetraprolin regulates prostate cancer cell growth through suppression of E2F1. J Microbiol Biotechnol. 2014;24(2):287-294.

DOI

56
Park SB, Lee JH, Jeong WW, et al. TTP mediates cisplatin-induced apoptosis of head and neck cancer cells by down-regulating the expression of Bcl-2. J Chemother. 2015;27(3):174-180.

DOI

57
Wang LJ, Lee YC, Huang CH, et al. Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation. Biochem Pharmacol. 2019;162:154-168.

DOI

58
Lee SK, Kim SB, Kim JS, et al. Butyrate response factor 1 enhances cisplatin sensitivity in human head and neck squamous cell carcinoma cell lines. Int J Cancer. 2005;117(1):32-40.

DOI

59
Montorsi L, Guizzetti F, Alecci C, et al. Loss of ZFP36 expression in colorectal cancer correlates to wnt/ ß-catenin activity and enhances epithelial-to-mesenchymal transition through upregulation of ZEB1, SOX9 and MACC1. Oncotarget. 2016;7(37):59144-59157.

DOI

60
Wang C, Chen F, Fan Z, Yao C, Xiao L. lncRNA CCAT1/miR-490-3p/MAPK1/c-Myc positive feedback loop drives progression of acute myeloid leukaemia. J Biochem. 2020;167(4):379-388.

DOI

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