MicroRNA-18a targeting of the STK4/MST1 tumour suppressor is necessary for transformation in HPV positive cervical cancer
Autoři:
Ethan L. Morgan aff001; Molly R. Patterson aff001; Emma L. Ryder aff001; Siu Yi Lee aff001; Christopher W. Wasson aff001; Katherine L. Harper aff001; Yigen Li aff001; Stephen Griffin aff002; G. Eric Blair aff001; Adrian Whitehouse aff001; Andrew Macdonald aff001
Působiště autorů:
School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, U.K, United Kingdom
aff001; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, West Yorkshire, U.K, United Kingdom
aff002; Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K, United Kingdom
aff003
Vyšlo v časopise:
MicroRNA-18a targeting of the STK4/MST1 tumour suppressor is necessary for transformation in HPV positive cervical cancer. PLoS Pathog 16(6): e32767. doi:10.1371/journal.ppat.1008624
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.ppat.1008624
Souhrn
Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a sub-set of other anogenital and head and neck cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3’UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment.
Klíčová slova:
Cell proliferation – Cervical cancer – Gene expression – HeLa cells – Human papillomavirus – Human papillomavirus infection – Protein expression – Small interfering RNAs
Zdroje
1. de Villiers E-M, Fauquet C, Broker TR, Bernard H-U, Hausen zur H. Classification of papillomaviruses. Virology. 2004;324: 17–27. doi: 10.1016/j.virol.2004.03.033 15183049
2. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14: 467–475. doi: 10.1158/1055-9965.EPI-04-0551 15734974
3. Moore KA, Mehta V. The Growing Epidemic of HPV-Positive Oropharyngeal Carcinoma: A Clinical Review for Primary Care Providers. J Am Board Fam Med. 2015;28: 498–503. doi: 10.3122/jabfm.2015.04.140301 26152442
4. Thomas M, Myers MP, Massimi P, Guarnaccia C, Banks L. Analysis of Multiple HPV E6 PDZ Interactions Defines Type-Specific PDZ Fingerprints That Predict Oncogenic Potential. PLoS Pathog. 2016;12: e1005766. doi: 10.1371/journal.ppat.1005766 27483446
5. Wasson CW, Morgan EL, Müller M, Ross RL, Hartley M, Roberts S, et al. Human papillomavirus type 18 E5 oncogene supports cell cycle progression and impairs epithelial differentiation by modulating growth factor receptor signalling during the virus life cycle. Oncotarget. 2017;8: 103581–103600. doi: 10.18632/oncotarget.21658 29262586
6. Morgan EL, Macdonald A. Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Rac1-NFκB-IL-6 signalling axis. PLoS Pathog. 2019;15: e1007835. doi: 10.1371/journal.ppat.1007835 31226168
7. Morgan EL, Macdonald A. JAK2 Inhibition Impairs Proliferation and Sensitises Cervical Cancer Cells to Cisplatin-Induced Cell Death. Cancers (Basel). 2019;11: 1934.
8. Wu S, Huang J, Dong J, Pan D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell. 2003;114: 445–456. doi: 10.1016/s0092-8674(03)00549-x 12941273
9. Udan RS, Kango-Singh M, Nolo R, Tao C, Halder G. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nature cell biology. 2003;5: 914–920. doi: 10.1038/ncb1050 14502294
10. Kango-Singh M, Singh A. Regulation of organ size: insights from the Drosophila Hippo signaling pathway. Dev Dyn. 2009;238: 1627–1637. doi: 10.1002/dvdy.21996 19517570
11. Edgar BA. From cell structure to transcription: Hippo forges a new path. Cell. 2006;124: 267–273. doi: 10.1016/j.cell.2006.01.005 16439203
12. Zhao B, Li L, Tumaneng K, Wang C-Y, Guan K-L. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(β-TRCP). Genes Dev. 2010;24: 72–85. doi: 10.1101/gad.1843810 20048001
13. Muramatsu T, Imoto I, Matsui T, Kozaki K-I, Haruki S, Sudol M, et al. YAP is a candidate oncogene for esophageal squamous cell carcinoma. Carcinogenesis. 2011;32: 389–398. doi: 10.1093/carcin/bgq254 21112960
14. Li L, Fang R, Liu B, Shi H, Wang Y, Zhang W, et al. Deacetylation of tumor-suppressor MST1 in Hippo pathway induces its degradation through HBXIP-elevated HDAC6 in promotion of breast cancer growth. Oncogene. 2016;35: 4048–4057. doi: 10.1038/onc.2015.476 26657153
15. Kim W, Khan SK, Liu Y, Xu R, Park O, He Y, et al. Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut. 2018;67: 1692–1703. doi: 10.1136/gutjnl-2017-314061 28866620
16. Baia GS, Caballero OL, Orr BA, Lal A, Ho JSY, Cowdrey C, et al. Yes-associated protein 1 is activated and functions as an oncogene in meningiomas. Mol Cancer Res. 2012;10: 904–913. doi: 10.1158/1541-7786.MCR-12-0116 22618028
17. Yeo M-K, Kim S-H, Kim JM, Huang S-M, Kim M-R, Song KS, et al. Correlation of Expression of Phosphorylated and Non-phosphorylated Yes-associated Protein with Clinicopathological Parameters in Esophageal Squamous Cell Carcinoma in a Korean Population. Anticancer Res. 2012;32: 3835–3840. 22993326
18. Zhou D, Conrad C, Xia F, Park J-S, Payer B, Yin Y, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress the development of hepatocellular carcinoma through inactivation of the Yap1 oncogene. Cancer Cell. 2009;16: 425–438. doi: 10.1016/j.ccr.2009.09.026 19878874
19. Sun Z-Q, Shi K, Zhou Q-B, Zeng X-Y, Liu J, Yang S-X, et al. MiR-590-3p promotes proliferation and metastasis of colorectal cancer via Hippo pathway. Oncotarget. 2017;8: 58061–58071. doi: 10.18632/oncotarget.19487 28938537
20. Yu J, Zhai X, Li X, Zhong C, Guo C, Yang F, et al. Identification of MST1 as a potential early detection biomarker for colorectal cancer through a proteomic approach. Sci Rep. 2017;7: 14265. doi: 10.1038/s41598-017-14539-x 29079854
21. He C, Mao D, Hua G, Lv X, Chen X, Angeletti PC, et al. The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. EMBO Mol Med. 2015;7: 1426–1449. doi: 10.15252/emmm.201404976 26417066
22. Dacus D, Cotton C, McCallister TX, Wallace NA. β-HPV 8E6 Attenuates LATS Phosphorylation After Failed Cytokinesis. J Virol. 2020.
23. Bansal N, Wright JD, Cohen CJ, Herzog TJ. Natural history of established low grade cervical intraepithelial (CIN 1) lesions. Anticancer Res. 2008;28: 1763–1766. 18630456
24. Scotto L, Narayan G, Nandula SV, Arias-Pulido H, Subramaniyam S, Schneider A, et al. Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: potential role in progression. Genes Chromosomes Cancer. 2008;47: 755–765. doi: 10.1002/gcc.20577 18506748
25. Galan JA, Avruch J. MST1/MST2 Protein Kinases: Regulation and Physiologic Roles. Biochemistry. 2016;55: 5507–5519. doi: 10.1021/acs.biochem.6b00763 27618557
26. Fan F, He Z, Kong L-L, Chen Q, Yuan Q, Zhang S, et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci Transl Med. 2016;8: 352ra108–352ra108. doi: 10.1126/scitranslmed.aaf2304 27535619
27. Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10: 550–560. doi: 10.1038/nrc2886 20592731
28. Morgan EL, Wasson CW, Hanson L, Kealy D, Pentland I, McGuire V, et al. STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle. PLoS Pathog. 2018;14: e1006975. doi: 10.1371/journal.ppat.1006975 29630659
29. Chang JT-C, Kuo T-F, Chen Y-J, Chiu C-C, Lu Y-C, Li H-F, et al. Highly potent and specific siRNAs against E6 or E7 genes of HPV16- or HPV18-infected cervical cancers. Cancer Gene Ther. 2010;17: 827–836. doi: 10.1038/cgt.2010.38 20885450
30. Wen W, Zhu F, Zhang J, Keum Y-S, Zykova T, Yao K, et al. MST1 promotes apoptosis through phosphorylation of histone H2AX. J Biol Chem. 2010;285: 39108–39116. doi: 10.1074/jbc.M110.151753 20921231
31. Belmokhtar CA, Hillion J, Ségal-Bendirdjian E. Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms. Oncogene. 2001;20: 3354–3362. doi: 10.1038/sj.onc.1204436 11423986
32. Uhl L, Gerstel A, Chabalier M, Dukan S. Hydrogen peroxide induced cell death: One or two modes of action? Heliyon. 2015;1: e00049. doi: 10.1016/j.heliyon.2015.e00049 27441232
33. Tamamori-Adachi M, Koga A, Susa T, Fujii H, Tsuchiya M, Okinaga H, et al. DNA damage response induced by Etoposide promotes steroidogenesis via GADD45A in cultured adrenal cells. Sci Rep. 2018;8: 9636–13. doi: 10.1038/s41598-018-27938-5 29941883
34. Lee KK, Murakawa M, Nishida E, Tsubuki S, Kawashima S, Sakamaki K, et al. Proteolytic activation of MST/Krs, STE20-related protein kinase, by caspase during apoptosis. Oncogene. 1998;16: 3029–3037. doi: 10.1038/sj.onc.1201840 9662336
35. Wang X, Wang H-K, Li Y, Hafner M, Banerjee NS, Tang S, et al. microRNAs are biomarkers of oncogenic human papillomavirus infections. Proc Natl Acad Sci USA. 2014;111: 4262–4267. doi: 10.1073/pnas.1401430111 24591631
36. Satapathy S, Batra J, Jeet V, Thompson EW, Punyadeera C. MicroRNAs in HPV associated cancers: small players with big consequences. Expert Rev Mol Diagn. 2017;17: 711–722. doi: 10.1080/14737159.2017.1339603 28597695
37. Santos JMO, Peixoto da Silva S, Costa NR, Gil da Costa RM, Medeiros R. The Role of MicroRNAs in the Metastatic Process of High-Risk HPV-Induced Cancers. Cancers (Basel). 2018;10: 493.
38. Liu S, Pan X, Yang Q, Wen L, Jiang Y, Zhao Y, et al. MicroRNA-18a enhances the radiosensitivity of cervical cancer cells by promoting radiation-induced apoptosis. Oncol Rep. 2015;33: 2853–2862. doi: 10.3892/or.2015.3929 25963391
39. Dong P, Xiong Y, Yu J, Chen L, Tao T, Yi S, et al. Control of PD-L1 expression by miR-140/142/340/383 and oncogenic activation of the OCT4-miR-18a pathway in cervical cancer. Oncogene. 2018;37: 5257–5268. doi: 10.1038/s41388-018-0347-4 29855617
40. Ng LFP, Chan M, Chan S-H, Cheng PC-P, Leung EH-C, Chen W-N, et al. Host heterogeneous ribonucleoprotein K (hnRNP K) as a potential target to suppress hepatitis B virus replication. PLoS Med. 2005;2: e163. doi: 10.1371/journal.pmed.0020163 16033304
41. Schumann S, Jackson BR, Yule I, Whitehead SK, Revill C, Foster R, et al. Targeting the ATP-dependent formation of herpesvirus ribonucleoprotein particle assembly as an antiviral approach. Nat Microbiol. 2016;2: 16201. doi: 10.1038/nmicrobiol.2016.201 27798559
42. Bekerman E, Neveu G, Shulla A, Brannan J, Pu S-Y, Wang S, et al. Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects. J Clin Invest. 2017;127: 1338–1352. doi: 10.1172/JCI89857 28240606
43. Pan D. The Hippo Signaling Pathway in Development and Cancer. Developmental cell. 2010;19: 491–505. doi: 10.1016/j.devcel.2010.09.011 20951342
44. He C, Mao D, Hua G, Lv X, Chen X, Angeletti PC, et al. The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. EMBO Mol Med. 2015;7: 1426–1449. doi: 10.15252/emmm.201404976 26417066
45. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993;75: 495–505. doi: 10.1016/0092-8674(93)90384-3 8221889
46. Boyer SN, Wazer DE, Band V. E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res. 1996;56: 4620–4624. 8840974
47. Ishiwatari H, Hayasaka N, Inoue H, Yutsudo M, Hakura A. Degradation of p53 only is not sufficient for the growth stimulatory effect of human papillomavirus 16 E6 oncoprotein in human embryonic fibroblasts. J Med Virol. 1994;44: 243–249. doi: 10.1002/jmv.1890440306 7852968
48. Shin M-K, Sage J, Lambert PF. Inactivating all three rb family pocket proteins is insufficient to initiate cervical cancer. Cancer Res. 2012;72: 5418–5427. doi: 10.1158/0008-5472.CAN-12-2083 22942253
49. Hsu T-I, Hsu C-H, Lee K-H, Lin J-T, Chen C-S, Chang K-C, et al. MicroRNA-18a is elevated in prostate cancer and promotes tumorigenesis through suppressing STK4 in vitro and in vivo. Oncogenesis. 2014;3: e99–e99. doi: 10.1038/oncsis.2014.12 24752237
50. Chen M, Wang M, Xu S, Guo X, Jiang J. Upregulation of miR-181c contributes to chemoresistance in pancreatic cancer by inactivating the Hippo signaling pathway. Oncotarget. 2015;6: 44466–44479. doi: 10.18632/oncotarget.6298 26561204
51. Wang LQ, Deng AC, Zhao L, Li Q, Wang M, Zhang Y. MiR-1178-3p promotes the proliferation, migration and invasion of nasopharyngeal carcinoma Sune-1 cells by targeting STK4. J Biol Regul Homeost Agents. 2019;33: 321–330. 30972994
52. Wilting SM, Snijders PJF, Verlaat W, Jaspers A, van de Wiel MA, van Wieringen WN, et al. Altered microRNA expression associated with chromosomal changes contributes to cervical carcinogenesis. Oncogene. 2013;32: 106–116. doi: 10.1038/onc.2012.20 22330141
53. Johnson R, Halder G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov. 2014;13: 63–79. doi: 10.1038/nrd4161 24336504
54. Jiang M, Milner J. Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference. Oncogene. 2002;21: 6041–6048. doi: 10.1038/sj.onc.1205878 12203116
55. Hall AHS, Alexander KA. RNA interference of human papillomavirus type 18 E6 and E7 induces senescence in HeLa cells. J Virol. 2003;77: 6066–6069. doi: 10.1128/jvi.77.10.6066-6069.2003 12719599
56. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29: e45. doi: 10.1093/nar/29.9.e45 11328886
Článek vyšel v časopise
PLOS Pathogens
2020 Číslo 6
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Proč při poslechu některé muziky prostě musíme tančit?
- Chůze do schodů pomáhá prodloužit život a vyhnout se srdečním chorobám
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- „Jednohubky“ z klinického výzkumu – 2024/44
Nejčtenější v tomto čísle
- Exploring potential of vaginal Lactobacillus isolates from South African women for enhancing treatment for bacterial vaginosis
- Microbiome factors in HPV-driven carcinogenesis and cancers
- Biological sex impacts COVID-19 outcomes
- Bacterial killing by complement requires direct anchoring of membrane attack complex precursor C5b-7
