nach oben

Medical Oncology

Erschienen in:

01.01.2020 | Original Paper

Association and clinicopathologic significance of p38MAPK-ERK-JNK-CDC25C with polyploid giant cancer cell formation

verfasst von: Kai Liu, Rui Lu, Qi Zhao, Jiaxing Du, Yuwei Li, Minying Zheng, Shiwu Zhang

Erschienen in: Medical Oncology | Ausgabe 1/2020

Einloggen, um Zugang zu erhalten

Abstract

Background

We previously showed that cobalt chloride (CoCl₂) induction of polyploid giant cancer cells (PGCCs) was characterized by abnormal cell cycle-related protein expression and G2/M arrest. The role of the p38MAPK-ERK-JNK signaling pathway in cell cycle regulation has been reported, but the mechanism by which p38MAPK-ERK-JNK regulates PGCCs formation remains unclear. This study examined p38MAPK-ERK-JNK-CDC25C expression in PGCCs and their daughter and control cells and assessed the clinicopathological significance of p38MAPK, ERK, JNK, and CDC25C expression in human ovarian and breast cancers.

Methods

CoCl₂ was used to induce the formation of PGCCs in HEY and BT-549 cells. Western blotting and immunocytochemical staining were used to compare the expression and subcellular localization of p38MAPK, ERK, JNK, and CDC25C in the control group and CDC25C knockdown before and after CoCl₂ treatment. The specific combination of p38MAPK and ERK with pCDC25C-Ser216 was detected by immunoprecipitation. In addition, p38MAPK, ERK, JNK, and CDC25C immunohistochemical staining were performed to compare the clinicopathologic significances in 81 cases of ovarian cancer tissue, including 20 cases of primary breast cancer with lymph node metastasis (group I), and their corresponding metastatic lymph nodes (group II), 31 cases of primary breast cancer without metastasis (group III), and 10 cases of benign breast tumors (group IV). Breast tumor tissue from 229 was divided into two groups: 167 cases of primary invasive breast cancer (group 1) and 62 cases of lymph node metastatic breast cancer (group 2).

Results

Compared to the control cells, p38MAPK and JNK expression were higher and CDC25C expression was lower in CoCl₂-treated cells. Moreover, ERK displayed a trend of increased expression in HEY PGCCs and decreased expression in BT-549 PGCCs. p38MAPK and ERK regulated CDC25C by phosphorylating the CDC25C-Ser216 site and participated in the G2/M phase transition. Immunohistochemical (IHC) analysis of the ovarian tumor tissues showed significant positive staining rates of p38MAPK (P = 0.001), ERK (P = 0.002), JNK (P = 0.000), and CDC25C (P = 0.000) among the four groups. In breast tumor tissues, the overall expression in p38MAPK (P = 0.029), ERK (P = 0.002), JNK (P = 0.013), and CDC25C (P = 0.001) also differed significantly between the two groups.

Conclusion

The p38MAPK-ERK-JNK signaling pathway was involved in cell cycle progression and the formation of PGCCs by regulation of CDC25C.

Nur mit Berechtigung zugänglich

Zhang S, Mercado-Uribe I, Xing Z, Sun B, Kuang J, Liu J. Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene. 2014;33:116–28. https://doi.org/10.1038/onc.2013.96.CrossRefPubMed

Fei F, Li C, Wang X, Du J, Liu K, Li B, Yao P, Li Y, Zhang S. Syncytin 1, CD9, and CD47 regulating cell fusion to form PGCCs associated with cAMP/PKA and JNK signaling pathway. Cancer Med. 2019;8:3047–58. https://doi.org/10.1002/cam4.2173.CrossRefPubMedPubMedCentral

Zhang S, Zhang D, Yang Z, Zhang X. Tumor budding, micropapillary pattern, and polyploidy giant cancer cells in colorectal cancer: current status and future prospects. Stem Cells Int. 2016;2016:4810734. https://doi.org/10.1155/2016/4810734.CrossRefPubMedPubMedCentral

Fei F, Zhang D, Yang Z, Wang S, Wang X, Wu Z, Wu Q, Zhang S. The number of polyploid giant cancer cells and epithelial-mesenchymal transition-related proteins are associated with invasion and metastasis in human breast cancer. J Exp Clin Cancer Res. 2015;34:158. https://doi.org/10.1186/s13046-015-0277-8.CrossRefPubMedPubMedCentral

Fei F, Qu J, Liu K, Li C, Wang X, Li Y, Zhang S. The subcellular location of cyclin B1 and CDC25 associated with the formation of polyploid giant cancer cells and their clinicopathological significance. Lab Invest. 2019;99:483–98. https://doi.org/10.1038/s41374-018-0157-x.CrossRefPubMed

Wenzel ES, Singh ATK. Cell-cycle checkpoints and aneuploidy on the path to cancer. In vivo (Athens, Greece). 2018;32:1–5. https://doi.org/10.21873/invivo.11197.CrossRef

Chen J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harbor Perspect Med. 2016;6:a026104. https://doi.org/10.1101/cshperspect.a026104.CrossRef

Boutros R, Lobjois V, Ducommun B. CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer. 2007;7:495–507. https://doi.org/10.1038/nrc2169.CrossRefPubMed

Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev: MMBR. 2004;68:320–44. https://doi.org/10.1128/mmbr.68.2.320-344.2004.CrossRefPubMed

10.

Gkouveris I, Nikitakis NG. Role of JNK signaling in oral cancer: a mini review. Tumour Biol. 2017;39:1010428317711659. https://doi.org/10.1177/1010428317711659.CrossRefPubMed

11.

Eymin B, Claverie P, Salon C, Brambilla C, Brambilla E, Gazzeri S. p14ARF triggers G2 arrest through ERK-mediated Cdc25C phosphorylation, ubiquitination and proteasomal degradation. Cell Cycle. 2006;5:759–65. https://doi.org/10.4161/cc.5.7.2625.CrossRefPubMed

12.

Johnson MD, Reeder JE, O’Connell M. p38MAPK activation and DUSP10 expression in meningiomas. J Clin Neurosci. 2016;30:110–4. https://doi.org/10.1016/j.jocn.2015.12.031.CrossRefPubMed

13.

Wang Y, Liu J, Cui J, Xing L, Wang J, Yan X, Zhang X. ERK and p38 MAPK signaling pathways are involved in ochratoxin A-induced G2 phase arrest in human gastric epithelium cells. Toxicol Lett. 2012;209:186–92. https://doi.org/10.1016/j.toxlet.2011.12.011.CrossRefPubMed

14.

Lv H, Shi Y, Zhang L, Zhang D, Liu G, Yang Z, Li Y, Fei F, Zhang S. Polyploid giant cancer cells with budding and the expression of cyclin E, S-phase kinase-associated protein 2, stathmin associated with the grading and metastasis in serous ovarian tumor. BMC Cancer. 2014;14:576. https://doi.org/10.1186/1471-2407-14-576.CrossRefPubMedPubMedCentral

15.

Niu N, Zhang J, Zhang N, Mercado-Uribe I, Tao F, Han Z, Pathak S, Multani AS, Kuang J, Yao J, et al. Linking genomic reorganization to tumor initiation via the giant cell cycle. Oncogenesis. 2016;5:e281. https://doi.org/10.1038/oncsis.2016.75.CrossRefPubMedPubMedCentral

16.

Duncan AW, Taylor MH, Hickey RD, Hanlon Newell AE, Lenzi ML, Olson SB, Finegold MJ, Grompe M. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature. 2010;467:707–10. https://doi.org/10.1038/nature09414.CrossRefPubMedPubMedCentral

17.

Orr-Weaver TL. When bigger is better: the role of polyploidy in organogenesis. Trends Genet: TIG. 2015;31:307–15. https://doi.org/10.1016/j.tig.2015.03.011.CrossRefPubMed

18.

Geigl JB, Obenauf AC, Schwarzbraun T, Speicher MR. Defining ‘chromosomal instability’. Trends Genet: TIG. 2008;24:64–9. https://doi.org/10.1016/j.tig.2007.11.006.CrossRefPubMed

19.

Holland AJ, Cleveland DW. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol. 2009;10:478–87. https://doi.org/10.1038/nrm2718.CrossRefPubMedPubMedCentral

20.

Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66. https://doi.org/10.1038/nrc2602.CrossRefPubMed

21.

Nair JJ, van Staden J. Cell cycle modulatory effects of Amaryllidaceae alkaloids. Life Sci. 2018;213:94–101. https://doi.org/10.1016/j.lfs.2018.08.073.CrossRefPubMed

22.

Smith J, Tho LM, Xu N, Gillespie DA. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010;108:73–112. https://doi.org/10.1016/b978-0-12-380888-2.00003-0.CrossRefPubMed

23.

Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem. 2004;73:39–85. https://doi.org/10.1146/annurev.biochem.73.011303.073723.CrossRefPubMed

24.

Sun Y, Liu WZ, Liu T, Feng X, Yang N, Zhou HF. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res. 2015;35:600–4. https://doi.org/10.3109/10799893.2015.1030412.CrossRefPubMed

25.

Brenner AK, Reikvam H, Lavecchia A, Bruserud O. Therapeutic targeting the cell division cycle 25 (CDC25) phosphatases in human acute myeloid leukemia–the possibility to target several kinases through inhibition of the various CDC25 isoforms. Molecules (Basel, Switzerland). 2014;19:18414–47. https://doi.org/10.3390/molecules191118414.CrossRef

26.

Boutros R, Dozier C, Ducommun B. The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol. 2006;18:185–91. https://doi.org/10.1016/j.ceb.2006.02.003.CrossRefPubMed

27.

Sur S, Agrawal DK. Phosphatases and kinases regulating CDC25 activity in the cell cycle: clinical implications of CDC25 overexpression and potential treatment strategies. Mol Cell Biochem. 2016;416:33–46. https://doi.org/10.1007/s11010-016-2693-2.CrossRefPubMedPubMedCentral

28.

Palanivel K, Kanimozhi V, Kadalmani B. Verrucarin A alters cell-cycle regulatory proteins and induces apoptosis through reactive oxygen species-dependent p38MAPK activation in the human breast cancer cell line MCF-7. Tumour Biol. 2014;35:10159–67. https://doi.org/10.1007/s13277-014-2286-1.CrossRefPubMed

29.

Zeke A, Misheva M, Remenyi A, Bogoyevitch MA. JNK signaling: regulation and functions based on complex protein-protein partnerships. Microbiol Mol Biol Rev: MMBR. 2016;80:793–835. https://doi.org/10.1128/mmbr.00043-14.CrossRefPubMed

30.

Zhou YY, Li Y, Jiang WQ, Zhou LF. MAPK/JNK signalling: a potential autophagy regulation pathway. Biosci Rep. 2015. https://doi.org/10.1042/bsr20140141.CrossRefPubMedPubMedCentral

31.

Bubici C, Papa S. JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol. 2014;171:24–37. https://doi.org/10.1111/bph.12432.CrossRefPubMed

32.

Yang Z, Cheng B, Song J, Wan Y, Wang Q, Cheng B, Chen X. Estrogen accelerates G1 to S phase transition and induces a G2/M phase-predominant apoptosis in synthetic vascular smooth muscle cells. Int J Cardiol. 2007;118:381–8. https://doi.org/10.1016/j.ijcard.2006.07.049.CrossRefPubMed

33.

Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9:537–49. https://doi.org/10.1038/nrc2694.CrossRefPubMed

34.

Lee CF, Qiao M, Schroder K, Zhao Q, Asmis R. Nox4 is a novel inducible source of reactive oxygen species in monocytes and macrophages and mediates oxidized low density lipoprotein-induced macrophage death. Circ Res. 2010;106:1489–97. https://doi.org/10.1161/circresaha.109.215392.CrossRefPubMedPubMedCentral

35.

Demiroglu-Zergeroglu A, Candemir G, Turhanlar E, Sagir F, Ayvali N. EGFR-dependent signalling reduced and p38 dependent apoptosis required by Gallic acid in malignant mesothelioma cells. Biomed Pharmacother Biomed Pharmacother. 2016;84:2000–7. https://doi.org/10.1016/j.biopha.2016.11.005.CrossRefPubMed

36.

Li H, Tian Z, Qu Y, Yang Q, Guan H, Shi B, Ji M, Hou P. SIRT7 promotes thyroid tumorigenesis through phosphorylation and activation of Akt and p70S6K1 via DBC1/SIRT1 axis. Oncogene. 2019;38:345–59. https://doi.org/10.1038/s41388-018-0434-6.CrossRefPubMed

37.

Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell. 2007;11:175–89. https://doi.org/10.1016/j.ccr.2006.11.024.CrossRefPubMedPubMedCentral

38.

Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011;30:1536–48. https://doi.org/10.1038/emboj.2011.69.CrossRefPubMedPubMedCentral

39.

Garcia-Cano J, Roche O, Cimas FJ, Pascual-Serra R, Ortega-Muelas M, Fernandez-Aroca DM, Sanchez-Prieto R. p38MAPK and chemotherapy: we always need to hear both sides of the story. Front Cell Dev Biol. 2016;4:69. https://doi.org/10.3389/fcell.2016.00069.CrossRefPubMedPubMedCentral

40.

Xue Q, Wang X, Wang P, Zhang K, Liu Q. Role of p38MAPK in apoptosis and autophagy responses to photodynamic therapy with Chlorin e6. Photodiagn Photodyn Ther. 2015;12:84–91. https://doi.org/10.1016/j.pdpdt.2014.12.001.CrossRef

41.

Ma, M.M.; Zhu, X.L.; Wang, L.; Hu, X.F.; Wang, Z.; Zhao, J.; Ma, Y.T.; Yang, Y.N.; Chen, B.D.; Liu, F. beta3-adrenoceptor impacts apoptosis in cultured cardiomyocytes via activation of PI3 K/Akt and p38MAPK. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 2016, 36, 1–7, https://doi.org/10.1007/s11596-016-1533-7.CrossRef

42.

Sun WJ, Huang H, He B, Hu DH, Li PH, Yu YJ, Zhou XH, Lv Z, Zhou L, Hu TY, et al. Romidepsin induces G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis induction through JNK/c-Jun/caspase3 pathway in hepatocellular carcinoma cells. Biochem Pharmacol. 2017;127:90–100. https://doi.org/10.1016/j.bcp.2016.12.008.CrossRefPubMed

43.

Kumar A, Singh UK, Kini SG, Garg V, Agrawal S, Tomar PK, Pathak P, Chaudhary A, Gupta P, Malik A. JNK pathway signaling: a novel and smarter therapeutic targets for various biological diseases. Future Med Chem. 2015;7:2065–86. https://doi.org/10.4155/fmc.15.132.CrossRefPubMed

Titel: Association and clinicopathologic significance of p38MAPK-ERK-JNK-CDC25C with polyploid giant cancer cell formation
verfasst von: Kai Liu
Rui Lu
Qi Zhao
Jiaxing Du
Yuwei Li
Minying Zheng
Shiwu Zhang
Publikationsdatum: 01.01.2020
Verlag: Springer US
Erschienen in: Medical Oncology / Ausgabe 1/2020
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI: https://doi.org/10.1007/s12032-019-1330-9

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Association and clinicopathologic significance of p38MAPK-ERK-JNK-CDC25C with polyploid giant cancer cell formation

Abstract

Background

Methods

Results

Conclusion

Neu im Fachgebiet Onkologie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

Update Onkologie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Background

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2020

Mitotic checkpoint kinase Mps1/TTK predicts prognosis of colon cancer patients and regulates tumor proliferation and differentiation via PKCα/ERK1/2 and PI3K/Akt pathway

Inhibition of PI3K/AKT/mTOR and MAPK signaling pathways decreases progranulin expression in ovarian clear cell carcinoma (OCCC) cell line: a potential biomarker for therapy response to signaling pathway inhibitors

Prognostic impact of C-reactive protein-albumin ratio for the lethality in castration-resistant prostate cancer

Venous thromboprophylaxis in urological cancer surgery

Prehabilitation for patient positioning: pelvic exercises assist in minimizing inter-fraction sacral slope variability during radiation therapy

Pentoxifylline and vitamin E reduce the severity of radiotherapy-induced oral mucositis and dysphagia in head and neck cancer patients: a randomized, controlled study

Neu im Fachgebiet Onkologie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

Update Onkologie