Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

High Expression of PKMYT1 Predicts Poor Prognosis and Aggravates the Progression of Osteosarcoma via the NF-κB Pathway in MG63 Cells

Author(s): Yang Lu*, Ping Li, Yuandong Zhou and Jian Zhang*

Volume 23, Issue 6, 2023

Published on: 13 February, 2023

Page: [496 - 504] Pages: 9

DOI: 10.2174/1568009623666230206154944

Price: $65

conference banner
Abstract

Background: Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1) contributes to the proliferative, migratory, invasive and colony-forming capabilities of oncocytes. Dysregulated expression of PKMYT1 is associated with numerous malignancies. However, at present, the functional role of PKMYT1 in osteosarcoma is still not clarified.

Objective: The present study, therefore, aimed to investigate the prognostic value of PKMYT1 in osteosarcoma, and to explore the underlying molecular mechanism(s).

Methods: To meet this end, the expression level of PKMYT1 in osteosarcoma was measured by immunohistochemical analysis. The prognostic value of PKMYT1 in osteosarcoma was analyzed on the basis of R2: Genomics Analysis and Visualization Platform. The functional role of PKMYT1 was subsequently investigated in MG63 cells by knocking down PKMYT1 expression via lentivirus encoding shRNA. MTT assay, scratch-wound and Transwell assays were then used to determine whether PKMYT1 fulfills a role in the proliferative and invasive capabilities of the MG63 cells. Subsequently, the role of PKMYT1 in the apoptosis of the cells was assessed using western blot and immunofluorescence analyses. Finally, to determine whether PKMYT1 exerts its role through the NF-κB pathway, fibroblast-stimulating lipopeptide-1 (FSL-1) was used as an NF-κB activator.

Results: Compared with normal tissues, osteosarcoma tissues showed a significantly increased level of PKMYT1 expression. The clinical survival analysis indicated that patients with high PKMYT1 expression were associated with lower probabilities of overall survival and metastasis-free survival compared with those with low PKMYT1 expression levels. Knockdown of PKMYT1 inhibited the migratory and invasive capabilities of the MG63 cells, and also facilitated their apoptosis. Moreover, the knockdown of PKMYT1 restrained the NF-κB pathway in MG63 cells, whereas activating the NF- κB pathway ameliorated the effects of silencing PKMYT1 on MG63 cells, suggesting that PKMYT1 functions via the NF-κB pathway in MG63 cells.

Conclusion: Taken together, the results of the present study have shown that a high expression level of PKMYT1 is associated with poor prognosis of osteosarcoma, and that PKMYT1 is able to aggravate the malignant progression of MG63 cells via negatively regulating the NF-κB pathway, suggesting that PKMYT1 may be a potential molecular therapeutic target for the treatment of osteosarcoma.

« Previous
Graphical Abstract

[1]
Chen, C.; Xie, L.; Ren, T.; Huang, Y.; Xu, J.; Guo, W. Immunotherapy for osteosarcoma: Fundamental mechanism, rationale, and recent breakthroughs. Cancer Lett., 2021, 500, 1-10.
[http://dx.doi.org/10.1016/j.canlet.2020.12.024] [PMID: 33359211]
[2]
Rabelo, A.C.S.; Borghesi, J.; Noratto, G.D. The role of dietary polyphenols in osteosarcoma: A possible clue about the molecular mechanisms involved in a process that is just in its infancy. J. Food Biochem., 2022, 46(1)e14026
[http://dx.doi.org/10.1111/jfbc.14026] [PMID: 34873724]
[3]
Belayneh, R.; Fourman, M.S.; Bhogal, S.; Weiss, K.R. Update on osteosarcoma. Curr. Oncol. Rep., 2021, 23(6), 71.
[http://dx.doi.org/10.1007/s11912-021-01053-7] [PMID: 33880674]
[4]
Zhao, X.; Wu, Q.; Gong, X.; Liu, J.; Ma, Y. Osteosarcoma: A review of current and future therapeutic approaches. Biomed. Eng. Online, 2021, 20(1), 24.
[http://dx.doi.org/10.1186/s12938-021-00860-0] [PMID: 33653371]
[5]
Robert, J. Biology of metastasis. Bull. Cancer, 2013, 100(4), 333-342.
[http://dx.doi.org/10.1684/bdc.2013.1724] [PMID: 23587644]
[6]
Mohammadi, L.; Mosayyebi, B.; Imani, M.; Zarghami, N.; Alizadeh, E.; Rahmati, M. Correlation between dexamethasone and miRNAs in the regulation of apoptosis, drug-resistance, and metastasis of cancer cell. Curr. Mol. Med., 2021, 21(5), 392-401.
[http://dx.doi.org/10.2174/1566524020666200925155614] [PMID: 32981504]
[7]
Gallo, D.; Young, J.T.F.; Fourtounis, J.; Martino, G.; Álvarez-Quilón, A.; Bernier, C.; Duffy, N.M.; Papp, R.; Roulston, A.; Stocco, R.; Szychowski, J.; Veloso, A.; Alam, H.; Baruah, P.S.; Fortin, A.B.; Bowlan, J.; Chaudhary, N.; Desjardins, J.; Dietrich, E.; Fournier, S.; Fugère-Desjardins, C.; Goullet de Rugy, T.; Leclaire, M.E.; Liu, B.; Bhaskaran, V.; Mamane, Y.; Melo, H.; Nicolas, O.; Singhania, A.; Szilard, R.K.; Tkáč, J.; Yin, S.Y.; Morris, S.J.; Zinda, M.; Marshall, C.G.; Durocher, D. CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Nature, 2022, 604(7907), 749-756.
[http://dx.doi.org/10.1038/s41586-022-04638-9] [PMID: 35444283]
[8]
Chen, J.; Hua, X.; Chen, H.; Qiu, X.; Xiao, H.; Ge, S.; Liang, C.; Zhou, Q. PKMYT1, exacerbating the progression of clear cell renal cell carcinoma, is implied as a biomarker for the diagnosis and prognosis. Aging, 2021, 13(24), 25778-25798.
[http://dx.doi.org/10.18632/aging.203759] [PMID: 34959223]
[9]
Zhang, Q.Y.; Chen, X.Q.; Liu, X.C.; Wu, D.M. PKMYT1 promotes gastric cancer cell proliferation and apoptosis resistance. OncoTargets Ther., 2020, 13, 7747-7757.
[http://dx.doi.org/10.2147/OTT.S255746] [PMID: 32801781]
[10]
Liu, L.; Wu, J.; Wang, S.; Luo, X.; Du, Y.; Huang, D.; Gu, D.; Zhang, F. PKMYT1 promoted the growth and motility of hepatocellular carcinoma cells by activating beta-catenin/TCF signaling. Exp. Cell Res., 2017, 358(2), 209-216.
[http://dx.doi.org/10.1016/j.yexcr.2017.06.014] [PMID: 28648520]
[11]
Xuan, Z.H.; Wang, H.P.; Zhang, X.N.; Chen, Z.X.; Zhang, H.Y.; Gu, M.M. PKMYT1 aggravates the progression of ovarian cancer by targeting SIRT3. Eur. Rev. Med. Pharmacol. Sci., 2020, 24(10), 5259-5266.
[http://dx.doi.org/10.26355/eurrev_202005_21308] [PMID: 32495859]
[12]
Zhang, Q.; Zhao, X.; Zhang, C.; Wang, W.; Li, F.; Liu, D.; Wu, K.; Zhu, D.; Liu, S.; Shen, C.; Yuan, X.; Zhang, K.; Yang, Y.; Zhang, Y.; Zhao, S. Overexpressed PKMYT1 promotes tumor progression and associates with poor survival in esophageal squamous cell carcinoma. Cancer Manag. Res., 2019, 11, 7813-7824.
[http://dx.doi.org/10.2147/CMAR.S214243] [PMID: 31695486]
[13]
Cai, Y.; Yang, W. PKMYT1 regulates the proliferation and epithelial mesenchymal transition of oral squamous cell carcinoma cells by targeting CCNA2. Oncol. Lett., 2021, 23(2), 63.
[http://dx.doi.org/10.3892/ol.2021.13181] [PMID: 35069872]
[14]
Wu, Y.; Zhou, L.; Wang, Z.; Wang, X.; Zhang, R.; Zheng, L.; Kang, T. Systematic screening for potential therapeutic targets in osteosarcoma through a kinome-wide CRISPR-Cas9 library. Cancer Biol. Med., 2020, 17(3), 782-794.
[http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0162] [PMID: 32944406]
[15]
Motolani, A.; Martin, M.; Sun, M.; Lu, T. Phosphorylation of the regulators, a Complex Facet of NF-κB signaling in cancer. Biomolecules, 2020, 11(1), 15.
[http://dx.doi.org/10.3390/biom11010015] [PMID: 33375283]
[16]
DiDonato, J.A.; Mercurio, F.; Karin, M. NF-κB and the link between inflammation and cancer. Immunol. Rev., 2012, 246(1), 379-400.
[http://dx.doi.org/10.1111/j.1600-065X.2012.01099.x] [PMID: 22435567]
[17]
Wu, M.; Chen, J.; Wang, Y.; Hu, J.; Liu, C.; Feng, C.; Zeng, X. URGCP/URG4 promotes apoptotic resistance in bladder cancer cells by activating NF-κB signaling. Oncotarget, 2015, 6(31), 30887-30901.
[http://dx.doi.org/10.18632/oncotarget.5134] [PMID: 26429874]
[18]
Gong, T.; Su, X.; Xia, Q.; Wang, J.; Kan, S. Expression of NF-κB and PTEN in osteosarcoma and its clinical significance. Oncol. Lett., 2017, 14(6), 6744-6748.
[http://dx.doi.org/10.3892/ol.2017.6972] [PMID: 29151913]
[19]
Wang, X.Z.; Zhang, S.F.; Yang, Z.H.; Ye, Z.W.; Liu, J. Punicalagin suppresses osteosarcoma growth and metastasis by regulating NF-κB signaling. J. Biol. Regul. Homeost. Agents, 2020, 34(5), 1699-1708.
[http://dx.doi.org/10.23812/20-23-A] [PMID: 33148374]
[20]
Liu, Q.; Cheng, Z.; Huang, B.; Luo, S.; Guo, Y. Palmitic acid promotes endothelial-to-mesenchymal transition via activation of the cytosolic DNA-sensing cGAS-STING pathway. Arch. Biochem. Biophys., 2022, 727109321
[http://dx.doi.org/10.1016/j.abb.2022.109321] [PMID: 35697075]
[21]
Liu, J.; Zhang, Y.; Liu, W.; Zhang, Q.; Xiao, H.; Song, H.; Luo, B. MiR-BART1-5p targets core 2β-1,6-acetylglucosaminyltransferase GCNT3 to inhibit cell proliferation and migration in EBV-associated gastric cancer. Virology, 2020, 541, 63-74.
[http://dx.doi.org/10.1016/j.virol.2019.12.004] [PMID: 32056716]
[22]
Huang, T.; Luo, X.; Wu, B.; Peng, P.; Dai, Y.; Hu, G.; Qiu, H.; Yuan, X. Pyrotinib enhances the radiosensitivity of HER2 overexpressing gastric and breast cancer cells. Oncol. Rep., 2020, 44(6), 2634-2644.
[http://dx.doi.org/10.3892/or.2020.7820] [PMID: 33125154]
[23]
Bi, L.; Liu, Y.; Yang, Q.; Zhou, X.; Li, H.; Liu, Y.; Li, J.; Lu, Y.; Tang, H. Paris saponin H inhibits the proliferation of glioma cells through the A1 and A3 adenosine receptor mediated pathway. Int. J. Mol. Med., 2021, 47(4), 30.
[http://dx.doi.org/10.3892/ijmm.2021.4863] [PMID: 33537802]
[24]
Meazza, C.; Bastoni, S.; Scanagatta, P. What is the best clinical approach to recurrent/refractory osteosarcoma? Expert Rev. Anticancer Ther., 2020, 20(5), 415-428.
[http://dx.doi.org/10.1080/14737140.2020.1760848] [PMID: 32379504]
[25]
Shao, C.; Wang, Y.; Pan, M.; Guo, K.; Molnar, T.F.; Kocher, F.; Seeber, A.; Barr, M.P.; Navarro, A.; Han, J.; Ma, Z.; Yan, X. The DNA damage repair-related gene PKMYT1 is a potential biomarker in various malignancies. Transl. Lung Cancer Res., 2021, 10(12), 4600-4616.
[http://dx.doi.org/10.21037/tlcr-21-973] [PMID: 35070764]
[26]
Ghelli Luserna di Rorà, A.; Cerchione, C.; Martinelli, G.; Simonetti, G.A. WEE1 family business: Regulation of mitosis, cancer progression, and therapeutic target. J. Hematol. Oncol., 2020, 13(1), 126.
[http://dx.doi.org/10.1186/s13045-020-00959-2] [PMID: 32958072]
[27]
Sun, S.C. The noncanonical NF-κB pathway. Immunol. Rev., 2012, 246(1), 125-140.
[http://dx.doi.org/10.1111/j.1600-065X.2011.01088.x] [PMID: 22435551]
[28]
Pflug, K.M.; Sitcheran, R. Targeting NF-κB-Inducing Kinase (NIK) in immunity, inflammation, and cancer. Int. J. Mol. Sci., 2020, 21(22), 8470.
[http://dx.doi.org/10.3390/ijms21228470] [PMID: 33187137]
[29]
Piotrowska, A.; Izykowska, I.; Podhorska-Okolow, M.; Zabel, M.; Dziegiel, P. The structure of NF- kappaB family proteins and their role in apoptosis. Postepy Hig. Med. Dosw., 2008, 62, 64-74.
[30]
Wu, C.H.; Lin, K.H.; Fu, B.S.; Hsu, F.T.; Tsai, J.J.; Weng, M.C.; Pan, P.J. Sorafenib induces apoptosis and inhibits NF-κB-mediated anti-apoptotic and metastatic potential in osteosarcoma cells. Anticancer Res., 2021, 41(3), 1251-1259.
[http://dx.doi.org/10.21873/anticanres.14882] [PMID: 33788716]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy