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

ZIP14 Affects the Proliferation, Apoptosis, and Migration of Cervical Cancer Cells by Regulating the P38 MAPK Pathway

Author(s): Lixia Jiang*, Ting Xie, Yu Xia, Feng Li, Tianyu Zhong and Mi Lai

Volume 24, Issue 8, 2024

Published on: 21 November, 2023

Page: [779 - 790] Pages: 12

DOI: 10.2174/0115680096250711231024063841

Price: $65

Abstract

Background: Cervical cancer (CC) remains a major public health concern and is a leading cause of female mortality worldwide. Understanding the molecular basis of its pathogenesis is essential for the development of novel therapeutic strategies. In this study, we aimed to dissect the role of a specific molecule, ZIP14, in the initiation and progression of CC.

Methods: We used Gene Expression Omnibus for target gene identification, while KEGG was used to delineate CC-related pathways. Proliferation, migration, and apoptosis levels in CC cells were assessed using CCK8, Transwell, and flow cytometry, respectively. The effect of the target genes on the in vivo tumorigenesis of CC cells was evaluated using the subcutaneous tumorigenesis assay.

Results: ZIP14 (SLC39A14) was found to be underexpressed in CC samples. Our KEGG pathway analysis revealed the potential involvement of the P38 mitogen-activated protein kinase (MAPK) pathway in CC pathogenesis. Overexpression of ZIP14 in HeLa and Caski cells increased p38 phosphorylation, inhibited cell growth and migration, and enhanced apoptosis. Conversely, ZIP14 knockdown produced the opposite effects. Importantly, the bioeffects induced by ZIP14 overexpression could be counteracted by the p38 MAPK pathway inhibitor SB203580. In vivo experiments further confirmed the influence of ZIP14 on CC cell migration.

Conclusion: Our study is the first to elucidate the pivotal role of ZIP14 in the pathogenesis of CC, revealing its inhibitory effects through the activation of the p38 MAPK signaling pathway. The discovery not only provides a deeper understanding of CC's molecular underpinnings, but also highlights ZIP14 as a promising therapeutic target. As ZIP14 holds significant potential for therapeutic interventions, our findings lay a robust foundation for further studies and pave the way for the exploration of novel treatment modalities for cervical cancer.

Next »
Graphical Abstract

[1]
Fang, J.; Zhang, H.; Jin, S. Epigenetics and cervical cancer: From pathogenesis to therapy. Tumour Biol., 2014, 35(6), 5083-5093.
[http://dx.doi.org/10.1007/s13277-014-1737-z] [PMID: 24554414]
[2]
Xiong, H.; Wang, N.; Chen, H.; Zhang, M.; Lin, Q. MicroRNA199a/b5p inhibits endometrial cancer cell metastasis and invasion by targeting FAM83B in the epithelialtomesenchymal transition signaling pathway. Mol Med Rep., 2021, 23(5), 304.
[3]
Cohen, P.A.; Jhingran, A.; Oaknin, A.; Denny, L. Cervical cancer. Lancet, 2019, 393(10167), 169-182.
[http://dx.doi.org/10.1016/S0140-6736(18)32470-X] [PMID: 30638582]
[4]
Xie, Y.; Wang, J.; Zhao, X.; Zhou, X.; Nie, X.; Li, C.; Huang, F.; Yuan, H. Higher serum zinc levels may reduce the risk of cervical cancer in Asian women: A meta-analysis. J. Int. Med. Res., 2018, 46(12), 4898-4906.
[http://dx.doi.org/10.1177/0300060518805600] [PMID: 30370809]
[5]
Lim, S.S.; Vos, T.; Flaxman, A.D.; Danaei, G.; Shibuya, K.; Adair-Rohani, H.; AlMazroa, M.A.; Amann, M.; Anderson, H.R.; Andrews, K.G.; Aryee, M.; Atkinson, C.; Bacchus, L.J.; Bahalim, A.N.; Balakrishnan, K.; Balmes, J.; Barker-Collo, S.; Baxter, A.; Bell, M.L.; Blore, J.D.; Blyth, F.; Bonner, C.; Borges, G.; Bourne, R.; Boussinesq, M.; Brauer, M.; Brooks, P.; Bruce, N.G.; Brunekreef, B.; Bryan-Hancock, C.; Bucello, C.; Buchbinder, R.; Bull, F.; Burnett, R.T.; Byers, T.E.; Calabria, B.; Carapetis, J.; Carnahan, E.; Chafe, Z.; Charlson, F.; Chen, H.; Chen, J.S.; Cheng, A.T-A.; Child, J.C.; Cohen, A.; Colson, K.E.; Cowie, B.C.; Darby, S.; Darling, S.; Davis, A.; Degenhardt, L.; Dentener, F.; Des Jarlais, D.C.; Devries, K.; Dherani, M.; Ding, E.L.; Dorsey, E.R.; Driscoll, T.; Edmond, K.; Ali, S.E.; Engell, R.E.; Erwin, P.J.; Fahimi, S.; Falder, G.; Farzadfar, F.; Ferrari, A.; Finucane, M.M.; Flaxman, S.; Fowkes, F.G.R.; Freedman, G.; Freeman, M.K.; Gakidou, E.; Ghosh, S.; Giovannucci, E.; Gmel, G.; Graham, K.; Grainger, R.; Grant, B.; Gunnell, D.; Gutierrez, H.R.; Hall, W.; Hoek, H.W.; Hogan, A.; Hosgood, H.D., III; Hoy, D.; Hu, H.; Hubbell, B.J.; Hutchings, S.J.; Ibeanusi, S.E.; Jacklyn, G.L.; Jasrasaria, R.; Jonas, J.B.; Kan, H.; Kanis, J.A.; Kassebaum, N.; Kawakami, N.; Khang, Y-H.; Khatibzadeh, S.; Khoo, J-P.; Kok, C.; Laden, F.; Lalloo, R.; Lan, Q.; Lathlean, T.; Leasher, J.L.; Leigh, J.; Li, Y.; Lin, J.K.; Lipshultz, S.E.; London, S.; Lozano, R.; Lu, Y.; Mak, J.; Malekzadeh, R.; Mallinger, L.; Marcenes, W.; March, L.; Marks, R.; Martin, R.; McGale, P.; McGrath, J.; Mehta, S.; Memish, Z.A.; Mensah, G.A.; Merriman, T.R.; Micha, R.; Michaud, C.; Mishra, V.; Hanafiah, K.M.; Mokdad, A.A.; Morawska, L.; Mozaffarian, D.; Murphy, T.; Naghavi, M.; Neal, B.; Nelson, P.K.; Nolla, J.M.; Norman, R.; Olives, C.; Omer, S.B.; Orchard, J.; Osborne, R.; Ostro, B.; Page, A.; Pandey, K.D.; Parry, C.D.H.; Passmore, E.; Patra, J.; Pearce, N.; Pelizzari, P.M.; Petzold, M.; Phillips, M.R.; Pope, D.; Pope, C.A., III; Powles, J.; Rao, M.; Razavi, H.; Rehfuess, E.A.; Rehm, J.T.; Ritz, B.; Rivara, F.P.; Roberts, T.; Robinson, C.; Rodriguez-Portales, J.A.; Romieu, I.; Room, R.; Rosenfeld, L.C.; Roy, A.; Rushton, L.; Salomon, J.A.; Sampson, U.; Sanchez-Riera, L.; Sanman, E.; Sapkota, A.; Seedat, S.; Shi, P.; Shield, K.; Shivakoti, R.; Singh, G.M.; Sleet, D.A.; Smith, E.; Smith, K.R.; Stapelberg, N.J.C.; Steenland, K.; Stöckl, H.; Stovner, L.J.; Straif, K.; Straney, L.; Thurston, G.D.; Tran, J.H.; Van Dingenen, R.; van Donkelaar, A.; Veerman, J.L.; Vijayakumar, L.; Weintraub, R.; Weissman, M.M.; White, R.A.; Whiteford, H.; Wiersma, S.T.; Wilkinson, J.D.; Williams, H.C.; Williams, W.; Wilson, N.; Woolf, A.D.; Yip, P.; Zielinski, J.M.; Lopez, A.D.; Murray, C.J.L.; Ezzati, M. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet, 2012, 380(9859), 2224-2260.
[http://dx.doi.org/10.1016/S0140-6736(12)61766-8] [PMID: 23245609]
[6]
Huang, Z.L.; Dufner-Beattie, J.; Andrews, G.K. Expression and regulation of SLC39A family zinc transporters in the developing mouse intestine. Dev. Biol., 2006, 295(2), 571-579.
[http://dx.doi.org/10.1016/j.ydbio.2006.03.045] [PMID: 16682017]
[7]
Bowers, K.; Srai, S.K.S. The trafficking of metal ion transporters of the Zrt- and Irt-like protein family. Traffic, 2018, 19(11), 813-822.
[http://dx.doi.org/10.1111/tra.12602] [PMID: 29952128]
[8]
Anderson, K.J.; Cormier, R.T.; Scott, P.M. Role of ion channels in gastrointestinal cancer. World J. Gastroenterol., 2019, 25(38), 5732-5772.
[http://dx.doi.org/10.3748/wjg.v25.i38.5732] [PMID: 31636470]
[9]
Jenkitkasemwong, S.; Akinyode, A.; Paulus, E.; Weiskirchen, R.; Hojyo, S.; Fukada, T.; Giraldo, G.; Schrier, J.; Garcia, A.; Janus, C.; Giasson, B.; Knutson, M.D. SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice. Proc. Natl. Acad. Sci., 2018, 115(8), E1769-E1778.
[http://dx.doi.org/10.1073/pnas.1720739115] [PMID: 29437953]
[10]
Balint, B.; Bhatia, K.P. SLC39A14 mutations expand the spectrum of manganese transporter defects causing parkinsonism-dystonia. Mov. Disord., 2016, 31(11), 1630.
[http://dx.doi.org/10.1002/mds.26821] [PMID: 27739105]
[11]
Liu, Y.; Li, L.; Liu, Y.; Geng, P.; Li, G.; Yang, Y.; Song, H. RECK inhibits cervical cancer cell migration and invasion by promoting p53 signaling pathway. J. Cell. Biochem., 2018, 119(4), 3058-3066.
[http://dx.doi.org/10.1002/jcb.26441] [PMID: 29064588]
[12]
Rodrigues, C.; Joy, L.R.; Sachithanandan, S.P.; Krishna, S. Notch signalling in cervical cancer. Exp. Cell Res., 2019, 385(2), 111682.
[http://dx.doi.org/10.1016/j.yexcr.2019.111682] [PMID: 31634483]
[13]
Ramos-Solano, M.; Alvarez-Zavala, M.; Garcia-Castro, B.; Jave-Suarez, L. F.; Aguilar-Lemarroy, A. Wnt signalling pathway and cervical cancer. Rev Med Inst Mex Seguro Soc, 2015, 53(S2), S218-S224.
[14]
Che, Y.; Li, Y.; Zheng, F. TRIP4 promotes tumor growth and metastasis and regulates radiosensitivity of cervical cancer by activating MAPK, PI3K/AKT, and hTERT signaling. Cancer Lett, 2019, 452, 1-13.
[http://dx.doi.org/10.1016/j.canlet.2019.03.017]
[15]
Yuan, Z.; Liang, Z.; Yi, J. Koumine promotes ROS production to suppress hepatocellular carcinoma cell proliferation via NF-kappaB and ERK/p38 MAPK signaling. Biomolecules, 2019, 9(10), 559.
[16]
Cui, D.; Xiao, J.; Zhou, Y.; Zhou, X.; Liu, Y.; Peng, Y.; Yu, Y.; Li, H.; Zhou, X.; Yuan, Q.; Wan, M.; Zheng, L. Epiregulin enhances odontoblastic differentiation of dental pulp stem cells via activating MAPK signalling pathway. Cell Prolif., 2019, 52(6), e12680.
[http://dx.doi.org/10.1111/cpr.12680] [PMID: 31454111]
[17]
Liu, F.; Chang, L.; Hu, J. Activating transcription factor 6 regulated cell growth, migration and inhibiteds cell apoptosis and autophagy via MAPK pathway in cervical cancer. J Reprod Immunol, 2020, 139, 103120.
[http://dx.doi.org/10.1016/j.jri.2020.103120]
[18]
Gan, L.; Chen, Y.; Liu, H.; Ju, W.H. Long non-coding RNA ZEB1-antisense 1 affects cell migration and invasion of cervical cancer by regulating epithelial-mesenchymal transition via the p38MAPK signaling pathway. Gynecol. Obstet. Invest., 2019, 84(2), 136-144.
[http://dx.doi.org/10.1159/000493265] [PMID: 30253398]
[19]
Zhu, J.; Zheng, Y.; Zhang, H.; Liu, Y.; Sun, H.; Zhang, P. Galectin-1 induces metastasis and epithelial-mesenchymal transition (EMT) in human ovarian cancer cells via activation of the MAPK JNK/p38 signalling pathway. Am. J. Transl. Res., 2019, 11(6), 3862-3878.
[PMID: 31312395]
[20]
Zhang, A.; Lakshmanan, J.; Motameni, A.; Harbrecht, B.G. MicroRNA-203 suppresses proliferation in liver cancer associated with PIK3CA, p38 MAPK, c-Jun, and GSK3 signaling. Mol. Cell. Biochem., 2018, 441(1-2), 89-98.
[http://dx.doi.org/10.1007/s11010-017-3176-9] [PMID: 28887744]
[21]
Moriguchi, M.; Watanabe, T.; Kadota, A.; Fujimuro, M. Capsaicin induces apoptosis in KSHV-positive primary effusion lymphoma by suppressing ERK and p38 MAPK signaling and IL-6 expression. Front Oncol., 2019, 9, 83.
[http://dx.doi.org/10.3389/fonc.2019.00083]
[22]
Kim, M.S.; Lee, E.J.; Kim, H.R.; Moon, A. p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res., 2003, 63(17), 5454-5461.
[PMID: 14500381]
[23]
Nimmanon, T.; Ziliotto, S.; Morris, S.; Flanagan, L.; Taylor, K.M. Phosphorylation of zinc channel ZIP7 drives MAPK, PI3K and mTOR growth and proliferation signalling. Metallomics, 2017, 9(5), 471-481.
[http://dx.doi.org/10.1039/C6MT00286B] [PMID: 28205653]
[24]
Zhu, B.; Huo, R.; Zhi, Q. Increased expression of zinc transporter ZIP4, ZIP11, ZnT1, and ZnT6 predicts poor prognosis in pancreatic cancer. J Trace Elem Med Biol., 2021, 65, 126734.
[http://dx.doi.org/10.1016/j.jtemb.2021.126734]
[25]
Feng, M.; Wang, Y.; Chen, K.; Bian, Z.; Jinfang Wu; Gao, Q. IL-17A promotes the migration and invasiveness of cervical cancer cells by coordinately activating MMPs expression via the p38/NF-κB signal pathway. PLoS One, 2014, 9(9), e108502.
[http://dx.doi.org/10.1371/journal.pone.0108502] [PMID: 25250801]
[26]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001, 25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[27]
Thomas, P.; Pang, Y.; Dong, J. Membrane androgen receptor characteristics of human ZIP9 (SLC39A) zinc transporter in prostate cancer cells: Androgen-specific activation and involvement of an inhibitory G protein in zinc and MAP kinase signaling. Mol Cell Endocrinol, 2017, 23
[http://dx.doi.org/10.1016/j.mce.2017.02.025]
[28]
Liu, L.; Yang, J.; Wang, C. Analysis of the prognostic significance of solute carrier (SLC) family 39 genes in breast cancer. Biosci Rep, 2020, 40(8), 2020.
[http://dx.doi.org/10.1042/BSR20200764]
[29]
Shakri, A.R.; Zhong, T.J.; Ma, W. Upregulation of ZIP14 and altered zinc homeostasis in muscles in pancreatic cancer cachexia. Cancers, 2019, 12(1), 3.
[http://dx.doi.org/10.3390/cancers12010003]
[30]
Ziliotto, S.; Gee, J.M.W.; Ellis, I.O.; Green, A.R.; Finlay, P.; Gobbato, A.; Taylor, K.M. Activated zinc transporter ZIP7 as an indicator of anti-hormone resistance in breast cancer. Metallomics, 2019, 11(9), 1579-1592.
[http://dx.doi.org/10.1039/c9mt00136k] [PMID: 31483418]
[31]
Mei, Z.; Yan, P.; Wang, Y.; Liu, S.; He, F. Knockdown of zinc transporter ZIP8 expression inhibits neuroblastoma progression and metastasis in vitro. Mol. Med. Rep., 2018, 18(1), 477-485.
[http://dx.doi.org/10.3892/mmr.2018.8944] [PMID: 29749445]
[32]
Franklin, R.B.; Levy, B.A.; Zou, J.; Hanna, N.; Desouki, M.M.; Bagasra, O.; Johnson, L.A.; Costello, L.C. ZIP14 zinc transporter downregulation and zinc depletion in the development and progression of hepatocellular cancer. J. Gastrointest. Cancer, 2012, 43(2), 249-257.
[http://dx.doi.org/10.1007/s12029-011-9269-x] [PMID: 21373779]
[33]
Liu, Y.; Zhu, X.; Zhu, J.; Liao, S.; Tang, Q.; Liu, K.; Guan, X.; Zhang, J.; Feng, Z. Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray. Oncol. Rep., 2007, 18(4), 943-951.
[http://dx.doi.org/10.3892/or.18.4.943] [PMID: 17786358]
[34]
Taylor, K.M.; Morgan, H.E.; Johnson, A.; Nicholson, R.I. Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14. FEBS Lett., 2005, 579(2), 427-432.
[http://dx.doi.org/10.1016/j.febslet.2004.12.006] [PMID: 15642354]
[35]
Shakri, A.R.; James Zhong, T.; Ma, W.; Coker, C.; Hegde, R.; Scholze, H.; Chin, V.; Szabolcs, M.; Hibshoosh, H.; Tanji, K.; Baer, R.; Kumar Biswas, A.; Acharyya, S. Aberrant Zip14 expression in muscle is associated with cachexia in a Bard1 -deficient mouse model of breast cancer metastasis. Cancer Med., 2020, 9(18), 6766-6775.
[http://dx.doi.org/10.1002/cam4.3242] [PMID: 32730698]
[36]
Gaundar, S.S.; Bendall, L.J. The potential and limitations of p38MAPK as a drug target for the treatment of hematological malignancies. Curr. Drug Targets, 2010, 11(7), 823-833.
[http://dx.doi.org/10.2174/138945010791320854] [PMID: 20370645]
[37]
Huang, S.W.; Chyuan, I.T.; Shiue, C.; Yu, M.C.; Hsu, Y.F.; Hsu, M.J. Lovastatin-mediated MCF-7 cancer cell death involves LKB1-AMPK-p38MAPK-p53-survivin signalling cascade. J. Cell. Mol. Med., 2020, 24(2), 1822-1836.
[http://dx.doi.org/10.1111/jcmm.14879] [PMID: 31821701]
[38]
Chou, R.H.; Hsieh, S.C.; Yu, Y.L.; Huang, M.H.; Huang, Y.C.; Hsieh, Y.H. Fisetin inhibits migration and invasion of human cervical cancer cells by down-regulating urokinase plasminogen activator expression through suppressing the p38 MAPK-dependent NF-κB signaling pathway. PLoS One, 2013, 8(8), e71983.
[http://dx.doi.org/10.1371/journal.pone.0071983] [PMID: 23940799]

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