Login Register Cart 0
Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

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

Expression and Prognostic Significance of Ferroptosis-related Proteins SLC7A11 and GPX4 in Renal Cell Carcinoma

Author(s): Zongtao Ren, Xiaoyu Zhang and Jingya Han*

Volume 30, Issue 10, 2023

Published on: 02 October, 2023

Page: [868 - 876] Pages: 9

DOI: 10.2174/0109298665255704230920063254

Price: $65

conference banner
Abstract

Background: The ferroptosis inhibitory gene solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) inhibit ferroptosis in carcinoma cells. However, whether SLC7A11 and GPX4 serve as an oncogene in renal cell carcinoma (RCC) remains unclear.

Methods: Immunohistochemistry (IHC) assays were performed to assess the expression of SLC7A11 and GPX4 in human RCC tissues. Clinical-pathological analysis was performed to explore the correlation between SLC7A11 and GPX4 expression. Kaplan-Meier survival analysis was performed to characterise the associations between protein expression and patient progressionfree survival (PFS).

Results: The upregulation of SLC7A11 and GPX4 was detected by IHC in RCC tissues compared with that in normal renal tissues. Meanwhile, the expression level of SLC7A11 and GPX4 was correlated with tumour diameter and distant metastasis (P<0.05). Kaplan-Meier survival analysis indicated that patients with high SLC7A11 and GPX4 expression levels exhibited worse PFS than those with low SLC7A11 and GPX4 expression levels (P<0.05).

Conclusion: The upregulation of SLC7A11 and GPX4 expression was associated with poor prognosis in patients with RCC. SLC7A11 and GPX4 may serve as diagnostic and prognostic biomarkers for patients with RCC.

« Previous Next »
Graphical Abstract

[1]
Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin., 2021, 71(1), 7-33.
[http://dx.doi.org/10.3322/caac.21654] [PMID: 33433946]
[2]
Greef, B.; Eisen, T. Medical treatment of renal cancer: new horizons. Br. J. Cancer, 2016, 115(5), 505-516.
[http://dx.doi.org/10.1038/bjc.2016.230] [PMID: 27490806]
[3]
Mikami, S.; Oya, M.; Mizuno, R.; Kosaka, T.; Ishida, M.; Kuroda, N.; Nagashima, Y.; Katsube, K.; Okada, Y. Recent advances in renal cell carcinoma from a pathological point of view. Pathol. Int., 2016, 66(9), 481-490.
[http://dx.doi.org/10.1111/pin.12433] [PMID: 27461942]
[4]
Jermann, M.; Stahel, R.A.; Salzberg, M.; Cerny, T.; Joerger, M.; Gillessen, S.; Morant, R.; Egli, F.; Rhyner, K.; Bauer, J.A.; Pless, M. A phase II, open-label study of gefitinib (IRESSA) in patients with locally advanced, metastatic, or relapsed renal-cell carcinoma. Cancer Chemother. Pharmacol., 2006, 57(4), 533-539.
[http://dx.doi.org/10.1007/s00280-005-0070-z] [PMID: 16052341]
[5]
Ueda, K.; Suekane, S.; Kurose, H.; Chikui, K.; Nakiri, M.; Nishihara, K.; Matsuo, M.; Kawahara, A.; Yano, H.; Igawa, T. Prognostic value of PD-1 and PD-L1 expression in patients with metastatic clear cell renal cell carcinoma. Urol. Oncol., 2018, 36(11), 499.e9-499.e16.
[http://dx.doi.org/10.1016/j.urolonc.2018.07.003] [PMID: 30131293]
[6]
Siska, P.J.; Beckermann, K.E.; Rathmell, W.K.; Haake, S.M. Strategies to overcome therapeutic resistance in renal cell carcinoma. Urol. Oncol., 2017, 35(3), 102-110.
[http://dx.doi.org/10.1016/j.urolonc.2016.12.002] [PMID: 28089416]
[7]
Qin, Y.; Qiao, Y.; Wang, D.; Tang, C.; Yan, G. Ferritinophagy and ferroptosis in cardiovascular disease: Mechanisms and potential applications. Biomed. Pharmacother., 2021, 141, 111872.
[http://dx.doi.org/10.1016/j.biopha.2021.111872] [PMID: 34246187]
[8]
Gao, M.; Jiang, X. To eat or not to eat — the metabolic flavor of ferroptosis. Curr. Opin. Cell Biol., 2018, 51, 58-64.
[http://dx.doi.org/10.1016/j.ceb.2017.11.001] [PMID: 29175614]
[9]
Bersuker, K.; Hendricks, J.M.; Li, Z.; Magtanong, L.; Ford, B.; Tang, P.H.; Roberts, M.A.; Tong, B.; Maimone, T.J.; Zoncu, R.; Bassik, M.C.; Nomura, D.K.; Dixon, S.J.; Olzmann, J.A. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature, 2019, 575(7784), 688-692.
[http://dx.doi.org/10.1038/s41586-019-1705-2] [PMID: 31634900]
[10]
Stockwell, B.R.; Friedmann Angeli, J.P.; Bayir, H.; Bush, A.I.; Conrad, M.; Dixon, S.J.; Fulda, S.; Gascón, S.; Hatzios, S.K.; Kagan, V.E.; Noel, K.; Jiang, X.; Linkermann, A.; Murphy, M.E.; Overholtzer, M.; Oyagi, A.; Pagnussat, G.C.; Park, J.; Ran, Q.; Rosenfeld, C.S.; Salnikow, K.; Tang, D.; Torti, F.M.; Torti, S.V.; Toyokuni, S.; Woerpel, K.A.; Zhang, D.D. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 2017, 171(2), 273-285.
[http://dx.doi.org/10.1016/j.cell.2017.09.021] [PMID: 28985560]
[11]
Dixon, S.J.; Patel, D.N.; Welsch, M.; Skouta, R.; Lee, E.D.; Hayano, M.; Thomas, A.G.; Gleason, C.E.; Tatonetti, N.P.; Slusher, B.S.; Stockwell, B.R. Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife, 2014, 3, e02523.
[http://dx.doi.org/10.7554/eLife.02523] [PMID: 24844246]
[12]
Imai, H.; Matsuoka, M.; Kumagai, T.; Sakamoto, T.; Koumura, T. Lipid peroxidation dependent cell death regulated by GPx4 and Ferroptosis. Curr. Top. Microbiol. Immunol., 2016, 403, 143-170.
[http://dx.doi.org/10.1007/82_2016_508] [PMID: 28204974]
[13]
Lachaier, E.; Louandre, C.; Godin, C.; Saidak, Z.; Baert, M.; Diouf, M.; Chauffert, B.; Galmiche, A. Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res., 2014, 34(11), 6417-6422.
[PMID: 25368241] [PMID: 25368241]
[14]
Eling, N.; Reuter, L.; Hazin, J.; Hamacher-Brady, A.; Brady, N.R. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience, 2015, 2(5), 517-532.
[http://dx.doi.org/10.18632/oncoscience.160] [PMID: 26097885]
[15]
Louandre, C.; Marcq, I.; Bouhlal, H.; Lachaier, E.; Godin, C.; Saidak, Z.; François, C.; Chatelain, D.; Debuysscher, V.; Barbare, J.C.; Chauffert, B.; Galmiche, A. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett., 2015, 356(2)(2 Pt B), 971-977.
[http://dx.doi.org/10.1016/j.canlet.2014.11.014] [PMID: 25444922]
[16]
Delahunt, B.; Eble, J.N.; Egevad, L.; Samaratunga, H. Grading of renal cell carcinoma. Histopathology, 2019, 74(1), 4-17.
[http://dx.doi.org/10.1111/his.13735] [PMID: 30565310]
[17]
Chatzizacharias, N.A.; Rosich-Medina, A.; Dajani, K.; Harper, S.; Huguet, E.; Liau, S.S.; Praseedom, R.K.; Jah, A. Surgical management of hepato-pancreatic metastasis from renal cell carcinoma. World J. Gastrointest. Oncol., 2017, 9(2), 70-77.
[http://dx.doi.org/10.4251/wjgo.v9.i2.70] [PMID: 28255428]
[18]
Hsieh, J.J.; Purdue, M.P.; Signoretti, S.; Swanton, C.; Albiges, L.; Schmidinger, M.; Heng, D.Y.; Larkin, J.; Ficarra, V. Renal cell carcinoma. Nat. Rev. Dis. Primers, 2017, 3(1), 17009.
[http://dx.doi.org/10.1038/nrdp.2017.9] [PMID: 28276433]
[19]
Sathianathen, N.J.; Krishna, S.; Anderson, J.K.; Weight, C.J.; Gupta, S.; Konety, B.R.; Griffith, T.S. The current status of immunobased therapies for metastatic renal-cell carcinoma. ImmunoTargets Ther., 2017, 6, 83-93.
[http://dx.doi.org/10.2147/ITT.S134850] [PMID: 29255699]
[20]
Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; Morrison, B., III; Stockwell, B.R. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5), 1060-1072.
[http://dx.doi.org/10.1016/j.cell.2012.03.042] [PMID: 22632970]
[21]
Friedmann Angeli, J.P.; Schneider, M.; Proneth, B.; Tyurina, Y.Y.; Tyurin, V.A.; Hammond, V.J.; Herbach, N.; Aichler, M.; Walch, A.; Eggenhofer, E.; Basavarajappa, D.; Rådmark, O.; Kobayashi, S.; Seibt, T.; Beck, H.; Neff, F.; Esposito, I.; Wanke, R.; Förster, H.; Yefremova, O.; Heinrichmeyer, M.; Bornkamm, G.W.; Geissler, E.K.; Thomas, S.B.; Stockwell, B.R.; O’Donnell, V.B.; Kagan, V.E.; Schick, J.A.; Conrad, M. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol., 2014, 16(12), 1180-1191.
[http://dx.doi.org/10.1038/ncb3064] [PMID: 25402683]
[22]
Conrad, M.; Sato, H. The oxidative stress-inducible cystine/glutamate antiporter, system xc−: cystine supplier and beyond. Amino Acids, 2012, 42(1), 231-246.
[http://dx.doi.org/10.1007/s00726-011-0867-5] [PMID: 21409388]
[23]
Yang, Y.; Chen, J.; Gao, Q.; Shan, X.; Wang, J.; Lv, Z. Study on the attenuated effect of Ginkgolide B on ferroptosis in high fat diet induced nonalcoholic fatty liver disease. Toxicology, 2020, 445, 152599.
[http://dx.doi.org/10.1016/j.tox.2020.152599] [PMID: 32976958]
[24]
Liu, T.; Jiang, L.; Tavana, O.; Gu, W. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res., 2019, 79(8), 1913-1924.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3037] [PMID: 30709928]
[25]
Liu, X.X.; Li, X.J.; Zhang, B.; Liang, Y.J.; Zhou, C.X.; Cao, D.X.; He, M.; Chen, G.Q.; He, J.R.; Zhao, Q. MicroRNA-26b is underexpressed in human breast cancer and induces cell apoptosis by targeting SLC7A11. FEBS Lett., 2011, 585(9), 1363-1367.
[http://dx.doi.org/10.1016/j.febslet.2011.04.018] [PMID: 21510944]
[26]
Yang, Y.; Yang, L.; Jiang, S.; Yang, T.; Lan, J.; Lei, Y.; Tan, H.; Pan, K. HMGB1 mediates lipopolysaccharide-induced inflammation via interacting with GPX4 in colon cancer cells. Cancer Cell Int., 2020, 20(1), 205.
[http://dx.doi.org/10.1186/s12935-020-01289-6] [PMID: 32514250]
[27]
Lee, N.; Carlisle, A.E.; Peppers, A.; Park, S.J.; Doshi, M.B.; Spears, M.E.; Kim, D. xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers. Antioxidants, 2021, 10(2), 317.
[http://dx.doi.org/10.3390/antiox10020317] [PMID: 33672555]
[28]
Shi, Z.Z.; Tao, H.; Fan, Z.W.; Song, S.J.; Bai, J. Prognostic and immunological role of key genes of ferroptosis in pan-cancer. Front. Cell Dev. Biol., 2021, 9, 748925.
[http://dx.doi.org/10.3389/fcell.2021.748925]
[29]
Polewski, M.D.; Reveron-Thornton, R.F.; Cherryholmes, G.A.; Marinov, G.K.; Cassady, K.; Aboody, K.S. Increased expression of system xc− in glioblastoma confers an altered metabolic state and temozolomide resistance. Mol. Cancer Res., 2016, 14(12), 1229-1242.
[http://dx.doi.org/10.1158/1541-7786.MCR-16-0028] [PMID: 27658422]
[30]
Robert, S.M.; Buckingham, S.C.; Campbell, S.L.; Robel, S.; Holt, K.T.; Ogunrinu-Babarinde, T.; Warren, P.P.; White, D.M.; Reid, M.A.; Eschbacher, J.M.; Berens, M.E.; Lahti, A.C.; Nabors, L.B.; Sontheimer, H. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci. Transl. Med., 2015, 7(289), 289ra86.
[http://dx.doi.org/10.1126/scitranslmed.aaa8103] [PMID: 26019222]
[31]
Shen, L.; Qian, C.; Cao, H.; Wang, Z.; Luo, T.; Liang, C. Upregulation of the solute carrier family 7 genes is indicative of poor prognosis in papillary thyroid carcinoma. World J. Surg. Oncol., 2018, 16(1), 235.
[http://dx.doi.org/10.1186/s12957-018-1535-y] [PMID: 30558624]
[32]
Zhang, X.; Sui, S.; Wang, L.; Li, H.; Zhang, L.; Xu, S.; Zheng, X. Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin. J. Cell. Physiol., 2020, 235(4), 3425-3437.
[http://dx.doi.org/10.1002/jcp.29232] [PMID: 31556117]
[33]
Xu, F.; Guan, Y.; Xue, L.; Zhang, P.; Li, M.; Gao, M.; Chong, T. The roles of ferroptosis regulatory gene SLC7A11 in renal cell carcinoma: A multi‐omics study. Cancer Med., 2021, 10(24), 9078-9096.
[http://dx.doi.org/10.1002/cam4.4395] [PMID: 34761566]

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