Knockdown of Ubiquitin-Conjugating Enzyme E2 T Abolishes the Progression of Head and Neck Squamous Cell Carcinoma by Inhibiting NF-Κb Signaling and inducing Ferroptosis


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Background:Ubiquitin-conjugating enzyme 2T (UBE2T) has been reported to be associated with uncontrolled cell growth and tumorigenesis in multiple cancer types. However, the understanding of its regulatory role in the carcinogenesis of Head And Neck Squamous Cell Carcinoma (HNSC) is limited.

Methods:UBE2T expression in HNSC patient samples and the correlation between its expression and patients’ survival rates were evaluated using The Cancer Genome Atlas (TCGA) database. Cell survival and proliferation were investigated in UM-SCC1 and UM-SCC15 cells infected with control and shUBE2T lentivirus. The xenograft mouse model was established using UM-SCC15 cells to examine HNSC tumorigenesis with or without UBE2T. Western blot, qRT-PCR, and ferroptosis assays were carried out to disclose the interaction between UBE2T and NF-κB signaling and ferroptosis.

Results:The increased expression of UBE2T was noted in tumor tissues of patients with HNSC, correlating with a significantly reduced overall survival time in this patient cohort. Knockdown of UBE2T inhibited HNSC tumorigenesis and tumor growth. Mechanistically, inhibition of UBE2T suppressed NF-κB signaling and induced ferroptosis in HNSC.

Conclusion:Our study underscores the multifaceted role of UBE2T in HNSC, illuminating its potential as a biomarker and therapeutic target.

作者简介

Feng Cai

Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Hongbo Xu

Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Shilong Song

Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Gengming Wang

Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Yajun Zhang

Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Jing Qian

Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Lu Xu

Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College

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Email: info@benthamscience.net

参考

  1. Lang, Y.; Dong, D. Cetuximab plus chemotherapy versus chemotherapy alone in recurrent or metastatic head and neck squamous cell carcinoma: A cost-effectiveness analysis. Cancer Manag. Res., 2020, 12, 11383-11390. doi: 10.2147/CMAR.S272149 PMID: 33204154
  2. Barsouk, A.; Aluru, J.S.; Rawla, P.; Saginala, K.; Barsouk, A. Epidemiology, risk factors, and prevention of head and neck squamous cell carcinoma. Med. Sci., 2023, 11(2), 42. doi: 10.3390/medsci11020042 PMID: 37367741
  3. Johnson, D.E.; Burtness, B.; Leemans, C.R.; Lui, V.W.Y.; Bauman, J.E.; Grandis, J.R. Head and neck squamous cell carcinoma. Nat. Rev. Dis. Primers, 2020, 6(1), 92. doi: 10.1038/s41572-020-00224-3 PMID: 33243986
  4. Marur, S.; Forastiere, A.A. Head and neck cancer: Changing epidemiology, diagnosis, and treatment. Mayo Clin. Proc., 2008, 83(4), 489-501. doi: 10.4065/83.4.489 PMID: 18380996
  5. Chamoli, A.; Gosavi, A.S.; Shirwadkar, U.P.; Wangdale, K.V.; Behera, S.K.; Kurrey, N.K.; Kalia, K.; Mandoli, A. Overview of oral cavity squamous cell carcinoma: Risk factors, mechanisms, and diagnostics. Oral Oncol., 2021, 121, 105451. doi: 10.1016/j.oraloncology.2021.105451 PMID: 34329869
  6. Gillison, M.L.; Chaturvedi, A.K.; Anderson, W.F.; Fakhry, C. Epidemiology of human papillomavirus–positive head and neck squamous cell carcinoma. J. Clin. Oncol., 2015, 33(29), 3235-3242. doi: 10.1200/JCO.2015.61.6995 PMID: 26351338
  7. Kitamura, N.; Sento, S.; Yoshizawa, Y.; Sasabe, E.; Kudo, Y.; Yamamoto, T. Current trends and future prospects of molecular targeted therapy in head and neck squamous cell carcinoma. Int. J. Mol. Sci., 2020, 22(1), 240. doi: 10.3390/ijms22010240 PMID: 33383632
  8. Solomon, B.; Young, R.J.; Rischin, D. Head and neck squamous cell carcinoma: Genomics and emerging biomarkers for immunomodulatory cancer treatments. Semin. Cancer Biol., 2018, 52(Pt 2), 228-240. doi: 10.1016/j.semcancer.2018.01.008 PMID: 29355614
  9. Parmar, K.; Mohamed, A.; Vaish, E.; Thawani, R.; Cetnar, J.; Thein, K.Z. Immunotherapy in head and neck squamous cell carcinoma: An updated review. Cancer Treat. Res. Commun., 2022, 33, 100649. doi: 10.1016/j.ctarc.2022.100649 PMID: 36279709
  10. Vos, J.L.; Elbers, J.B.W.; Krijgsman, O.; Traets, J.J.H.; Qiao, X.; van der Leun, A.M.; Lubeck, Y.; Seignette, I.M.; Smit, L.A.; Willems, S.M.; van den Brekel, M.W.M.; Dirven, R.; Baris Karakullukcu, M.; Karssemakers, L.; Klop, W.M.C.; Lohuis, P.J.F.M.; Schreuder, W.H.; Smeele, L.E.; van der Velden, L.A.; Bing Tan, I.; Onderwater, S.; Jasperse, B.; Vogel, W.V.; Al-Mamgani, A.; Keijser, A.; Van der Noort, V.; Broeks, A.; Hooijberg, E.; Peeper, D.S.; Schumacher, T.N.; Blank, C.U.; De Boer, J.P.; Haanen, J.B.A.G.; Zuur, C.L. Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma. Nat. Commun., 2021, 12(1), 7348. doi: 10.1038/s41467-021-26472-9 PMID: 34937871
  11. Alpi, A.F.; Chaugule, V.; Walden, H. Mechanism and disease association of E2-conjugating enzymes: Lessons from UBE2T and UBE2L3. Biochem. J., 2016, 473(20), 3401-3419. doi: 10.1042/BCJ20160028 PMID: 27729585
  12. Machida, Y.J.; Machida, Y.; Chen, Y.; Gurtan, A.M.; Kupfer, G.M.; D’Andrea, A.D.; Dutta, A. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol. Cell, 2006, 23(4), 589-596. doi: 10.1016/j.molcel.2006.06.024 PMID: 16916645
  13. Wen, M.; Kwon, Y.; Wang, Y.; Mao, J.H.; Wei, G. Elevated expression of UBE2T exhibits oncogenic properties in human prostate cancer. Oncotarget, 2015, 6(28), 25226-25239. doi: 10.18632/oncotarget.4712 PMID: 26308072
  14. Xu, F.; Xiong, N.; Yuan, Y.; Liu, J. Prognostic value of UBE2T and its correlation with immune infiltrates in lung adenocarcinoma. J. Oncol., 2022, 2022, 1-9. doi: 10.1155/2022/5244820 PMID: 36245987
  15. Xiao, Y.; Deng, Z.; Li, Y.; Wei, B.; Chen, X.; Zhao, Z.; Xiu, Y.; Hu, M.; Alahdal, M.; Deng, Z.; Wang, D.; Liu, J.; Li, W. ANLN and UBE2T are prognostic biomarkers associated with immune regulation in breast cancer: A bioinformatics analysis. Cancer Cell Int., 2022, 22(1), 193. doi: 10.1186/s12935-022-02611-0 PMID: 35578283
  16. Cao, K.; Ling, X.; Jiang, X.; Ma, J.; Zhu, J. Pan-cancer analysis of UBE2T with a focus on prognostic and immunological roles in lung adenocarcinoma. Respir. Res., 2022, 23(1), 306. doi: 10.1186/s12931-022-02226-z PMID: 36357897
  17. Yu, Z.; Jiang, X.; Qin, L.; Deng, H.; Wang, J.; Ren, W.; Li, H.; Zhao, L.; Liu, H.; Yan, H.; Shi, W.; Wang, Q.; Luo, C.; Long, B.; Zhou, H.; Sun, H.; Jiao, Z. A novel UBE2T inhibitor suppresses Wnt/β-catenin signaling hyperactivation and gastric cancer progression by blocking RACK1 ubiquitination. Oncogene, 2021, 40(5), 1027-1042. doi: 10.1038/s41388-020-01572-w PMID: 33323973
  18. Chai, F.; Zhang, J.; Fu, T.; Jiang, P.; Huang, Y.; Wang, L.; Yan, S.; Yan, X.; Yu, L.; Xu, Z.; Wang, R.; Xu, B.; Du, X.; Jiang, Y.; Zhang, J. Identification of SLC2A3 as a prognostic indicator correlated with the NF-κB/EMT axis and immune response in head and neck squamous cell carcinoma. Channels, 2023, 17(1), 2208928. doi: 10.1080/19336950.2023.2208928 PMID: 37134043
  19. Mele, L.; Del Vecchio, V.; Marampon, F.; Regad, T.; Wagner, S.; Mosca, L.; Bimonte, S.; Giudice, A.; Liccardo, D.; Prisco, C.; Schwerdtfeger, M.; La Noce, M.; Tirino, V.; Caraglia, M.; Papaccio, G.; Desiderio, V.; Barbieri, A. β2-AR blockade potentiates MEK1/2 inhibitor effect on HNSCC by regulating the Nrf2-mediated defense mechanism. Cell Death Dis., 2020, 11(10), 850. doi: 10.1038/s41419-020-03056-x PMID: 33051434
  20. Zhao, L.; Liang, J.; Zhong, W.; Han, C.; Liu, D.; Chen, X. Expression and prognostic analysis of BGN in head and neck squamous cell carcinoma. Gene, 2022, 827, 146461. doi: 10.1016/j.gene.2022.146461 PMID: 35358652
  21. Mitchell, S.; Vargas, J.; Hoffmann, A. Signaling via the NFκB system. Wiley Interdiscip. Rev. Syst. Biol. Med., 2016, 8(3), 227-241. doi: 10.1002/wsbm.1331 PMID: 26990581
  22. Schlein, L.J.; Thamm, D.H. Review: NF-kB activation in canine cancer. Vet. Pathol., 2022, 59(5), 724-732. doi: 10.1177/03009858221092017 PMID: 35499088
  23. Zinatizadeh, M.R.; Schock, B.; Chalbatani, G.M.; Zarandi, P.K.; Jalali, S.A.; Miri, S.R. The nuclear factor kappa B (NF-kB) signaling in cancer development and immune diseases. Genes Dis., 2021, 8(3), 287-297. doi: 10.1016/j.gendis.2020.06.005 PMID: 33997176
  24. Chan, L.P.; Liu, C.; Chiang, F.Y.; Wang, L.F.; Lee, K.W.; Chen, W.T.; Kuo, P.L.; Liang, C.H. IL-8 promotes inflammatory mediators and stimulates activation of p38 MAPK/ERK-NF-κB pathway and reduction of JNK in HNSCC. Oncotarget, 2017, 8(34), 56375-56388. doi: 10.18632/oncotarget.16914 PMID: 28915597
  25. Chang, H.; Xu, Q.; Li, J.; Li, M.; Zhang, Z.; Ma, H.; Yang, X. Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC. Cell Death Dis., 2021, 12(8), 725. doi: 10.1038/s41419-021-03990-4 PMID: 34290225
  26. Vander Broek, R.; Snow, G.E.; Chen, Z.; Van Waes, C. Chemoprevention of head and neck squamous cell carcinoma through inhibition of NF-κB signaling. Oral Oncol., 2014, 50(10), 930-941. doi: 10.1016/j.oraloncology.2013.10.005 PMID: 24177052
  27. Li, M.; Jin, S.; Zhang, Z.; Ma, H.; Yang, X. Interleukin-6 facilitates tumor progression by inducing ferroptosis resistance in head and neck squamous cell carcinoma. Cancer Lett., 2022, 527, 28-40. doi: 10.1016/j.canlet.2021.12.011 PMID: 34902522
  28. Tang, Y.; Li, C.; Zhang, Y.J.; Wu, Z.H. Ferroptosis-related long non-coding RNA signature predicts the prognosis of head and neck squamous cell carcinoma. Int. J. Biol. Sci., 2021, 17(3), 702-711. doi: 10.7150/ijbs.55552 PMID: 33767582
  29. Zhao, Y.Y.; Lian, J.X.; Lan, Z.; Zou, K.L.; Wang, W.M.; Yu, G.T. Ferroptosis promotes anti-tumor immune response by inducing immunogenic exposure in HNSCC. Oral Dis., 2023, 29(3), 933-941. doi: 10.1111/odi.14077 PMID: 34773344
  30. Jiang, X.; Stockwell, B.R.; Conrad, M. Ferroptosis: Mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol., 2021, 22(4), 266-282. doi: 10.1038/s41580-020-00324-8 PMID: 33495651
  31. Li, J.; Cao, F.; Yin, H.; Huang, Z.; Lin, Z.; Mao, N.; Sun, B.; Wang, G. Ferroptosis: Past, present and future. Cell Death Dis., 2020, 11(2), 88. doi: 10.1038/s41419-020-2298-2 PMID: 32015325
  32. Xu, N.; Cui, Y.; Shi, H.; Guo, G.; Sun, F.; Jian, T.; Rao, H. UBE2T/STAT3 Signaling promotes the proliferation and tumorigenesis in retinoblastoma. Invest. Ophthalmol. Vis. Sci., 2022, 63(9), 20. doi: 10.1167/iovs.63.9.20 PMID: 35980647
  33. Wang, T.; He, X.; Liu, X.; Liu, Y.; Zhang, W.; Huang, Q.; Liu, W.; Xiong, L.; Tan, R.; Wang, H.; Zeng, H. Weighted gene co-expression network analysis identifies FKBP11 as a key regulator in acute aortic dissection through a NF-kB dependent pathway. Front. Physiol., 2017, 8, 1010. doi: 10.3389/fphys.2017.01010 PMID: 29255427
  34. Tzani, M.A.; Gioftsidou, D.K.; Kallitsakis, M.G.; Pliatsios, N.V.; Kalogiouri, N.P.; Angaridis, P.A.; Lykakis, I.N.; Terzidis, M.A. Direct and indirect chemiluminescence: Reactions, mechanisms and challenges. Molecules, 2021, 26(24), 7664. doi: 10.3390/molecules26247664 PMID: 34946744
  35. Hao, J.; Xu, A.; Xie, X.; Hao, J.; Tian, T.; Gao, S.; Xiao, X.; He, D. Elevated expression of UBE2T in lung cancer tumors and cell lines. Tumour Biol., 2008, 29(3), 195-203. doi: 10.1159/000148187 PMID: 18667844
  36. Leung, R.W.H.; Ho, N.P.Y.; Leung, C.O.N.; Lee, T.K.W. UBE2T: A new molecular regulator of cancer stemness in hepatocellular carcinoma. Oncotarget, 2021, 12(17), 1727-1728. doi: 10.18632/oncotarget.28033 PMID: 34434501
  37. Luo, C.; Yao, Y.; Yu, Z.; Zhou, H.; Guo, L.; Zhang, J.; Cao, H.; Zhang, G.; Li, Y.; Jiao, Z. UBE2T knockdown inhibits gastric cancer progression. Oncotarget, 2017, 8(20), 32639-32654. doi: 10.18632/oncotarget.15947 PMID: 28427240
  38. Zhu, X.; Li, T.; Niu, X.; Chen, L.; Ge, C. Identification of UBE2T as an independent prognostic biomarker for gallbladder cancer. Oncol. Lett., 2020, 20(4), 44. doi: 10.3892/ol.2020.11903 PMID: 32802166
  39. Hartwell, L.; Mankoff, D.; Paulovich, A.; Ramsey, S.; Swisher, E. Cancer biomarkers: A systems approach. Nat. Biotechnol., 2006, 24(8), 905-908. doi: 10.1038/nbt0806-905 PMID: 16900126
  40. Henry, N.L.; Hayes, D.F. Cancer biomarkers. Mol. Oncol., 2012, 6(2), 140-146. doi: 10.1016/j.molonc.2012.01.010 PMID: 22356776
  41. Gerber, D.E. Targeted therapies: A new generation of cancer treatments. Am. Fam. Physician, 2008, 77(3), 311-319. PMID: 18297955
  42. Lee, Y.T.; Tan, Y.J.; Oon, C.E. Molecular targeted therapy: Treating cancer with specificity. Eur. J. Pharmacol., 2018, 834, 188-196. doi: 10.1016/j.ejphar.2018.07.034 PMID: 30031797
  43. Dolcet, X.; Llobet, D.; Pallares, J.; Matias-Guiu, X. NF-kB in development and progression of human cancer. Virchows Arch., 2005, 446(5), 475-482. doi: 10.1007/s00428-005-1264-9 PMID: 15856292
  44. Kleiger, G.; Mayor, T. Perilous journey: A tour of the ubiquitin–proteasome system. Trends Cell Biol., 2014, 24(6), 352-359. doi: 10.1016/j.tcb.2013.12.003 PMID: 24457024
  45. Lei, G.; Zhuang, L.; Gan, B. Targeting ferroptosis as a vulnerability in cancer. Nat. Rev. Cancer, 2022, 22(7), 381-396. doi: 10.1038/s41568-022-00459-0 PMID: 35338310

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