Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Ubiquitin D Promotes Progression of Oral Squamous Cell Carcinoma via NF-Kappa B Signaling

  • Song, An (Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University) ;
  • Wang, Yi (Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University) ;
  • Jiang, Feng (Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University) ;
  • Yan, Enshi (Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University) ;
  • Zhou, Junbo (Department of Stomatology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital) ;
  • Ye, Jinhai (Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University) ;
  • Zhang, Hongchuang (Department of Stomatology, Xuzhou No. 1 Peoples Hospital) ;
  • Ding, Xu (Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University) ;
  • Li, Gang (Department of Stomatology, Affiliated Hospital of Xuzhou Medical University) ;
  • Wu, Yunong (Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University) ;
  • Zheng, Yang (Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University) ;
  • Song, Xiaomeng (Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University)
  • Received : 2020.11.16
  • Accepted : 2021.05.12
  • Published : 2021.07.31
Download PDF
⟨ Previous Next ⟩

Abstract

Ubiquitin D (UBD) is highly upregulated in many cancers, and plays a pivotal role in the pathophysiological processes of cancers. However, its roles and underlying mechanisms in oral squamous cell carcinoma (OSCC) are still unclear. In the present study, we investigated the role of UBD in patients with OSCC. Quantitative real-time polymerase chain reaction and Western blot were used to measure the expression of UBD in OSCC tissues. Immunohistochemistry assay was used to detect the differential expressions of UBD in 244 OSCC patients and 32 cases of normal oral mucosae. In addition, CCK-8, colony formation, wound healing and Transwell assays were performed to evaluate the effect of UBD on the cell proliferation, migration, and invasion in OSCC. Furthermore, a xenograft tumor model was established to verify the role of UBD on tumor formation in vivo. We found that UBD was upregulated in human OSCC tissues and cell lines and was associated with clinical and pathological features of patients. Moreover, the overexpression of UBD promoted the proliferation, migration and invasion of OSCC cells; however, the knockdown of UBD exerted the opposite effects. In this study, our results also suggested that UBD promoted OSCC progression through NF-κB signaling. Our findings indicated that UBD played a critical role in OSCC and may serve as a prognostic biomarker and potential therapeutic target for OSCC treatment.

Keywords

Acknowledgement

This research was supported by the National Natural Science Foundation of China (81772887). Jiangsu Provincial Medical Innovation Team (CXTDA2017036), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, 2018-87), Jiangsu Provincial Medical Youth Talent (QNRC2016854), and Natural Science Foundation of Jiangsu Province of China (BK20171488).

References

  1. Aichem, A. and Groettrup, M. (2016). The ubiquitin-like modifier FAT10 in cancer development. Int. J. Biochem. Cell Biol. 79, 451-461. https://doi.org/10.1016/j.biocel.2016.07.001
  2. Awasthee, N., Rai, V., Chava, S., Nallasamy, P., Kunnumakkara, A.B., Bishayee, A., Chauhan, S.C., Challagundla, K.B., and Gupta, S.C. (2019). Targeting IkappaappaB kinases for cancer therapy. Semin. Cancer Biol. 56, 12-24. https://doi.org/10.1016/j.semcancer.2018.02.007
  3. Bai, Y., Sha, J., and Kanno, T. (2020). The role of carcinogenesisrelated biomarkers in the Wnt pathway and their effects on epithelialmesenchymal transition (EMT) in oral squamous cell carcinoma. Cancers (Basel) 12, 555. https://doi.org/10.3390/cancers12030555
  4. Bialas, J., Boehm, A.N., Catone, N., Aichem, A., and Groettrup, M. (2019). The ubiquitin-like modifier FAT10 stimulates the activity of deubiquitylating enzyme OTUB1. J. Biol. Chem. 294, 4315-4330. https://doi.org/10.1074/jbc.ra118.005406
  5. Cappadocia, L. and Lima, C.D. (2018). Ubiquitin-like protein conjugation: structures, chemistry, and mechanism. Chem. Rev. 118, 889-918. https://doi.org/10.1021/acs.chemrev.6b00737
  6. Chai, A.W.Y., Lim, K.P., and Cheong, S.C. (2020). Translational genomics and recent advances in oral squamous cell carcinoma. Semin. Cancer Biol. 61, 71-83. https://doi.org/10.1016/j.semcancer.2019.09.011
  7. Choi, Y., Kim, J.K., and Yoo, J.Y. (2014). NFkappaB and STAT3 synergistically activate the expression of FAT10, a gene counteracting the tumor suppressor p53. Mol. Oncol. 8, 642-655. https://doi.org/10.1016/j.molonc.2014.01.007
  8. Chu, W., Song, X., Yang, X., Ma, L., Zhu, J., He, M., Wang, Z., and Wu, Y. (2014). Neuropilin-1 promotes epithelial-to-mesenchymal transition by stimulating nuclear factor-kappa B and is associated with poor prognosis in human oral squamous cell carcinoma. PLoS One 9, e101931. https://doi.org/10.1371/journal.pone.0101931
  9. Deng, X., Deng, J., Yi, X., Zou, Y., Liu, H., Li, C., Deng, B., Fan, H., and Hao, L. (2020). Ubiquitin-like protein FAT10 promotes osteosarcoma glycolysis and growth by upregulating PFKFB3 via stabilization of EGFR. Am. J. Cancer Res. 10, 2066-2082.
  10. Derakhshan, A., Chen, Z., and Van Waes, C. (2017). Therapeutic small molecules target inhibitor of apoptosis proteins in cancers with deregulation of extrinsic and intrinsic cell death pathways. Clin. Cancer Res. 23, 1379-1387. https://doi.org/10.1158/1078-0432.CCR-16-2172
  11. Eluard, B., Thieblemont, C., and Baud, V. (2020). NF-kappaB in the new era of cancer therapy. Trends Cancer 6, 677-687. https://doi.org/10.1016/j.trecan.2020.04.003
  12. Ferlay, J., Shin, H.R., Bray, F., Forman, D., Mathers, C., and Parkin, D.M. (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127, 2893-2917. https://doi.org/10.1002/ijc.25516
  13. Gao, Y., Theng, S.S., Zhuo, J., Teo, W.B., Ren, J., and Lee, C.G. (2014). FAT10, an ubiquitin-like protein, confers malignant properties in non-tumorigenic and tumorigenic cells. Carcinogenesis 35, 923-934. https://doi.org/10.1093/carcin/bgt407
  14. Groettrup, M., Pelzer, C., Schmidtke, G., and Hofmann, K. (2008). Activating the ubiquitin family: UBA6 challenges the field. Trends Biochem. Sci. 33, 230-237. https://doi.org/10.1016/j.tibs.2008.01.005
  15. Harris, J., Oliere, S., Sharma, S., Sun, Q., Lin, R., Hiscott, J., and Grandvaux, N. (2006). Nuclear accumulation of cRel following C-terminal phosphorylation by TBK1/IKK epsilon. J. Immunol. 177, 2527-2535. https://doi.org/10.4049/jimmunol.177.4.2527
  16. Harsha, C., Banik, K., Ang, H.L., Girisa, S., Vikkurthi, R., Parama, D., Rana, V., Shabnam, B., Khatoon, E., Kumar, A.P., et al. (2020). Targeting AKT/mTOR in oral cancer: mechanisms and advances in clinical trials. Int. J. Mol. Sci. 21, 3285. https://doi.org/10.3390/ijms21093285
  17. Hayden, M.S. and Ghosh, S. (2012). NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev. 26, 203-234. https://doi.org/10.1101/gad.183434.111
  18. Ishida, K., Tomita, H., Nakashima, T., Hirata, A., Tanaka, T., Shibata, T., and Hara, A. (2017). Current mouse models of oral squamous cell carcinoma: genetic and chemically induced models. Oral Oncol. 73, 16-20. https://doi.org/10.1016/j.oraloncology.2017.07.028
  19. Kaltschmidt, B., Greiner, J.F.W., Kadhim, H.M., and Kaltschmidt, C. (2018). Subunit-specific role of NF-kappaB in cancer. Biomedicines 6, 44. https://doi.org/10.3390/biomedicines6020044
  20. Kawamoto, A., Nagata, S., Anzai, S., Takahashi, J., Kawai, M., Hama, M., Nogawa, D., Yamamoto, K., Kuno, R., Suzuki, K., et al. (2019). Ubiquitin D is upregulated by synergy of Notch signalling and TNF-alpha in the inflamed intestinal epithelia of IBD patients. J. Crohns Colitis 13, 495-509. https://doi.org/10.1093/ecco-jcc/jjy180
  21. King, K.E., Ponnamperuma, R.M., Allen, C., Lu, H., Duggal, P., Chen, Z., Van Waes, C., and Weinberg, W.C. (2008). The p53 homologue DeltaNp63alpha interacts with the nuclear factor-kappaB pathway to modulate epithelial cell growth. Cancer Res. 68, 5122-5131. https://doi.org/10.1158/0008-5472.CAN-07-6123
  22. Liu, X., Ge, J., Chen, C., Shen, Y., Xie, J., Zhu, X., Liu, M., Hu, J., Chen, L., Guo, L., et al. (2021). FAT10 protects against ischemia-induced ventricular arrhythmia by decreasing Nedd4-2/Nav1.5 complex formation. Cell Death Dis. 12, 25. https://doi.org/10.1038/s41419-020-03290-3
  23. Luo, C., Xiong, H., Chen, L., Liu, X., Zou, S., Guan, J., and Wang, K. (2018). GRP78 promotes hepatocellular carcinoma proliferation by increasing FAT10 expression through the NF-kappaB pathway. Exp. Cell Res. 365, 1-11. https://doi.org/10.1016/j.yexcr.2018.02.007
  24. Mortezaee, K., Najafi, M., Farhood, B., Ahmadi, A., Shabeeb, D., and Musa, A.E. (2019). NF-kappaB targeting for overcoming tumor resistance and normal tissues toxicity. J. Cell. Physiol. 234, 17187-17204. https://doi.org/10.1002/jcp.28504
  25. Neumann, M. and Naumann, M. (2007). Beyond IkappaBs: alternative regulation of NF-kappaB activity. FASEB J. 21, 2642-2654. https://doi.org/10.1096/fj.06-7615rev
  26. Panarese, I., Aquino, G., Ronchi, A., Longo, F., Montella, M., Cozzolino, I., Roccuzzo, G., Colella, G., Caraglia, M., and Franco, R. (2019). Oral and oropharyngeal squamous cell carcinoma: prognostic and predictive parameters in the etiopathogenetic route. Expert Rev. Anticancer Ther. 19, 105-119. https://doi.org/10.1080/14737140.2019.1561288
  27. Patel, S., Shah, K., Mirza, S., Daga, A., and Rawal, R. (2015). Epigenetic regulators governing cancer stem cells and epithelial-mesenchymal transition in oral squamous cell carcinoma. Curr. Stem Cell Res. Ther. 10, 140-152. https://doi.org/10.2174/1574888X09666141020163700
  28. Petersen, P.E. (2009). Oral cancer prevention and control--the approach of the World Health Organization. Oral Oncol. 45, 454-460. https://doi.org/10.1016/j.oraloncology.2008.05.023
  29. Qing, X., French, B.A., Oliva, J., and French, S.W. (2011). Increased expression of FAT10 in colon benign, premalignant and malignant epithelial neoplasms. Exp. Mol. Pathol. 90, 51-54. https://doi.org/10.1016/j.yexmp.2010.09.005
  30. Siriwardena, S., Tsunematsu, T., Qi, G., Ishimaru, N., and Kudo, Y. (2018). Invasion-related factors as potential diagnostic and therapeutic targets in oral squamous cell carcinoma-a review. Int. J. Mol. Sci. 19, 1462. https://doi.org/10.3390/ijms19051462
  31. Sovak, M.A., Bellas, R.E., Kim, D.W., Zanieski, G.J., Rogers, A.E., Traish, A.M., and Sonenshein, G.E. (1997). Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. J. Clin. Invest. 100, 2952-2960. https://doi.org/10.1172/JCI119848
  32. Steinbichler, T.B., Savic, D., Dudas, J., Kvitsaridze, I., Skvortsov, S., Riechelmann, H., and Skvortsova, I.I. (2020). Cancer stem cells and their unique role in metastatic spread. Semin. Cancer Biol. 60, 148-156. https://doi.org/10.1016/j.semcancer.2019.09.007
  33. Tampa, M., Mitran, M.I., Mitran, C.I., Sarbu, M.I., Matei, C., Nicolae, I., Caruntu, A., Tocut, S.M., Popa, M.I., Caruntu, C., et al. (2018). Mediators of inflammation - a potential source of biomarkers in oral squamous cell carcinoma. J. Immunol. Res. 2018, 1061780. https://doi.org/10.1155/2018/1061780
  34. Terzuoli, E., Bellan, C., Aversa, S., Ciccone, V., Morbidelli, L., Giachetti, A., Donnini, S., and Ziche, M. (2019). ALDH3A1 overexpression in melanoma and lung tumors drives cancer stem cell expansion, impairing immune surveillance through enhanced PD-L1 output. Cancers (Basel) 11, 1963. https://doi.org/10.3390/cancers11121963
  35. Wang, F. and Zhao, B. (2019). UBA6 and its bispecific pathways for ubiquitin and FAT10. Int. J. Mol. Sci. 20, 2250. https://doi.org/10.3390/ijms20092250
  36. Wang, Z., Chen, J., Zhang, W., Zheng, Y., Wang, Z., Liu, L., Wu, H., Ye, J., Zhang, W., Qi, B., et al. (2016). Axon guidance molecule semaphorin3A is a novel tumor suppressor in head and neck squamous cell carcinoma. Oncotarget 7, 6048-6062. https://doi.org/10.18632/oncotarget.6831
  37. Wang, Z., Zhu, W.G., and Xu, X. (2017). Ubiquitin-like modifications in the DNA damage response. Mutat. Res. 803-805, 56-75. https://doi.org/10.1016/j.mrfmmm.2017.07.001
  38. Wilken, R., Veena, M.S., Wang, M.B., and Srivatsan, E.S. (2011). Curcumin: a review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol. Cancer 10, 12. https://doi.org/10.1186/1476-4598-10-12
  39. Xia, Y., Shen, S., and Verma, I.M. (2014). NF-kappaB, an active player in human cancers. Cancer Immunol. Res. 2, 823-830. https://doi.org/10.1158/2326-6066.CIR-14-0112
  40. Xiang, S., Shao, X., Cao, J., Yang, B., He, Q., and Ying, M. (2020). FAT10: function and relationship with cancer. Curr. Mol. Pharmacol. 13, 182-191. https://doi.org/10.2174/1874467212666191113130312
  41. Xue, F., Zhu, L., Meng, Q.W., Wang, L., Chen, X.S., Zhao, Y.B., Xing, Y., Wang, X.Y., and Cai, L. (2016). FAT10 is associated with the malignancy and drug resistance of non-small-cell lung cancer. Onco Targets Ther. 9, 4397-4409. https://doi.org/10.2147/OTT.S98410
  42. Yan, J., Lei, J., Chen, L., Deng, H., Dong, D., Jin, T., Liu, X., Yuan, R., Qiu, Y., Ge, J., et al. (2018). Human leukocyte antigen F locus adjacent transcript 10 overexpression disturbs WISP1 protein and mRNA expression to promote hepatocellular carcinoma progression. Hepatology 68, 2268-2284. https://doi.org/10.1002/hep.30105
  43. Yang, H., Kuo, Y.H., Smith, Z.I., and Spangler, J. (2021). Targeting cancer metastasis with antibody therapeutics. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2021 Jan 18 [Epub]. https://doi.org/10.1002/wnan.1698
  44. Yang, L., Shi, P., Zhao, G., Xu, J., Peng, W., Zhang, J., Zhang, G., Wang, X., Dong, Z., Chen, F., et al. (2020). Targeting cancer stem cell pathways for cancer therapy. Signal Transduct. Target. Ther. 5, 8. https://doi.org/10.1038/s41392-020-0110-5
  45. Yanjia, H. and Xinchun, J. (2007). The role of epithelial-mesenchymal transition in oral squamous cell carcinoma and oral submucous fibrosis. Clin. Chim. Acta 383, 51-56. https://doi.org/10.1016/j.cca.2007.04.014
  46. Yuan, J., Tu, Y., Mao, X., He, S., Wang, L., Fu, G., Zong, J., and Zhang, Y. (2012). Increased expression of FAT10 is correlated with progression and prognosis of human glioma. Pathol. Oncol. Res. 18, 833-839. https://doi.org/10.1007/s12253-012-9511-2
  47. Yuan, R., Wang, K., Hu, J., Yan, C., Li, M., Yu, X., Liu, X., Lei, J., Guo, W., Wu, L., et al. (2014). Ubiquitin-like protein FAT10 promotes the invasion and metastasis of hepatocellular carcinoma by modifying beta-catenin degradation. Cancer Res. 74, 5287-5300.
  48. Zamo, A., Malpeli, G., Scarpa, A., Doglioni, C., Chilosi, M., and Menestrina, F. (2005). Expression of TP73L is a helpful diagnostic marker of primary mediastinal large B-cell lymphomas. Mod. Pathol. 18, 1448-1453. https://doi.org/10.1038/modpathol.3800440
  49. Zhou, X., Liu, S., Cai, G., Kong, L., Zhang, T., Ren, Y., Wu, Y., Mei, M., Zhang, L., and Wang, X. (2015). Long non coding RNA MALAT1 promotes tumor growth and metastasis by inducing epithelial-mesenchymal transition in oral squamous cell carcinoma. Sci. Rep. 5, 15972. https://doi.org/10.1038/srep15972
  50. Zielinska, K.A. and Katanaev, V.L. (2019). Information theory: new look at oncogenic signaling pathways. Trends Cell Biol. 29, 862-875. https://doi.org/10.1016/j.tcb.2019.08.005
  51. Zou, Y., Du, Y., Cheng, C., Deng, X., Shi, Z., Lu, X., Hu, H., Qiu, J., and Jiang, W. (2021). FAT10 promotes the progression of bladder cancer by upregulating HK2 through the EGFR/AKT pathway. Exp. Cell Res. 398, 112401. https://doi.org/10.1016/j.yexcr.2020.112401