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Current Protein & Peptide Science

Author(s): Xiaoqi Yang, Minfa Zhang, Tongdong Su, Shuangmei Tang, Yin Wang, Heng Liu, Pin Wang, Juan Wang* and Xinliang Pan*

DOI: 10.2174/1389203723666220727090317

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TIPE2 Inhibits Migration and Promotes Apoptosis as a Tumor Suppressor in Hypopharyngeal Carcinoma

Page: [424 - 436] Pages: 13

  • * (Excluding Mailing and Handling)

Abstract

Background: Hypopharyngeal squamous cell carcinoma (HSCC) is a common malignant cancer characterized by high metastasis and infiltration. The development of new approaches for the early diagnosis and identification of new therapeutic targets is essential. TIPE2 is well known as a tumor suppressor and related to a favorable prognosis of HSCC. However, its underlying mechanism remains unclear.

Methods and Materials: TIPE2 expression was determined by immunohistochemistry and RT-qPCR. A TIPE2 overexpression stable cell line was generated by lentivirus infection. TIPE2 and other related protein levels were detected by western blotting. The cell cycle and apoptosis were performed by flow cytometric analysis. Cell proliferation was measured with a Cell Counting Kit-8 (CCK-8) assay, and the activity of caspase-3 and caspase-7 was assessed by Caspase-Glo® 3/7 Assay. All data were analyzed with SPSS 25 and GraphPad Prism 8.0.

Results: TIPE2 expression was significantly down-regulated in HSCC. Low TIPE2 expression may be associated with poor prognosis in HSCC. TIPE2 overexpression markedly inhibited tumor cell migration. Moreover, TIPE2 decreased cell proliferation but promoted apoptosis. TIPE2 suppressed tumor growth by activating Epithelial-Mesenchymal Transition (EMT) and the extrinsic apoptosis pathway.

Conclusion: TIPE2 inhibited tumor progression by suppressing cell migration but promoting apoptosis. TIPE2 can be a new therapeutic target in HSCC.

Keywords: Hypopharyngeal squamous cell carcinoma, TIPE2, migration, invasion, EMT, biomarker.

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]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN esti-mates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[3]
Niture, S.; Dong, X.; Arthur, E.; Chimeh, U.; Niture, S.S.; Zheng, W.; Kumar, D. Oncogenic role of tumor necrosis factor α-induced pro-tein 8 (TNFAIP8). Cells, 2018, 8(1), 9.
[http://dx.doi.org/10.3390/cells8010009] [PMID: 30586922]
[4]
Bi, J.; Cheng, C.; Zheng, C.; Huang, C.; Zheng, X.; Wan, X.; Chen, Y.H.; Tian, Z.; Sun, H. TIPE2 is a checkpoint of natural killer cell matu-ration and antitumor immunity. Sci. Adv., 2021, 7(38), eabi6515.
[http://dx.doi.org/10.1126/sciadv.abi6515] [PMID: 34524845]
[5]
Sun, X.; Li, X.; Zhou, Y.; Wang, Y.; Liu, X. Up-regulating TIPE2 alleviates inflammatory pain by suppressing microglial activation-mediated inflammatory response via inhibiting Rac1/NF-κB pathway. Exp. Cell Res., 2021, 404(1), 112631.
[http://dx.doi.org/10.1016/j.yexcr.2021.112631] [PMID: 33933441]
[6]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[7]
Li, W.; Li, Y.; Guan, Y.; Du, Y.; Zhao, M.; Chen, X.; Zhu, F.; Guo, C.; Jia, Y.; Li, Y.; Wang, X.; Wang, X.; Shi, Y.; Wang, Q.; Li, Y.; Zhang, L. TNFAIP8L2/TIPE2 impairs autolysosome reformation via modulating the RAC1-MTORC1 axis. Autophagy, 2021, 17(6), 1410-1425.
[http://dx.doi.org/10.1080/15548627.2020.1761748] [PMID: 32460619]
[8]
Cao, X.; Zhang, L.; Shi, Y.; Sun, Y.; Dai, S.; Guo, C.; Zhu, F.; Wang, Q.; Wang, J.; Wang, X.; Chen, Y.H.; Zhang, L. Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1. Mol. Cancer, 2013, 12(1), 149.
[http://dx.doi.org/10.1186/1476-4598-12-149] [PMID: 24274578]
[9]
Li, Z.; Guo, C.; Liu, X.; Zhou, C.; Zhu, F.; Wang, X.; Wang, Q.; Shi, Y.; Wang, J.; Zhao, W.; Zhang, L. TIPE2 suppresses angiogenesis and non-small cell lung cancer (NSCLC) invasiveness via inhibiting Rac1 activation and VEGF expression. Oncotarget, 2016, 7(38), 62224-62239.
[http://dx.doi.org/10.18632/oncotarget.11406] [PMID: 27556698]
[10]
Yang, J.; Antin, P.; Berx, G.; Blanpain, C.; Brabletz, T.; Bronner, M.; Campbell, K.; Cano, A.; Casanova, J.; Christofori, G.; Dedhar, S.; Derynck, R.; Ford, H.L.; Fuxe, J.; García de Herreros, A.; Goodall, G.J.; Hadjantonakis, A.K.; Huang, R.Y.J.; Kalcheim, C.; Kalluri, R.; Kang, Y.; Khew-Goodall, Y.; Levine, H.; Liu, J.; Longmore, G.D.; Mani, S.A.; Massagué, J.; Mayor, R.; McClay, D.; Mostov, K.E.; New-green, D.F.; Nieto, M.A.; Puisieux, A.; Runyan, R.; Savagner, P.; Stanger, B.; Stemmler, M.P.; Takahashi, Y.; Takeichi, M.; Theveneau, E.; Thiery, J.P.; Thompson, E.W.; Weinberg, R.A.; Williams, E.D.; Xing, J.; Zhou, B.P.; Sheng, G. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol., 2020, 21(6), 341-352.
[http://dx.doi.org/10.1038/s41580-020-0237-9] [PMID: 32300252]
[11]
Dongre, A.; Weinberg, R.A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol., 2019, 20(2), 69-84.
[http://dx.doi.org/10.1038/s41580-018-0080-4] [PMID: 30459476]
[12]
Scarpa, E.; Szabó, A.; Bibonne, A.; Theveneau, E.; Parsons, M.; Mayor, R. Cadherin switch during EMT in neural crest cells leads to con-tact inhibition of locomotion via repolarization of forces. Dev. Cell, 2015, 34(4), 421-434.
[http://dx.doi.org/10.1016/j.devcel.2015.06.012] [PMID: 26235046]
[13]
Stemmler, M.P.; Eccles, R.L.; Brabletz, S.; Brabletz, T. Non-redundant functions of EMT transcription factors. Nat. Cell Biol., 2019, 21(1), 102-112.
[http://dx.doi.org/10.1038/s41556-018-0196-y] [PMID: 30602760]
[14]
Li, Y.; Lv, Z.; Zhang, S.; Wang, Z.; He, L.; Tang, M.; Pu, W.; Zhao, H.; Zhang, Z.; Shi, Q.; Cai, D.; Wu, M.; Hu, G.; Lui, K.O.; Feng, J.; Nieto, M.A.; Zhou, B. Genetic fate mapping of transient cell fate reveals N-cadherin activity and function in tumor metastasis. Dev. Cell, 2020, 54(5), 593-607.e5.
[http://dx.doi.org/10.1016/j.devcel.2020.06.021] [PMID: 32668208]
[15]
Sánchez-Tilló, E. de Barrios, O.; Siles, L.; Cuatrecasas, M.; Castells, A.; Postigo, A. β-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness. Proc. Natl. Acad. Sci. USA, 2011, 108(48), 19204-19209.
[http://dx.doi.org/10.1073/pnas.1108977108] [PMID: 22080605]
[16]
Taube, J.H.; Herschkowitz, J.I.; Komurov, K.; Zhou, A.Y.; Gupta, S.; Yang, J.; Hartwell, K.; Onder, T.T.; Gupta, P.B.; Evans, K.W.; Holli-er, B.G.; Ram, P.T.; Lander, E.S.; Rosen, J.M.; Weinberg, R.A.; Mani, S.A. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc. Natl. Acad. Sci. USA, 2010, 107(35), 15449-15454.
[http://dx.doi.org/10.1073/pnas.1004900107] [PMID: 20713713]
[17]
Dhuriya, Y.K.; Sharma, D.; Naik, A.A. Cellular demolition: Proteins as molecular players of programmed cell death. Int. J. Biol. Macromol., 2019, 138, 492-503.
[http://dx.doi.org/10.1016/j.ijbiomac.2019.07.113] [PMID: 31330212]
[18]
Kesavardhana, S.; Malireddi, R.K.S.; Kanneganti, T.D. Caspases in cell death, inflammation, and pyroptosis. Annu. Rev. Immunol., 2020, 38, 567-595.
[http://dx.doi.org/10.1146/annurev-immunol-073119-095439] [PMID: 32017655]
[19]
Kranz, D.; Boutros, M. A synthetic lethal screen identifies FAT1 as an antagonist of caspase-8 in extrinsic apoptosis. EMBO J., 2014, 33(3), 181-197.
[http://dx.doi.org/10.1002/embj.201385686] [PMID: 24442637]
[20]
Pirnia, F.; Schneider, E.; Betticher, D.C.; Borner, M.M. Mitomycin C induces apoptosis and caspase-8 and -9 processing through a caspa-se-3 and Fas-independent pathway. Cell Death Differ., 2002, 9(9), 905-914.
[http://dx.doi.org/10.1038/sj.cdd.4401062] [PMID: 12181741]
[21]
Fritsch, M.; Günther, S.D.; Schwarzer, R.; Albert, M.C.; Schorn, F.; Werthenbach, J.P.; Schiffmann, L.M.; Stair, N.; Stocks, H.; Seeger, J.M.; Lamkanfi, M.; Krönke, M.; Pasparakis, M.; Kashkar, H. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyropto-sis. Nature, 2019, 575(7784), 683-687.
[http://dx.doi.org/10.1038/s41586-019-1770-6] [PMID: 31748744]
[22]
Newton, K.; Wickliffe, K.E.; Dugger, D.L.; Maltzman, A.; Roose-Girma, M.; Dohse, M. Kőműves, L.; Webster, J.D.; Dixit, V.M. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature, 2019, 574(7778), 428-431.
[http://dx.doi.org/10.1038/s41586-019-1548-x] [PMID: 31511692]
[23]
Feng, F.; Liu, C.; Bian, H.; Cai, W.; Zhou, Y.; Zhou, L.; Zhuang, Z. TIPE2 suppresses malignancy of pancreatic cancer through inhibiting TGFβ1 mediated signaling pathway. Front. Oncol., 2021, 11, 680985.
[http://dx.doi.org/10.3389/fonc.2021.680985] [PMID: 34249724]
[24]
Liu, W.; Wang, Y.; Chen, J.; Lin, Z.; Lin, M.; Lin, X.; Fan, Y. Beneficial effects of gracillin from Rhizoma paridis against gastric carcinoma via the potential TIPE2-mediated induction of endogenous apoptosis and inhibition of migration in BGC823 cells. Front. Pharmacol., 2021, 12, 669199.
[PMID: 34630074]
[25]
Zhu, L.; Zhang, X.; Fu, X.; Li, Z.; Sun, Z.; Wu, J.; Wang, X.; Wang, F.; Li, X.; Niu, S.; Ding, M.; Yang, Z.; Yang, W.; Yin, M.; Zhang, L.; Zhang, M. TIPE2 suppresses progression and tumorigenesis of esophageal carcinoma via inhibition of the Wnt/β-catenin pathway. J. Transl. Med., 2018, 16(1), 7.
[http://dx.doi.org/10.1186/s12967-018-1383-0] [PMID: 29343267]
[26]
Zhao, L.L. TIPE2 suppresses progression and tumorigenesis of the oral tongue squamous cell carcinoma by regulating FoxP3+ regulatory T cells. J. Bioenerg. Biomembr., 2020, 52(4), 279-289.
[http://dx.doi.org/10.1007/s10863-020-09840-w] [PMID: 32594290]
[27]
Liu, Y.; Wang, X.; Wan, L.; Liu, X.; Yu, H.; Zhang, D.; Sun, Y.; Shi, Y.; Zhang, L.; Zhou, H.; Wang, J.; Wei, Z. TIPE2 inhibits the migra-tion and invasion of endometrial cells by targeting β-catenin to reverse epithelial-mesenchymal transition. Hum. Reprod., 2020, 35(6), 1377-1390.
[http://dx.doi.org/10.1093/humrep/deaa062] [PMID: 32469403]
[28]
Jia, W.; Li, Z.; Chen, J.; Sun, L.; Liu, C.; Wang, S.; Chi, J.; Niu, J.; Lai, H. TIPE2 acts as a biomarker for tumor aggressiveness and sup-presses cell invasiveness in papillary thyroid cancer (PTC). Cell Biosci., 2018, 8, 49.
[http://dx.doi.org/10.1186/s13578-018-0247-x] [PMID: 30186591]
[29]
Wu, D.D.; Liu, S.Y.; Gao, Y.R.; Lu, D.; Hong, Y.; Chen, Y.G.; Dong, P.Z.; Wang, D.Y.; Li, T.; Li, H.M.; Ren, Z.G.; Guo, J.C.; He, F.; Ren, X.Q.; Sun, S.Y.; Duan, S.F.; Ji, X.Y. Tumour necrosis factor-α-induced protein 8-like 2 is a novel regulator of proliferation, migration, and invasion in human rectal adenocarcinoma cells. J. Cell. Mol. Med., 2019, 23(3), 1698-1713.
[http://dx.doi.org/10.1111/jcmm.14065] [PMID: 30637920]
[30]
Padmavathi, G.; Monisha, J.; Bordoloi, D.; Banik, K.; Roy, N.K.; Girisa, S.; Singh, A.K.; Longkumer, I.; Baruah, M.N.; Kunnumakkara, A.B. Tumor necrosis factor-α induced protein 8 (TNFAIP8/TIPE) family is differentially expressed in oral cancer and regulates tumor-igenesis through Akt/mTOR/STAT3 signaling cascade. Life Sci., 2021, 287, 120118.
[http://dx.doi.org/10.1016/j.lfs.2021.120118] [PMID: 34740574]
[31]
Li, Y.; Zhang, N.; Ma, C.; Xu, W.; Jin, G.; Zheng, Y.; Zhang, L.; Liu, B.; Gao, C.; Liu, S. The overexpression of Tipe2 in CRC cells sup-presses survival while endogenous Tipe2 accelerates AOM/DSS induced-tumor initiation. Cell Death Dis., 2021, 12(11), 1001.
[http://dx.doi.org/10.1038/s41419-021-04289-0] [PMID: 34702807]