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Protein & Peptide Letters

Editor-in-Chief

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

Research Article

Knockdown of Programmed Death 1 Inhibited Progression of Papillary Thyroid Carcinoma in Mice

Author(s): Hui Wang, Qianqian Chu, Shihong Ma* and Ying Tao

Volume 30, Issue 5, 2023

Published on: 14 April, 2023

Page: [396 - 400] Pages: 5

DOI: 10.2174/0929866530666230306112912

Price: $65

Abstract

Background: PD-L1 and PD1 mainly focused on melanoma, lung cancer and other tumors, while the related studies on early lymph node metastasis of papillary thyroid carcinoma were rarely reported.

Objective: For elucidating the role of programmed death 1 (PD1)/programmed death ligand 1 (PD-L1) pathway in tumor growth of papillary thyroid carcinoma (PTC).

Methods: Human thyroid cancer cell line and human normal thyroid cell line were obtained and transfected with si-PD1 or pCMV3-PD1 for the construction of PD1 knockdown or overexpression models. BALB/c mice were purchased for in vivo studies. Nivolumab was implemented for in vivo inhibition of PD1. Western blotting was performed for determining protein expression, while RTqPCR was used to measure relative mRNA levels.

Results: The PD1 and PD-L1 levels were both significantly upregulated in PTC mice, while the knockdown of PD1 downregulated both PD1 and PD-L1 levels. Protein expression of VEGF and FGF2 was increased in PTC mice, while si-PD1 decreased their expression. Silencing of PD1 using si-PD1 and nivolumab both inhibited tumor growth in PTC mice.

Conclusion: Suppressing PD1/PD-L1 pathway significantly contributed to the tumor regression of PTC in mice.

Graphical Abstract

[1]
Lin, Z.; Niu, Y.; Wan, A.; Chen, D.; Liang, H.; Chen, X.; Sun, L.; Zhan, S.; Chen, L.; Cheng, C.; Zhang, X.; Bu, X.; He, W.; Wan, G. RNA m6 A methylation regulates sorafenib resistance in liver cancer through FOXO 3‐mediated autophagy. EMBO J., 2020, 39(12), e103181.
[http://dx.doi.org/10.15252/embj.2019103181] [PMID: 32368828]
[2]
Yu, J.; Deng, Y.; Liu, T.; Zhou, J.; Jia, X.; Xiao, T.; Zhou, S.; Li, J.; Guo, Y.; Wang, Y.; Zhou, J.; Chang, C. Lymph node metastasis prediction of papillary thyroid carcinoma based on transfer learning radiomics. Nat. Commun., 2020, 11(1), 4807.
[http://dx.doi.org/10.1038/s41467-020-18497-3] [PMID: 32968067]
[3]
Liu, C.; Xiao, C.; Chen, J.; Li, X.; Feng, Z.; Gao, Q.; Liu, Z. Risk factor analysis for predicting cervical lymph node metastasis in papillary thyroid carcinoma: a study of 966 patients. BMC Cancer, 2019, 19(1), 622.
[http://dx.doi.org/10.1186/s12885-019-5835-6] [PMID: 31238891]
[4]
Konishi, J.; Yamazaki, K.; Azuma, M.; Kinoshita, I.; Dosaka-Akita, H.; Nishimura, M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin. Cancer Res., 2004, 10(15), 5094-5100.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-0428] [PMID: 15297412]
[5]
Capece, D.; Verzella, D.; Fischietti, M.; Zazzeroni, F.; Alesse, E. Targeting costimulatory molecules to improve antitumor immunity. J. Biomed. Biotechnol., 2012, 2012, 926321.
[http://dx.doi.org/10.1155/2012/926321] [PMID: 22500111]
[6]
Ni, L.; Dong, C. New B7 family checkpoints in human cancers. Mol. Cancer Ther., 2017, 16(7), 1203-1211.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0761] [PMID: 28679835]
[7]
Shen, X.; Zhao, B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ, 2018, 362, k3529.
[http://dx.doi.org/10.1136/bmj.k3529] [PMID: 30201790]
[8]
Yu, J.; Wang, X.; Teng, F.; Kong, L. PD-L1 expression in human cancers and its association with clinical outcomes. OncoTargets Ther., 2016, 9, 5023-5039.
[http://dx.doi.org/10.2147/OTT.S105862] [PMID: 27574444]
[9]
Rotman, J.; Otter, L.A.S.; Bleeker, M.C.G.; Samuels, S.S.; Heeren, A.M.; Roemer, M.G.M.; Kenter, G.G.; Zijlmans, H.J.M.A.A.; van Trommel, N.E.; de Gruijl, T.D.; Jordanova, E.S. PD-L1 and PD-L2 expression in cervical cancer: regulation and biomarker potential. Front. Immunol., 2020, 11, 596825.
[http://dx.doi.org/10.3389/fimmu.2020.596825] [PMID: 33424844]
[10]
Mahoney, K.M.; Freeman, G.J.; McDermott, D.F. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin. Ther., 2015, 37(4), 764-782.
[http://dx.doi.org/10.1016/j.clinthera.2015.02.018] [PMID: 25823918]
[11]
Lei, Q.; Wang, D.; Sun, K.; Wang, L.; Zhang, Y. Resistance mechanisms of anti-PD1/PDL1 therapy in solid tumors. Front. Cell Dev. Biol., 2020, 8, 672.
[http://dx.doi.org/10.3389/fcell.2020.00672] [PMID: 32793604]
[12]
Celada, L.J.; Kropski, J.A.; Herazo-Maya, J.D.; Luo, W.; Creecy, A.; Abad, A.T.; Chioma, O.S.; Lee, G.; Hassell, N.E.; Shaginurova, G.I.; Wang, Y.; Johnson, J.E.; Kerrigan, A.; Mason, W.R.; Baughman, R.P.; Ayers, G.D.; Bernard, G.R.; Culver, D.A.; Montgomery, C.G.; Maher, T.M.; Molyneaux, P.L.; Noth, I.; Mutsaers, S.E.; Prele, C.M.; Stokes Peebles, R., Jr; Newcomb, D.C.; Kaminski, N.; Blackwell, T.S.; Van Kaer, L.; Drake, W.P. PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production. Sci. Transl. Med., 2018, 10(460), eaar8356.
[http://dx.doi.org/10.1126/scitranslmed.aar8356] [PMID: 30257954]
[13]
Garcia-Diaz, A.; Shin, D.S.; Moreno, B.H.; Saco, J.; Escuin-Ordinas, H.; Rodriguez, G.A.; Zaretsky, J.M.; Sun, L.; Hugo, W.; Wang, X.; Parisi, G.; Saus, C.P.; Torrejon, D.Y.; Graeber, T.G.; Comin-Anduix, B.; Hu-Lieskovan, S.; Damoiseaux, R.; Lo, R.S.; Ribas, A. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep., 2017, 19(6), 1189-1201.
[http://dx.doi.org/10.1016/j.celrep.2017.04.031] [PMID: 28494868]
[14]
He, M.; Wu, N.; Leong, M.C.; Zhang, W.; Ye, Z.; Li, R.; Huang, J.; Zhang, Z.; Li, L.; Yao, X.; Zhou, W.; Liu, N.; Yang, Z.; Dong, X.; Li, Y.; Chen, L.; Li, Q.; Wang, X.; Wen, J.; Zhao, X.; Lu, B.; Yang, Y.; Wang, Q.; Hu, R. miR-145 improves metabolic inflammatory disease through multiple pathways. J. Mol. Cell Biol., 2020, 12(2), 152-162.
[http://dx.doi.org/10.1093/jmcb/mjz015] [PMID: 30941422]
[15]
Fife, B.T.; Pauken, K.E.; Eagar, T.N.; Obu, T.; Wu, J.; Tang, Q.; Azuma, M.; Krummel, M.F.; Bluestone, J.A. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat. Immunol., 2009, 10(11), 1185-1192.
[http://dx.doi.org/10.1038/ni.1790] [PMID: 19783989]
[16]
Maj, T.; Wang, W.; Crespo, J.; Zhang, H.; Wang, W.; Wei, S.; Zhao, L.; Vatan, L.; Shao, I.; Szeliga, W.; Lyssiotis, C.; Liu, J.R.; Kryczek, I.; Zou, W. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol., 2017, 18(12), 1332-1341.
[http://dx.doi.org/10.1038/ni.3868] [PMID: 29083399]
[17]
Li, Y.; Liang, L.; Dai, W.; Cai, G.; Xu, Y.; Li, X.; Li, Q.; Cai, S. Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer. Mol. Cancer, 2016, 15(1), 55.
[http://dx.doi.org/10.1186/s12943-016-0539-x] [PMID: 27552968]
[18]
Tekguc, M.; Wing, J.B.; Osaki, M.; Long, J.; Sakaguchi, S. Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells. Proc. Natl. Acad. Sci. USA, 2021, 118(30), e2023739118.
[http://dx.doi.org/10.1073/pnas.2023739118] [PMID: 34301886]
[19]
Zhao, R.; Song, Y.; Wang, Y.; Huang, Y.; Li, Z.; Cui, Y.; Yi, M.; Xia, L.; Zhuang, W.; Wu, X.; Zhou, Y. PD‐1/PD‐L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway. Cell Prolif., 2019, 52(3), e12571.
[http://dx.doi.org/10.1111/cpr.12571] [PMID: 30714229]
[20]
Coelho, M.A.; de Carné Trécesson, S.; Rana, S.; Zecchin, D.; Moore, C.; Molina-Arcas, M.; East, P.; Spencer-Dene, B.; Nye, E.; Barnouin, K.; Snijders, A.P.; Lai, W.S.; Blackshear, P.J.; Downward, J. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity, 2017, 47(6), 1083-1099.e6.
[http://dx.doi.org/10.1016/j.immuni.2017.11.016] [PMID: 29246442]
[21]
Becker, J.C.; Andersen, M.H.; Schrama, D. thor Straten, P. Immune-suppressive properties of the tumor microenvironment. Cancer Immunol. Immunother., 2013, 62(7), 1137-1148.
[http://dx.doi.org/10.1007/s00262-013-1434-6] [PMID: 23666510]
[22]
Taube, J.M.; Klein, A.; Brahmer, J.R.; Xu, H.; Pan, X.; Kim, J.H.; Chen, L.; Pardoll, D.M.; Topalian, S.L.; Anders, R.A. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res., 2014, 20(19), 5064-5074.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-3271] [PMID: 24714771]
[23]
Liu, H.; Bakthavatsalam, R.; Meng, Z.; Li, Z.; Li, W.; Perkins, J.D.; Reyes, J. PD-L1 signal on liver dendritic cells is critical for Foxp3(+)CD4(+)CD25(+) Treg and liver tolerance induction in mice. Transplant. Proc., 2013, 45(5), 1853-1855.
[http://dx.doi.org/10.1016/j.transproceed.2013.03.015] [PMID: 23769057]
[24]
Jilaveanu, L.B.; Shuch, B.; Zito, C.R.; Parisi, F.; Barr, M.; Kluger, Y.; Chen, L.; Kluger, H.M. PD-L1 Expression in clear cell renal cell carcinoma: an analysis of nephrectomy and sites of metastases. J. Cancer, 2014, 5(3), 166-172.
[http://dx.doi.org/10.7150/jca.8167] [PMID: 24563671]

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