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Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Research Article

Human Chorionic Gonadotropin Regulates the Smad Signaling Pathway by Antagonizing TGF-β in Giant Cell Tumor of Bone

Author(s): Tangbing Xu, Shenglin Xu, Guangwen Ma, Jun Chang, Chi Zhang, Ping Zhou, Chao Wang, Pengfei Xu, Junjun Yang, Yong Hu* and Yunfeng Wu*

Volume 19, Issue 2, 2024

Published on: 11 May, 2023

Page: [188 - 198] Pages: 11

DOI: 10.2174/1574892818666230413082909

Price: $65

Abstract

Background: Giant cell tumor of bone (GCTB) is a locally aggressive bone tumour aggravated by stromal cell proliferation and metastasis.

Objective: We investigated the mechanism of action of human chorionic gonadotropin (HCG) in mediating GCTB proliferation and invasion.

Methods: The expression of HCG was quantified using quantitative real-time PCR. After the primary stromal cells were isolated and identified, the function of HCG in GCTB was estimated using the cell counting kit-8, flow cytometry, scratch experiment, transwell assay, Western blot, and immunofluorescence. Moreover, the mechanism of HCG was assessed through western blotting.

Results: HCG expression was decreased in clinical tissue samples from patients with GCTB. We validated that HCG repressed stromal cell proliferation, migration, invasion, autophagy, and epithelial- mesenchymal transition (EMT) and promoted cell apoptosis in GCTB. We also verified that HCG repressed the autophagy and EMT of stromal cells through the Smad signaling axis in GCTB. HCG inhibited the transduction of the Smad signaling pathway by restraining the binding of the TGF-β II receptor to ligand Activin A.

Conclusion: HCG restrained the Smad signaling pathway by antagonizing TGF-β signaling in GCTB. HCG may serve as a useful patent to treat GCTB.

[1]
Montgomery C, Couch C, Emory C, Nicholas R. Giant cell tumor of bone: Review of current literature, evaluation, and treatment options. J Knee Surg 2019; 32(4): 331-6.
[http://dx.doi.org/10.1055/s-0038-1675815] [PMID: 30449024]
[2]
Werner M. Giant cell tumour of bone: Morphological, biological and histogenetical aspects. Int Orthop 2006; 30(6): 484-9.
[http://dx.doi.org/10.1007/s00264-006-0215-7] [PMID: 17013643]
[3]
Lau CPY, Fung CSH, Wong KC, et al. Simvastatin possesses antitumor and differentiation-promoting properties that affect stromal cells in giant cell tumor of bone. J Orthop Res 2020; 38(2): 297-310.
[4]
Liu S, Ye F, Li D, He C, He H, Zhang J. p62 overexpression promotes neoplastic stromal cell proliferation and is associated with the recurrence of giant cell tumor of bone. Oncol Lett 2020; 20(4): 1.
[http://dx.doi.org/10.3892/ol.2020.11947] [PMID: 32863919]
[5]
Chen HT, Liu H, Mao MJ, et al. Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy. Mol Cancer 2019; 18(1): 101.
[http://dx.doi.org/10.1186/s12943-019-1030-2] [PMID: 31126310]
[6]
Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer 2017; 17(9): 528-42.
[http://dx.doi.org/10.1038/nrc.2017.53] [PMID: 28751651]
[7]
Folkerts H, Hilgendorf S, Vellenga E, Bremer E, Wiersma VR. The multifaceted role of autophagy in cancer and the microenvironment. Med Res Rev 2019; 39(2): 517-60.
[http://dx.doi.org/10.1002/med.21531] [PMID: 30302772]
[8]
Ferraresi A, Girone C, Esposito A, et al. How autophagy shapes the tumor microenvironment in ovarian cancer. Front Oncol 2020; 10: 599915.
[http://dx.doi.org/10.3389/fonc.2020.599915] [PMID: 33364196]
[9]
Aiello NM, Kang Y. Context-dependent EMT programs in cancer metastasis. J Exp Med 2019; 216(5): 1016-26.
[http://dx.doi.org/10.1084/jem.20181827] [PMID: 30975895]
[10]
Saitoh M. Involvement of partial EMT in cancer progression. J Biochem 2018; 164(4): 257-64.
[http://dx.doi.org/10.1093/jb/mvy047] [PMID: 29726955]
[11]
Guo S, Deng CX. Effect of stromal cells in tumor microenvironment on metastasis initiation. Int J Biol Sci 2018; 14(14): 2083-93.
[http://dx.doi.org/10.7150/ijbs.25720] [PMID: 30585271]
[12]
Chen F, Wang S, Wei Y, et al. Norcantharidin modulates the miR-30a/Metadherin/AKT signaling axis to suppress proliferation and metastasis of stromal tumor cells in giant cell tumor of bone. Biomed Pharmacother 2018; 103: 1092-100.
[13]
Lund H, Paus E, Berger P, et al. Epitope analysis and detection of human chorionic gonadotropin (hCG) variants by monoclonal antibodies and mass spectrometry. Tumour Biol 2014; 35(2): 1013-22.
[http://dx.doi.org/10.1007/s13277-013-1135-y] [PMID: 24014048]
[14]
Fitzhugh VA, Katava G, Wenokor C, Roche N, Beebe KS. Giant cell tumor of bone with secondary aneurysmal bone cyst-like change producing β-human chorionic gonadotropin. Skeletal Radiol 2014; 43(6): 831-4.
[http://dx.doi.org/10.1007/s00256-013-1785-2] [PMID: 24362936]
[15]
Lawless ME, Jour G, Hoch BL, Rendi MH. Beta-human chorionic gonadotropin expression in recurrent and metastatic giant cell tumors of bone: A potential mimicker of germ cell tumor. Int J Surg Pathol 2014; 22(7): 617-22.
[http://dx.doi.org/10.1177/1066896914534466] [PMID: 24831855]
[16]
Fellenberg J, Lehner B, Witte D. Silencing of the UCHL1 gene in giant cell tumors of bone. Int J Cancer 2010; 127(8): 1804-12.
[http://dx.doi.org/10.1002/ijc.25205] [PMID: 20104524]
[17]
Baryawno N. Taxonomy and use of bone marrow stromal cell. US Patent US20200208114, 2020.
[18]
Zhou X, Liu X, Fan G, Wu S, Zhao J, Shi X. Expression of matrix metalloproteinase-9 and CD34 in giant cell tumor of bone. Orthop Surg 2016; 8(2): 220-5.
[http://dx.doi.org/10.1111/os.12250] [PMID: 27384731]
[19]
Balla P, Maros ME, Barna G, et al. Prognostic impact of reduced connexin43 expression and gap junction coupling of neoplastic stromal cells in giant cell tumor of bone. PLoS One 2015; 10(5): e0125316.
[http://dx.doi.org/10.1371/journal.pone.0125316] [PMID: 25933380]
[20]
Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer 2017; 5(1): 53.
[http://dx.doi.org/10.1186/s40425-017-0257-y] [PMID: 28716061]
[21]
Walpurgis K, Thomas A, Vogel M, et al. Testing for the erythropoiesis-stimulating agent Sotatercept/ACE-011 (ActRIIA-Fc) in serum by means of Western blotting and LC-HRMS. Drug Test Anal 2016; 8(11-12): 1152-61.
[http://dx.doi.org/10.1002/dta.2093] [PMID: 27649383]
[22]
Chawla S, Blay JY, Rutkowski P, et al. Denosumab in patients with giant-cell tumour of bone: A multicentre, open-label, phase 2 study. Lancet Oncol 2019; 20(12): 1719-29.
[http://dx.doi.org/10.1016/S1470-2045(19)30663-1] [PMID: 31704134]
[23]
Ravegnini G, Sammarini G, Nannini M, et al. Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis. Autophagy 2017; 13(3): 452-63.
[http://dx.doi.org/10.1080/15548627.2016.1256522] [PMID: 28055310]
[24]
Pei T, Huang X, Long Y, et al. Increased expression of YAP is associated with decreased cell autophagy in the eutopic endometrial stromal cells of endometriosis. Mol Cell Endocrinol 2019; 491: 110432.
[http://dx.doi.org/10.1016/j.mce.2019.04.012] [PMID: 31014943]
[25]
Deng W, Li Y, Ren Z, et al. Thioredoxin-interacting protein: A critical link between autophagy disorders and pancreatic β-cell dysfunction. Endocrine 2020; 70(3): 526-37.
[http://dx.doi.org/10.1007/s12020-020-02471-6] [PMID: 32892310]
[26]
Gao Q. Oxidative stress and autophagy. Adv Exp Med Biol 2019; 1206: 179-98.
[http://dx.doi.org/10.1007/978-981-15-0602-4_9] [PMID: 31776986]
[27]
Lane HA. Bachmann, Use of phospho-Akt as a biomarker of drug response. Patent US10724072 B2, 2020.
[28]
Pang M, Wang H, Rao P, et al. Autophagy links β-catenin and Smad signaling to promote epithelial-mesenchymal transition via upregulation of integrin linked kinase. Int J Biochem Cell Biol 2016; 76: 123-34.
[http://dx.doi.org/10.1016/j.biocel.2016.05.010] [PMID: 27177845]
[29]
Lee SJ, Lehar A, Liu Y, et al. Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A. Proc Natl Acad Sci USA 2020; 117(49): 30907-17.
[http://dx.doi.org/10.1073/pnas.2019263117] [PMID: 33219121]
[30]
Fennen M, Pap T, Dankbar B. Smad-dependent mechanisms of inflammatory bone destruction. Arthritis Res Ther 2016; 18(1): 279.
[http://dx.doi.org/10.1186/s13075-016-1187-7] [PMID: 27906049]
[31]
Bugni T, Zhang F, Braw D, Ananiev G, Hoffman FM. Biemamides and related scaffolds as inhibitors of transforming growth factor-beta signaling. Patent US10889551, 2021.
[32]
Thomas D, Henshaw R, Skubitz K, et al. Denosumab in patients with giant-cell tumour of bone: An open-label, phase 2 study. Lancet Oncol 2010; 11(3): 275-80.
[http://dx.doi.org/10.1016/S1470-2045(10)70010-3] [PMID: 20149736]
[33]
Zhou Z, Li Y, Wang X, et al. ALCAM+ stromal cells: Role in giant cell tumor of bone progression. Cell Death Dis 2018; 9(3): 299.
[http://dx.doi.org/10.1038/s41419-018-0361-z] [PMID: 29463803]
[34]
Wang Y, Zhang Y, Li MQ, et al. Interleukin-25 induced by human chorionic gonadotropin promotes the proliferation of decidual stromal cells by activation of JNK and AKT signal pathways. Fertil Steril 2014; 102(1): 257-63.
[http://dx.doi.org/10.1016/j.fertnstert.2014.03.025] [PMID: 24746746]
[35]
Vara-Perez M, Felipe-Abrio B, Agostinis P. Mitophagy in cancer: A tale of adaptation. Cells 2019; 8(5): 493.
[http://dx.doi.org/10.3390/cells8050493] [PMID: 31121959]
[36]
Mak IWY, Cowan RW, Popovic S, Colterjohn N, Singh G, Ghert M. Upregulation of MMP-13 via Runx2 in the stromal cell of giant cell tumor of bone. Bone 2009; 45(2): 377-86.
[http://dx.doi.org/10.1016/j.bone.2009.04.253] [PMID: 19422937]
[37]
Dash S, Sarashetti PM, Rajashekar B, Chowdhury R, Mukherjee S. TGF-β2-induced EMT is dampened by inhibition of autophagy and TNF-α treatment. Oncotarget 2018; 9(5): 6433-49.
[http://dx.doi.org/10.18632/oncotarget.23942] [PMID: 29464083]
[38]
Tong H, Yin H, Hossain MA, et al. Starvation‐induced autophagy promotes the invasion and migration of human bladder cancer cells via TGF‐β1/Smad3‐mediated epithelial‐mesenchymal transition activation. J Cell Biochem 2019; 120(4): 5118-27.
[http://dx.doi.org/10.1002/jcb.27788] [PMID: 30320898]
[39]
Moustakas A, Souchelnytskyi S, Heldin CH. Smad regulation in TGF-β signal transduction. J Cell Sci 2001; 114(24): 4359-69.
[http://dx.doi.org/10.1242/jcs.114.24.4359] [PMID: 11792802]
[40]
Philip B, Lu Z, Gao Y. Regulation of GDF-8 signaling by the p38 MAPK. Cell Signal 2005; 17(3): 365-75.
[http://dx.doi.org/10.1016/j.cellsig.2004.08.003] [PMID: 15567067]
[41]
Mahmoudabady M, Mathieu M, Dewachter L, et al. Activin-A, transforming growth factor-beta, and myostatin signaling pathway in experimental dilated cardiomyopathy. J Card Fail 2008; 14(8): 703-9.
[http://dx.doi.org/10.1016/j.cardfail.2008.05.003] [PMID: 18926443]

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