DUSP3 Restrains the Progression and Stemness Property of Osteosarcoma Through Regulating EGFR/STAT3/SOX2 Axis

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2025 Jan 2

PMID 39744427

Authors

Zhun Wei

Di Zheng

Kezhou Xia

Xinghan Huang

Wenda Liu

Zicheng Wei

Weichun Guo

Affiliations

Soon will be listed here.

Abstract

Dual-specificity phosphatase 3 (DUSP3) is a small-molecule dual-specificity phosphatase whose function has not yet been elucidated. This study investigated the effects of DUSP3 on the biological behavior of osteosarcoma and its potential mechanisms. We performed bioinformatics analysis of DUSP3 using "The Cancer Genome Atlas" and "The Tumor Immune Estimation Resource" databases. The impact of DUSP3 on osteosarcoma biological behavior was evaluated using CCK-8, wound-healing, transwell invasion, and tumor sphere formation assays. Immunoprecipitation assays confirmed the interaction between two proteins. We then established a nude mouse transplantation tumor model to examine the in effects of DUSP3 on osteosarcoma. Overexpression of DUSP3 significantly inhibited osteosarcoma cell proliferation, migration, invasion, and stemness. Conversely, DUSP3 knockdown yielded the opposite results. In an animal model, we administered subcutaneous injections of 143B osteosarcoma cells overexpressing DUSP3, and the results indicated that the overexpression of DUSP3 impaired osteosarcoma growth. Our findings indicate that DUSP3 could be an independent prognostic determinant in individuals diagnosed with osteosarcoma. Through modulating the EGFR/STAT3/SOX2 axis, DUSP3 restrains osteosarcoma cell growth, migration, invasion, and stemness. Therefore, targeting DUSP3 may serve as an effective therapeutic target in osteosarcoma treatment.

References

Jiang L, Zhao X, Mao Y, Wang J, Zheng H, You Q . Long non-coding RNA RP11-468E2.5 curtails colorectal cancer cell proliferation and stimulates apoptosis via the JAK/STAT signaling pathway by targeting STAT5 and STAT6. J Exp Clin Cancer Res. 2019; 38(1):465. PMC: 6852742. DOI: 10.1186/s13046-019-1428-0. View

Rosado-Galindo H, Domenech M . Surface roughness modulates EGFR signaling and stemness of triple-negative breast cancer cells. Front Cell Dev Biol. 2023; 11:1124250. PMC: 10030610. DOI: 10.3389/fcell.2023.1124250. View

Kansara M, Teng M, Smyth M, Thomas D . Translational biology of osteosarcoma. Nat Rev Cancer. 2014; 14(11):722-35. DOI: 10.1038/nrc3838. View

Wang Z, Yin F, Xu J, Zhang T, Wang G, Mao M . CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma. J Exp Clin Cancer Res. 2019; 38(1):44. PMC: 6357486. DOI: 10.1186/s13046-019-1047-9. View

Guo N, Zheng D, Sun J, Lv J, Wang S, Fang Y . NAP1L5 Promotes Nucleolar Hypertrophy and Is Required for Translation Activation During Cardiomyocyte Hypertrophy. Front Cardiovasc Med. 2022; 8:791501. PMC: 8718910. DOI: 10.3389/fcvm.2021.791501. View

Valverde A, Penarando J, Canas A, Lopez-Sanchez L, Conde F, Hernandez V . Simultaneous inhibition of EGFR/VEGFR and cyclooxygenase-2 targets stemness-related pathways in colorectal cancer cells. PLoS One. 2015; 10(6):e0131363. PMC: 4479446. DOI: 10.1371/journal.pone.0131363. View

Gao X, Xia X, Li F, Zhang M, Zhou H, Wu X . Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling. Nat Cell Biol. 2021; 23(3):278-291. DOI: 10.1038/s41556-021-00639-4. View

Lu X, An L, Fan G, Zang L, Huang W, Li J . EGFR signaling promotes nuclear translocation of plasma membrane protein TSPAN8 to enhance tumor progression via STAT3-mediated transcription. Cell Res. 2022; 32(4):359-374. PMC: 8975831. DOI: 10.1038/s41422-022-00628-8. View

Gao W, Wen H, Liang L, Dong X, Du R, Zhou W . IL20RA signaling enhances stemness and promotes the formation of an immunosuppressive microenvironment in breast cancer. Theranostics. 2021; 11(6):2564-2580. PMC: 7806486. DOI: 10.7150/thno.45280. View

10.

Isakoff M, Bielack S, Meltzer P, Gorlick R . Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. J Clin Oncol. 2015; 33(27):3029-35. PMC: 4979196. DOI: 10.1200/JCO.2014.59.4895. View

11.

Singh P, Dejager L, Amand M, Theatre E, Vandereyken M, Zurashvili T . DUSP3 Genetic Deletion Confers M2-like Macrophage-Dependent Tolerance to Septic Shock. J Immunol. 2015; 194(10):4951-62. PMC: 4417402. DOI: 10.4049/jimmunol.1402431. View

12.

Chou H, Cheng C, Yang C, Lin T, Liu Y, Tan T . DUSP3 regulates phosphorylation-mediated degradation of occludin and is required for maintaining epithelial tight junction. J Biomed Sci. 2022; 29(1):40. PMC: 9199239. DOI: 10.1186/s12929-022-00826-x. View

13.

Chen P, Hsu W, Han J, Xia Y, DePinho R . Cancer Stemness Meets Immunity: From Mechanism to Therapy. Cell Rep. 2021; 34(1):108597. PMC: 7839836. DOI: 10.1016/j.celrep.2020.108597. View

14.

Yang Q, Zhao S, Shi Z, Cao L, Liu J, Pan T . Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling. J Exp Clin Cancer Res. 2021; 40(1):120. PMC: 8022546. DOI: 10.1186/s13046-021-01901-1. View

15.

Walcher L, Kistenmacher A, Suo H, Kitte R, Dluczek S, Strauss A . Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies. Front Immunol. 2020; 11:1280. PMC: 7426526. DOI: 10.3389/fimmu.2020.01280. View

16.

Levantini E, Maroni G, Del Re M, Tenen D . EGFR signaling pathway as therapeutic target in human cancers. Semin Cancer Biol. 2022; 85:253-275. DOI: 10.1016/j.semcancer.2022.04.002. View

17.

Khbouz B, Rowart P, Poma L, Dahlke E, Bottner M, Stokes M . The genetic deletion of the Dual Specificity Phosphatase 3 (DUSP3) attenuates kidney damage and inflammation following ischaemia/reperfusion injury in mouse. Acta Physiol (Oxf). 2021; 234(2):e13735. DOI: 10.1111/apha.13735. View

18.

Yang Z, Liu Z, Lu W, Guo H, Chen J, Zhang Y . LncRNA WAC-AS1 promotes osteosarcoma Metastasis and stemness by sponging miR-5047 to upregulate SOX2. Biol Direct. 2023; 18(1):74. PMC: 10644615. DOI: 10.1186/s13062-023-00433-2. View

19.

Chen Y, Wang T, Huang M, Liu Q, Hu C, Wang B . MAFB Promotes Cancer Stemness and Tumorigenesis in Osteosarcoma through a Sox9-Mediated Positive Feedback Loop. Cancer Res. 2020; 80(12):2472-2483. DOI: 10.1158/0008-5472.CAN-19-1764. View

20.

Zhang B, Yu L, Han N, Hu Z, Wang S, Ding L . LINC01116 targets miR-520a-3p and affects IL6R to promote the proliferation and migration of osteosarcoma cells through the Jak-stat signaling pathway. Biomed Pharmacother. 2018; 107:270-282. DOI: 10.1016/j.biopha.2018.07.119. View