USP8-Dependent Family Tyrosine Kinase Promotes the Malignant Progression of Esophageal Squamous Cell Carcinoma by Upregulating Protein Tyrosine Kinase 2 Expression

Overview

Journal Thorac Cancer

Specialties Oncology
Pulmonary Medicine

Date 2024 Dec 20

PMID 39702934

Authors

Yuechang Wu

Dubiao Xian

Yunzhong Liu

Ding Huang

Qingfeng Liu

Shubo Yang

Affiliations

Soon will be listed here.

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is a lethal malignancy, and the molecular underpinnings of its aggressive behavior are not fully understood. FYN proto-oncogene, Src family tyrosine kinase (FYN) has been linked to cancer progression, yet its role in ESCC remains elusive. This study investigated the influence of FYN on ESCC malignancy.

Methods: Quantitative real-time polymerase chain reaction was used to assess the mRNA expression of FYN, while western blotting and immunohistochemistry (IHC) assays were performed to detect the protein expression of FYN, ubiquitin specific peptidase 8 (USP8) and protein tyrosine kinase 2 (PTK2). Cell viability was measured with a cell counting kit-8 assay, and cell apoptosis was evaluated using flow cytometry.

Results: FYN expression was increased in ESCC tissues and cells when compared with normal esophageal tissues and normal esophageal epithelial cells. Knockdown of FYN inhibited cell invasion, migration, stem-like traits, and glycolysis, while promoting apoptosis. USP8 was shown to stabilize FYN protein expression through its deubiquitinating activity in ESCC cells. Overexpression of FYN reversed the effects of USP8 silencing on the malignant phenotypes of ESCC cells in vitro and in vivo. FYN upregulated PTK2 expression in both TE1 and KYSE150 cell lines. Furthermore, PTK2 overexpression reversed the effects of FYN silencing on the malignant phenotypes of ESCC cells. Further, USP8 silencing-induced inhibitory effect on PTK2 protein expression was counteracted after FYN overexpression.

Conclusion: USP8-dependent FYN contributed to the malignant progression of ESCC by interacting with PTK2. Targeting this pathway may offer a novel therapeutic strategy for ESCC treatment.

References

Liu D, Gao M, Wu K, Zhu D, Yang Y, Zhao S . LINC00152 facilitates tumorigenesis in esophageal squamous cell carcinoma via miR-153-3p/FYN axis. Biomed Pharmacother. 2019; 112:108654. DOI: 10.1016/j.biopha.2019.108654. View

Goldsmith J, Hall C, Atkinson T . Identification of an alternatively spliced isoform of the fyn tyrosine kinase. Biochem Biophys Res Commun. 2002; 298(4):501-4. DOI: 10.1016/s0006-291x(02)02510-x. View

Xiong W, Gao X, Zhang T, Jiang B, Hu M, Bu X . USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy. Nat Commun. 2022; 13(1):1700. PMC: 8971425. DOI: 10.1038/s41467-022-29401-6. View

Chen W, Zhong M, Yu J, Xie R, Zhou T, Zhang S . KMT2B promotes SHPRH expression to regulate I sensitivity in thyroid carcinoma cells by affecting FYN protein stability. Cell Signal. 2021; 88:110165. DOI: 10.1016/j.cellsig.2021.110165. View

Hagymasi K, Tulassay Z . [Risk factors for esophageal cancer, and possible genetic background]. Orv Hetil. 2009; 150(9):407-13. DOI: 10.1556/OH.2009.28558. View

Xie F, Zhou X, Li H, Su P, Liu S, Li R . USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-β receptor TβRII. EMBO J. 2022; 41(16):e108791. PMC: 9379553. DOI: 10.15252/embj.2021108791. View

Durcan T, Tang M, Perusse J, Dashti E, Aguileta M, McLelland G . USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin. EMBO J. 2014; 33(21):2473-91. PMC: 4283406. DOI: 10.15252/embj.201489729. View

Wang Y, Lyu Z, Qin Y, Wang X, Sun L, Zhang Y . FOXO1 promotes tumor progression by increased M2 macrophage infiltration in esophageal squamous cell carcinoma. Theranostics. 2020; 10(25):11535-11548. PMC: 7546008. DOI: 10.7150/thno.45261. View

Sheikh M, Roshandel G, McCormack V, Malekzadeh R . Current Status and Future Prospects for Esophageal Cancer. Cancers (Basel). 2023; 15(3). PMC: 9913274. DOI: 10.3390/cancers15030765. View

10.

Qiu Y, Fang B, Thuy N, Li A, Yoo H, Zheng X . Narciclasine suppresses esophageal cancer cell proliferation and migration by inhibiting the FAK signaling pathway. Eur J Pharmacol. 2022; 921:174669. DOI: 10.1016/j.ejphar.2021.174669. View

11.

Islam M, Chen F, Chen H . The oncogenic role of ubiquitin specific peptidase (USP8) and its signaling pathways targeting for cancer therapeutics. Arch Biochem Biophys. 2021; 701:108811. DOI: 10.1016/j.abb.2021.108811. View

12.

Ma G, Jing C, Li L, Huang F, Ding F, Wang B . MicroRNA-92b represses invasion-metastasis cascade of esophageal squamous cell carcinoma. Oncotarget. 2016; 7(15):20209-22. PMC: 4991448. DOI: 10.18632/oncotarget.7747. View

13.

Li S, Liu C, Tang Y . Role of Fyn in hematological malignancies. J Cancer Res Clin Oncol. 2023; 149(9):6759-6767. DOI: 10.1007/s00432-023-04608-2. View

14.

Bray F, Laversanne M, Sung H, Ferlay J, Siegel R, Soerjomataram I . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3):229-263. DOI: 10.3322/caac.21834. View

15.

Cui J, Guo Y, Yin T, Gou S, Xiong J, Liang X . USP8 promotes gemcitabine resistance of pancreatic cancer via deubiquitinating and stabilizing Nrf2. Biomed Pharmacother. 2023; 166:115359. DOI: 10.1016/j.biopha.2023.115359. View

16.

Chu A, Sun C, Liu Z, Liu S, Li M, Song R . Circ-POSTN promotes the progression and reduces radiosensitivity in esophageal cancer by regulating the miR-876-5p/FYN axis. Thorac Cancer. 2024; 15(13):1082-1094. PMC: 11062886. DOI: 10.1111/1759-7714.15273. View

17.

Zhou X, Li Y, Wang W, Wang S, Hou J, Zhang A . Regulation of Hippo/YAP signaling and Esophageal Squamous Carcinoma progression by an E3 ubiquitin ligase PARK2. Theranostics. 2020; 10(21):9443-9457. PMC: 7449928. DOI: 10.7150/thno.46078. View

18.

Li L, Liu Y, Zhao Y, Feng R, Li Y, Yu X . Deubiquitinase USP8 increases ID1 stability and promotes esophageal squamous cell carcinoma tumorigenesis. Cancer Lett. 2022; 542:215760. DOI: 10.1016/j.canlet.2022.215760. View

19.

Sha B, Sun Y, Zhao S, Li M, Huang W, Li Z . USP8 inhibitor-induced DNA damage activates cell cycle arrest, apoptosis, and autophagy in esophageal squamous cell carcinoma. Cell Biol Toxicol. 2022; 39(5):2011-2032. DOI: 10.1007/s10565-021-09686-x. View

20.

Rao N, Ghosh A, Douillard P, Andoniou C, Zhou P, Band H . An essential role of ubiquitination in Cbl-mediated negative regulation of the Src-family kinase Fyn. Signal Transduct. 2009; 2(1-2):29-39. PMC: 2788922. DOI: 10.1002/1615-4061(200205)2:1/2<29::AID-SITA29>3.0.CO;2-7. View