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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2024 | Hepatocellular Carcinoma | Research

PSMD9 promotes the malignant progression of hepatocellular carcinoma by interacting with c-Cbl to activate EGFR signaling and recycling

Authors: Yuting Su, Lili Meng, Chao Ge, Yuqi Liu, Chi Zhang, Yue Yang, Wei Tian, Hua Tian

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

Abstract

Background

Mounting evidences shows that the ubiquitin‒proteasome pathway plays a pivotal role in tumor progression. The expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9) is correlated with recurrence and radiotherapy resistance in several tumor types. However, the role and mechanism of PSMD9 in hepatocellular carcinoma (HCC) progression remain largely unclear.

Methods

PSMD9 was identified as a prognosis-related biomarker for HCC based on analysis of clinical characteristics and RNA-seq data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and the JP Project of the International Cancer Genome Consortium (ICGC-LIRI-JP). PSMD9 expression was analyzed in cancer tissues and adjacent noncancerous tissues via immunohistochemistry and Western blotting. Multiple in vivo and in vitro experimental techniques (such as CCK-8, colony formation, EdU, and Transwell assays; flow cytometry; Western blotting; quantitative RT-PCR; Coimmunoprecipitation assay and immunofluorescence confocal imaging) were used to assess the functions of PSMD9 in the pathogenesis of HCC.

Results

We found that the expression of PSMD9 was upregulated and associated with a poor prognosis in HCC patients. PSMD9 promoted HCC cell proliferation, migration, invasion and metastasis. Knockdown of PSMD9 significantly inhibited HCC cell proliferation by inducing G1/S cell cycle arrest and apoptosis. Mechanistically, we demonstrated that PSMD9 promoted HCC cell proliferation and metastasis via direct interaction with the E3 ubiquitin ligase c-Cbl, suppresses EGFR ubiquitination, influenced EGFR endosomal trafficking and degradation and subsequently activated ERK1/2 and Akt signaling. In addition, we showed that PSMD9 knockdown sensitized HCC cells to the tyrosine kinase inhibitor erlotinib in vitro and in vivo.

Conclusions

Collectively, our results indicate that PSMD9 drives HCC progression and erlotinib resistance by suppressing c-Cbl mediated EGFR ubiquitination and therefore can be a potential therapeutic target for HCC.

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Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019;380:1450–62.CrossRefPubMed

Levantini E, Maroni G, Del Re M, Tenen DG. EGFR signaling pathway as therapeutic target in human cancers. Semin Cancer Biol. 2022;85:253–75.CrossRefPubMed

Singh M, Jadhav HR. Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors. Drug Discov Today. 2018;23:745–53.CrossRefPubMed

Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33:559–66.CrossRefPubMed

Mani A, Gelmann EP. The ubiquitin-proteasome pathway and its role in cancer. J Clin Oncol. 2005;23:4776–89.CrossRefPubMed

Collins GA, Goldberg AL. The Logic of the 26S Proteasome. Cell. 2017;169:792–806.CrossRefPubMedPubMedCentral

Majeed S, Aparnathi MK, Nixon KCJ, Venkatasubramanian V, Rahman F, Song L, et al. Targeting the Ubiquitin-Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer. Clin Cancer Res. 2022;28:1966–78.CrossRefPubMedPubMedCentral

Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017;14:417–33.CrossRefPubMedPubMedCentral

Jiang Z, Zhou Q, Ge C, Yang J, Li H, Chen T, et al. Rpn10 promotes tumor progression by regulating hypoxia-inducible factor 1 alpha through the PTEN/Akt signaling pathway in hepatocellular carcinoma. Cancer Lett. 2019;447:1–11.CrossRefPubMed

10.

Koster F, Sauer L, Hoellen F, Ribbat-Idel J, Brautigam K, Rody A, et al. PSMD9 expression correlates with recurrence after radiotherapy in patients with cervical cancer. Oncol Lett. 2020;20:581–8.CrossRefPubMedPubMedCentral

11.

Langlands FE, Dodwell D, Hanby AM, Horgan K, Millican-Slater RA, Speirs V, et al. PSMD9 expression predicts radiotherapy response in breast cancer. Mol Cancer. 2014;13:73.CrossRefPubMedPubMedCentral

12.

Zhao Y, Wen S, Li H, Pan CW, Wei Y, Huang T, et al. Enhancer RNA promotes resistance to radiotherapy in bone-metastatic prostate cancer by m(6)A modification. Theranostics. 2023;13:596–610.CrossRefPubMedPubMedCentral

13.

Ud Din Farooqee SB, Christie J, Venkatraman P. PSMD9 ribosomal protein network maintains nucleolar architecture and WT p53 levels. Biochem Biophys Res Commun. 2021;563:105–12

14.

Zhou Q, Huang T, Jiang Z, Ge C, Chen X, Zhang L, et al. Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway. Oncogene. 2020;39:2140–55.CrossRefPubMed

15.

Zhou Q, Tian W, Jiang Z, Huang T, Ge C, Liu T, et al. A Positive Feedback Loop of AKR1C3-Mediated Activation of NF-kappaB and STAT3 Facilitates Proliferation and Metastasis in Hepatocellular Carcinoma. Cancer Res. 2021;81:1361–74.CrossRefPubMed

16.

Sabbah DA, Hajjo R, Sweidan K. Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Curr Top Med Chem. 2020;20:815–34.CrossRefPubMed

17.

Hou J, Deng Q, Zhou J, Zou J, Zhang Y, Tan P, et al. CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR. Oncogene. 2017;36:1134–44.CrossRefPubMed

18.

Lin DC, Xu L, Chen Y, Yan H, Hazawa M, Doan N, et al. Genomic and Functional Analysis of the E3 Ligase PARK2 in Glioma. Cancer Res. 2015;75:1815–27.CrossRefPubMedPubMedCentral

19.

Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, et al. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell. 1999;4:1029–40.CrossRefPubMed

20.

Haglund K, Sigismund S, Polo S, Szymkiewicz I, Di Fiore PP, Dikic I. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol. 2003;5:461–6.CrossRefPubMed

21.

Gandolfi S, Laubach JP, Hideshima T, Chauhan D, Anderson KC, Richardson PG. The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev. 2017;36:561–84.CrossRefPubMed

22.

Zhang L, Wu M, Su R, Zhang D, Yang G. The Efficacy and Mechanism of Proteasome Inhibitors in Solid Tumor Treatment. Recent Pat Anticancer Drug Discov. 2022;17:268–83.CrossRefPubMed

23.

Li Y, Huang J, Zeng B, Yang D, Sun J, Yin X, et al. PSMD2 regulates breast cancer cell proliferation and cell cycle progression by modulating p21 and p27 proteasomal degradation. Cancer Lett. 2018;430:109–22.CrossRefPubMed

24.

Luo T, Fu J, Xu A, Su B, Ren Y, Li N, et al. PSMD10/gankyrin induces autophagy to promote tumor progression through cytoplasmic interaction with ATG7 and nuclear transactivation of ATG7 expression. Autophagy. 2016;12:1355–71.CrossRefPubMed

25.

Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011;11:558–72.CrossRefPubMed

26.

Lanaya H, Natarajan A, Komposch K, Li L, Amberg N, Chen L, et al. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat Cell Biol. 2014;16:972–7.CrossRefPubMedPubMedCentral

27.

Song S, Yu Z, You Y, Liu C, Xie X, Lv H, et al. EGFR/MET promotes hepatocellular carcinoma metastasis by stabilizing tumor cells and resisting to RTKs inhibitors in circulating tumor microemboli. Cell Death Dis. 2022;13:351.CrossRefPubMedPubMedCentral

28.

Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol. 2018;12:3–20.CrossRefPubMed

29.

Herber B, Truss M, Beato M, Muller R. Inducible regulatory elements in the human cyclin D1 promoter. Oncogene. 1994;9:1295–304.PubMed

30.

Tian H, Ge C, Li H, Zhao F, Hou H, Chen T, et al. Ribonucleotide reductase M2B inhibits cell migration and spreading by early growth response protein 1-mediated phosphatase and tensin homolog/Akt1 pathway in hepatocellular carcinoma. Hepatology. 2014;59:1459–70.CrossRefPubMed

31.

Tomas A, Futter CE, Eden ER. EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol. 2014;24:26–34.CrossRefPubMedPubMedCentral

32.

Berlin I, Sapmaz A, Stevenin V, Neefjes J. Ubiquitin and its relatives as wizards of the endolysosomal system. J Cell Sci. 2023;136(4):jcs260101.

33.

Tang R, Langdon WY, Zhang J. Negative regulation of receptor tyrosine kinases by ubiquitination: Key roles of the Cbl family of E3 ubiquitin ligases. Front Endocrinol (Lausanne). 2022;13: 971162.CrossRefPubMed

34.

Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res. 2006;12:6494–501.CrossRefPubMed

35.

Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–7.CrossRefPubMedPubMedCentral

36.

Narayanan S, Cai CY, Assaraf YG, Guo HQ, Cui Q, Wei L, et al. Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance. Drug Resist Updat. 2020;48: 100663.CrossRefPubMed

Title: PSMD9 promotes the malignant progression of hepatocellular carcinoma by interacting with c-Cbl to activate EGFR signaling and recycling
Authors: Yuting Su
Lili Meng
Chao Ge
Yuqi Liu
Chi Zhang
Yue Yang
Wei Tian
Hua Tian
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Erlotinib
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-024-03062-3

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Abstract

Background

Methods

Results

Conclusions

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