論文 - 詳細
| RRC ID | 79349 |
|---|---|
| 著者 | Su Y, Meng L, Ge C, Liu Y, Zhang C, Yang Y, Tian W, Tian H. |
| タイトル | PSMD9 promotes the malignant progression of hepatocellular carcinoma by interacting with c-Cbl to activate EGFR signaling and recycling. |
| ジャーナル | J Exp Clin Cancer Res |
| 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. |
| 巻・号 | 43(1) |
| ページ | 142 |
| 公開日 | 2024-5-14 |
| DOI | 10.1186/s13046-024-03062-3 |
| PII | 10.1186/s13046-024-03062-3 |
| PMID | 38745188 |
| PMC | PMC11092260 |
| MeSH | Animals Apoptosis Carcinoma, Hepatocellular* / genetics Carcinoma, Hepatocellular* / metabolism Carcinoma, Hepatocellular* / pathology Cell Line, Tumor Cell Movement Cell Proliferation Disease Progression* ErbB Receptors* / genetics ErbB Receptors* / metabolism Female Humans Liver Neoplasms* / genetics Liver Neoplasms* / metabolism Liver Neoplasms* / pathology Male Mice Mice, Nude Middle Aged Prognosis Proteasome Endopeptidase Complex / metabolism Proto-Oncogene Proteins c-cbl* / genetics Proto-Oncogene Proteins c-cbl* / metabolism Signal Transduction* |
| IF | 7.068 |
| リソース情報 | |
| ヒト・動物細胞 | HuH-7(RCB1366) |