المؤلفون: Kai Yue, Yansheng Wu, Beibei Ye, Peng Chen, Qingchuan Lai, Xudong Wang, Chao Jing, Yue Wu, Mengqian Zhou, Yuansheng Duan, Xingchen Li, Xiaofeng Yao, Dandan Liu, Hong Li, Linqi Li, Shengchi Zhang

المصدر: Theranostics

مصطلحات موضوعية: Male, 0301 basic medicine, Esophageal Neoplasms, Carcinogenesis, Medicine (miscellaneous), Snail, medicine.disease_cause, Metastasis, Mice, 0302 clinical medicine, Cell Movement, PSMD14, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Mice, Inbred BALB C, biology, SNAIL, EMT, Esophageal cancer, Pyrrolidinones, Up-Regulation, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Chemosensitivity, Research Paper, medicine.drug, Proteasome Endopeptidase Complex, Epithelial-Mesenchymal Transition, Mice, Nude, Antineoplastic Agents, 03 medical and health sciences, Downregulation and upregulation, Esophageal squamous cell carcinoma, In vivo, Cell Line, Tumor, biology.animal, Biomarkers, Tumor, medicine, Animals, Humans, Neoplasm Invasiveness, Cell Proliferation, Cisplatin, business.industry, Ubiquitination, medicine.disease, Thiolutin, 030104 developmental biology, Trans-Activators, Cancer research, Snail Family Transcription Factors, business

الوصف: Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). DUB PSMD14 is reported to be a promising therapeutic target in various cancers. Here, we explored the antitumor activity of Thiolutin (THL), the PSMD14 inhibitor, as a new therapy strategy in ESCC. Methods: Through 4-NQO-induced murine ESCC model, we investigated the expression of PSMD14 in esophageal tumorigenesis. Ubiquitin-AMC assay was performed to evaluate DUB activity of PSMD14 with THL treatment. The effect of THL on epithelial-to-mesenchymal transition (EMT), invasion, stemness and chemosensitivity was detected by using in vitro and in vivo experiments. Immunoprecipitation and in vivo ubiquitination assay were conducted to examine whether THL could impair the deubiquitination and stability of SNAIL regulated by PSMD14. Results: Compared with normal esophageal epithelium, PSMD14 was upregulated in 4-NQO-induced murine esophageal epithelium dysplasia and ESCC tissues. THL could significantly weaken DUB activity of PSMD14. Furthermore, the results of in vitro and in vivo assays showed that THL efficiently suppressed motility and stemness and increased sensitivity to cisplatin in ESCC. Mechanically, THL impaired the interaction between PSMD14 and SNAIL, then promoted the ubiquitination and degradation of SNAIL to inhibit EMT which plays a crucial role in ESCC metastasis, stemness and chemosensitivity. TCGA database analysis revealed that high concomitant PSMD14/SNAIL expression predicted shorter overall survival in esophageal cancer. Conclusion: Our findings demonstrate for the first time that suppression of PSMD14/SNAIL axis by THL could be a novel and promising therapeutic approach for ESCC clinical therapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8c47c33d3831d41492d14a4c177dc6b7Test
https://doi.org/10.7150/thno.46109Test

المؤلفون: Xudong Wang, Mengqian Zhou, Wenchao Zhang, Hui Wei, Xiaofeng Yao, Beibei Ye, Chao Jing, Yuansheng Duan, Xingchen Li, Shanshan Zhuo, Kai Yue, Yansheng Wu, Dandan Liu, Linqi Li, Qingchuan Lai

المصدر: Theranostics

مصطلحات موضوعية: 0301 basic medicine, Carcinogenesis, Medicine (miscellaneous), medicine.disease_cause, Deubiquitinating enzyme, Mice, 0302 clinical medicine, PSMD14, E2F1, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Mice, Inbred BALB C, Deubiquitinating Enzymes, Prognosis, Pyrrolidinones, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Chemoresistance, medicine.drug, Research Paper, Proteasome Endopeptidase Complex, Mice, Nude, Biology, 03 medical and health sciences, stomatognathic system, Cell Line, Tumor, medicine, otorhinolaryngologic diseases, Animals, Humans, Protein kinase B, neoplasms, PI3K/AKT/mTOR pathway, Cell Proliferation, Squamous Cell Carcinoma of Head and Neck, SOXB1 Transcription Factors, Ubiquitination, Head and neck squamous cell carcinoma, medicine.disease, Thiolutin, Head and neck squamous-cell carcinoma, stomatognathic diseases, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, biology.protein, Trans-Activators, Chromatin immunoprecipitation, Proto-Oncogene Proteins c-akt, E2F1 Transcription Factor

الوصف: Increasing evidence reveals a close relationship between deubiquitinating enzymes (DUBs) and cancer progression. In this study, we attempted to identify the roles and mechanisms of critical DUBs in head and neck squamous cell carcinoma (HNSCC). Methods: Bioinformatics analysis was performed to screen differentially expressed novel DUBs in HNSCC. Immunohistochemistry assay was used to measure the expression of DUB PSMD14 in HNSCC specimens and adjacent normal tissues. The level of PSMD14 in HNSCC tumorigenesis was investigated using a 4-NQO-induced murine HNSCC model. The function of PSMD14 was determined through loss-of-function assays. Chromatin immunoprecipitation, immunoprecipitation and in vivo ubiquitination assay were conducted to explore the potential mechanism of PSMD14. The anti-tumor activity of PSMD14 inhibitor Thiolutin was assessed by in vitro and in vivo experiments. Results: We identified PSMD14 as one of significantly upregulated DUBs in HNSCC tissues. Aberrant expression of PSMD14 was associated with tumorigenesis and malignant progression of HNSCC and further indicated poor prognosis. The results of in vitro and in vivo experiments demonstrated PSMD14 depletion significantly undermined HNSCC growth, chemoresistance and stemness. Mechanically, PSMD14 inhibited the ubiquitination and degradation of E2F1 to improve the activation of Akt pathway and the transcription of SOX2. Furthermore, PSMD14 inhibitor Thiolutin exhibited a potent anti-tumor effect on HNSCC in vivo and in vitro by impairing DUB activity of PSMD14. Conclusion: Our findings demonstrate the role and mechanism of PSMD14 in HNSCC, and provide a novel and promising target for diagnosis and clinical therapy of HNSCC.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::41457b31fc40f3f3f83e381a98fab731Test
http://europepmc.org/articles/PMC7806466Test