scholarly journals Label-free quantitative identification of abnormally ubiquitinated proteins as useful biomarkers for human lung squamous cell carcinomas

2020 ◽  
Vol 11 (1) ◽  
pp. 73-94 ◽  
Author(s):  
Miaolong Lu ◽  
Wei Chen ◽  
Wei Zhuang ◽  
Xianquan Zhan
Keyword(s):  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Interaction Network ◽  
Molecular Network ◽  
Label Free ◽  
Ubiquitinated Protein ◽  
Network Systems ◽  
Cell Lung Carcinoma ◽  
E3 Ligases ◽  
Ubiquitinated Proteins

Abstract Background Ubiquitination is an important molecular event in lung squamous cell carcinoma (LSCC), which currently is mainly studied in nonsmall cell lung carcinoma cell models but lacking of ubiquitination studies on LSCC tissues. Here, we presented the ubiquitinated protein profiles of LSCC tissues to explore ubiquitination-involved molecular network alterations and identify abnormally ubiquitinated proteins as useful biomarkers for predictive, preventive, and personalized medicine (PPPM) in LSCC. Methods Anti-ubiquitin antibody-based enrichment coupled with LC-MS/MS was used to identify differentially ubiquitinated proteins (DUPs) between LSCC and control tissues, followed by integrative omics analyses to identify abnormally ubiquitinated protein biomarkers for LSCC. Results Totally, 400 DUPs with 654 ubiquitination sites were identified,, and motifs A-X (1/2/3)-K* were prone to be ubiquitinated in LSCC tissues. Those DUPs were involved in multiple molecular network systems, including the ubiquitin–proteasome system (UPS), cell metabolism, cell adhesion, and signal transduction. Totally, 44 hub molecules were revealed by protein–protein interaction network analysis, followed by survival analysis in TCGA database (494 LSCC patients and 20,530 genes) to obtain 18 prognosis-related mRNAs, of which the highly expressed mRNAs VIM and IGF1R were correlated with poorer prognosis, while the highly expressed mRNA ABCC1 was correlated with better prognosis. VIM-encoded protein vimentin and ABCC1-encoded protein MRP1 were increased in LSCC, which were all associated with poor prognosis. Proteasome-inhibited experiments demonstrated that vimentin and MRP1 were degraded through UPS. Quantitative ubiquitinomics found ubiquitination level was decreased in vimentin and increased in MRP1 in LSCC. These findings showed that the increased vimentin in LSCC might be derived from its decreased ubiquitination level and that the increased MRP1 in LSCC might be derived from its protein synthesis > degradation. GSEA and co-expression gene analyses revealed that VIM and MRP1 were involved in multiple crucial biological processes and pathways. Further, TRIM2 and NEDD4L were predicted as E3 ligases to regulate ubiquitination of vimentin and MRP1, respectively. Conclusion These findings revealed ubiquitinomic variations and molecular network alterations in LSCC, which is in combination with multiomics analysis to identify ubiquitination-related biomarkers for in-depth insight into the molecular mechanism and therapeutic targets and for prediction, diagnosis, and prognostic assessment of LSCC.

scholarly journals Abnormal Ubiquitination of Ubiquitin-Proteasome System in Lung Squamous Cell Carcinomas

2020 ◽  
Author(s):  
Xianquan Zhan ◽  
Miaolong Lu
Keyword(s):  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Lung Squamous Cell Carcinoma ◽  
Ubiquitin Proteasome System ◽  
Quantitative Information ◽  
Scientific Data ◽  
Label Free ◽  
Ubiquitinated Proteins ◽  
The Status ◽  
Ubiquitin Proteasome

Ubiquitination is an important post-translational modification. Abnormal ubiquitination is extensively associated with cancers. Lung squamous cell carcinoma (LUSC) is the most common pathological type of lung cancer, with unclear molecular mechanism and the poor overall prognosis of LUSC patient. To uncover the existence and potential roles of ubiquitination in LUSC, label-free quantitative ubiquitomics was performed in human LUSC vs. control tissues. In total, 627 ubiquitinated proteins (UPs) with 1209 ubiquitination sites were identified, including 1133 (93.7%) sites with quantitative information and 76 (6.3%) sites with qualitative information. KEGG pathway enrichment analysis found that UPs were significantly enriched in ubiquitin-mediated proteolysis pathway (hsa04120) and proteasome complex (hsa03050). Further analysis of 400 differentially ubiquitinated proteins (DUPs) revealed that 11 subunits of the proteasome complex were differentially ubiquitinated. These findings clearly demonstrated that ubiquitination was widely present in the ubiquitin-proteasome pathway in LUSCs. At the same time, abnormal ubiquitination might affect the function of the proteasome to promote tumorigenesis and development. This book chapter discussed the status of protein ubiquitination in the ubiquitin-proteasome system (UPS) in human LUSC tissues, which offered the scientific data to elucidate the specific molecular mechanisms of abnormal ubiquitination during canceration and the development of anti-tumor drugs targeting UPS.

scholarly journals USP28 deletion and small molecule inhibition destabilises c-Myc and elicits regression of squamous cell lung carcinoma

2020 ◽  
Author(s):  
E. Josue Ruiz ◽  
Adan Pinto-Fernandez ◽  
Andrew P. Turnbull ◽  
Linxiang Lan ◽  
Thomas M. Charlton ◽  
...  
Keyword(s):  
Small Molecule ◽  
Squamous Cell ◽  
Lung Carcinoma ◽  
Treatment Options ◽  
Lung Squamous Cell Carcinoma ◽  
Squamous Cell Lung Carcinoma ◽  
Cell Lung Carcinoma ◽  
Small Molecule Inhibition ◽  
Promising Therapeutic Target ◽  
Specific Protease

AbstractLung squamous cell carcinoma (LSCC) is a considerable global health burden with an incidence of over 600,000 cases per year. Treatment options are limited, and patient 5-year survival rate is less than 5%. The ubiquitin specific protease 28 (USP28) has been implicated in tumorigenesis through its stabilization of the oncoprotein c-MYC. Here, we show that genetic inactivation of USP28 induced regression of established murine LSCC lung tumors. We developed a small molecule USP28 inhibitor that interfered with USP28 activity in the low nanomole range. While displaying considerable activity against the closest homologue, USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-Myc proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumors and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.

scholarly journals Case Report: Partial Response Following Nivolumab Plus Docetaxel in a Patient With EGFR Exon 20 Deletion/Insertion (p.N771delinsGF) Mutant Lung Adenocarcinoma Transdifferentiated From Squamous Cell Carcinoma

2022 ◽  
Vol 9 ◽  
Author(s):  
Lingling Zhu ◽  
Yanyang Liu ◽  
Honglin Gao ◽  
Jiewei Liu ◽  
Qinghua Zhou ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Lung Adenocarcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Small Cell Lung Carcinoma ◽  
Lung Squamous Cell Carcinoma ◽  
Insertion Mutation ◽  
Cell Lung Carcinoma ◽  
Histological Transformation ◽  
Exon 20

The histological transformation from lung squamous cell carcinoma (LUSC) to lung adenocarcinoma (LUAD) and p. N771delinsGF mutations in EGFR exon 20 (ex20) are exceedingly rare in non–small cell lung carcinoma (NSCLC). EGFR ex20 mutations are insensitive to EGFR tyrosine kinase inhibitors in NSCLC. Here, we present a 76-year-old male smoker harboring LUAD with a novel p. N771delinsGF deletion/insertion mutation in EGFR ex20 transdifferentiating from advanced LUSC after chemoradiotherapy. The patient presented reduced hydrothorax and relieved tightness with the treatment of nivolumab plus docetaxel and carboplatin after the failure of second-line chemotherapy. The case highlights the importance of rebiopsy and molecular retesting after the progression of lung cancer and supports the idea that the combination of immune checkpoint blockade and chemotherapy may be an attractive option for patients with EGFR ex20 mutations associated with LUSC–LUAD transformation.

scholarly journals USP28 deletion and small molecule inhibition destabilises c-MYC and elicits regression of squamous cell lung carcinoma

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
E Josue Ruiz ◽  
Adan Pinto-Fernandez ◽  
Andrew P Turnbull ◽  
Linxiang Lan ◽  
Thomas M Charlton ◽  
...  
Keyword(s):  
Small Molecule ◽  
Squamous Cell ◽  
Lung Carcinoma ◽  
Treatment Options ◽  
Lung Squamous Cell Carcinoma ◽  
Cross Reactivity ◽  
Squamous Cell Lung Carcinoma ◽  
Cell Lung Carcinoma ◽  
Promising Therapeutic Target ◽  
Specific Protease

Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient 5-year survival rate is less than 5%. The ubiquitin specific protease 28 (USP28) has been implicated in tumorigenesis through its stabilization of the oncoproteins c-MYC, c-JUN and Dp63. Here, we show that genetic inactivation of Usp28 induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN and Dp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumors and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.

Thyroid hormone receptor α1 acts as a new squamous cell lung cancer diagnostic marker and poor prognosis predictor: Can it be a novel therapeutic target?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20508-e20508
Author(s):  
Fatma El Zahraa Ammar Mohamed ◽  
Ali Omar Abdelaziz ◽  
Ahmed Hussein Kasem ◽  
Tarek Ellethy ◽  
Mariana Fathy Gayyed
Keyword(s):  
Lung Cancer ◽  
Thyroid Hormone ◽  
Squamous Cell ◽  
Cell Lung Cancer ◽  
Therapeutic Target ◽  
Hormone Receptor ◽  
Poor Prognosis ◽  
Thyroid Hormone Receptor ◽  
Lung Squamous Cell Carcinoma ◽  
Cell Lung Carcinoma

e20508 Background: Lung cancer is considered the first cause of cancer-related death worldwide. Unfortunately, all therapeutic regimens used in lung cancer treatment showed relatively equivalent efficacy. The search and subsequent testing of new therapeutic targets that can be used alternative to, after the failure of or in association with the currently used therapeutics to improve the prognosis is an urgent demand and consequently a very interesting era of oncological lung research. Up to date, it is known that Thyroid hormones and Thyroid hormone receptors (THRs) controls many tumors progression, nevertheless, its role in non-Small Cell Lung cancer (NSCLC) is not yet defineltly understood. This study investigated the expression of Thyroid hormone receptor alpha 1 (THRα1) in NSCLC cases. Methods: Immunohistochemistry using THRα1 antibody was performed on tissue sections collected from 80 patients diagnosed with NSCLC. We also analyzed the expression of THRα gene in Microarrays of squamous cell lung carcinoma (SCC) and adenocarcinoma (AC) patients by using GEO datasets on https://www.ncbi.nlm.nih.gov. Results: We showed, for the first time, the expression of THRa1 in NSCLC. Intermediate and high THRa1 expression was detected in (25% and 66.7%) of SCC cases respectively. High THRa1 expression was associated with shorter OS and poor prognosis. On the other hand, 86.7% of AC cases revealed low THRa1expression. By analyzing GEO data sets, a significant increase in THRa gene value was found in SCC compared to AC cases. Inflammatory cells in SCC cases showed high THRα1 expression. Conclusions: Our study is shedding a new light on the relevance of THRα1 in lung cancer not only as a possible prognostic marker but also as an innovative diagnostic additive tool for lung squamous cell carcinoma which could be tested as a therapeutic target as well.

Investigation of Targeting Relationship between Micro-Rna-22 and Vegfr3 in Lung Squamous Cell Carcinoma

2020 ◽  
Vol 23 ◽  
Author(s):  
Zheng Dong ◽  
Qing-Hua Xu ◽  
Yuan-Bin Zhu ◽  
Yong-Feng Wang ◽  
Jie Xiong ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Luciferase Reporter ◽  
Control Group ◽  
Vascular Endothelial ◽  
Luciferase Reporter Gene ◽  
Endothelial Growth Factor

Aims : The present study explored the clinical significance of microRNA-22 (miR-22) expression in lung squamous cell carcinoma and to explore the targeting relationship with vascular endothelial growth factor receptor 3 (VEGFR3). Methods: A total of 49 patients with lung squamous cell carcinoma who underwent surgical treatment was selected. The expression of miR-22 was detected by fluorescence quantitative real-time PCR (qPCR), the expression of VEGFR3 was detected by Western blotting assays, and D240 labeled microlymphatic vessels density (MLVD) was detected immunohistochemistry (IHC). Lung squamous cell carcinoma cell line SK-MES-1 was selected and the targeting relationship between miR-22 and VEGFR3 was analyzed by double luciferase reporter gene assay. Western blotting assays were used to detect the expression of vascular endothelial growth factor-D (VEGF-D) and D240 in the blank control group, empty vector transfection group, miR-22 transfection group, miR-22 and VEGFR3 co-transfection group. Results: The expression range of miR-22 in lung squamous cell carcinoma was 0.8-3.5. The expression of miR-22 in lung squamous cell carcinoma was significantly different by tumor maximum diameter, lymph node metastasis, vascular invasion and TNM stage. The expression of miR-22 was linked to survival time. There was a negative correlation between miR-22 and VEGFR3, miR-22 and MLVD. Double luciferase reporter gene assays showed that miR-22 reduced the luciferase activity of pGL3-VEGFR3-WT transfected cells. Compared with the control group, the expression of VEGF-D and D2-40 in the miR-22 transfection group was significantly decreased. However, VEGF-D and D240 in the miR-22 and VEGFR3 cotransfection group reversed the changes. Conclusion: We assumed that the abnormal expression of miR-22 in lung squamous cell carcinoma may be involved in the development and progression of lung squamous cell carcinoma. MiR-22 negatively regulated the target gene VEGFR3 to mediate lymphangiogenesis. The expression of miR-22 may also be linked to the prognosis of the disease.

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