High Expression of Ubiquitin C-terminal Hydrolase L1 Is Associated With Poor Prognosis in Endometrial Cancer Patients

Nakao, Kohshiro; Hirakawa, Takashi; Suwa, Hiroto; Kogure, Kayoko; Ikeda, Sadatomo; Yamashita, Soichi; Minegishi, Takashi; Kishi, Hiroshi

doi:10.1097/igc.0000000000001201

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…This raises the possibility that the increase in PADI2 we observe is a response to increased UCHL1 protein expression, or vice versa. While our research was ongoing, increased UCHL1 RNA expression was shown to be prognostic for poor overall survival for serous EC patients, 41 a result previously shown in a cohort of mostly endometrioid EC patients 42 . Immunohistochemical expression of UCHL1 in serous ECs and reduced proliferation and cell cycle progression with UCHL1 silencing were also published in this same report 41 .…”

Section: Discussionsupporting

confidence: 64%

“…While our research was ongoing, increased UCHL1 RNA expression was shown to be prognostic for poor overall survival for serous EC patients, 41 a result previously shown in a cohort of mostly endometrioid EC patients. 42 Immunohistochemical expression of UCHL1 in serous ECs and reduced proliferation and cell cycle progression with UCHL1 silencing were also published in this same report. 41 Our results provide the additional novel insight that UCHL1 expression is affected by FBXW7 mutation.…”

Section: Discussionmentioning

confidence: 52%

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Proteomic profiling of FBXW7‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

Urick

Bell

2020

Cancer Medicine

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Background:Despite advancements over the past decade revealing molecular aberrations characteristic of endometrial cancer (EC) subtypes, serous ECs remain difficult to treat and associated with poor outcomes. This is due, in part, to the rarity of these tumors within clinical trials and the inability to directly target the most frequent genomic abnormalities. One of the most commonly somatically mutated genes in serous ECs is the tumor suppressor F-box and WD repeat domain containing 7 (FBXW7). Methods: To identify changes in protein expression associated with FBXW7 mutation, we clustered regularly interspaced short palindromic repeats (CRISPR)-edited ARK4 FBXW7 nonmutant serous EC cells to insert recurrent FBXW7 mutations. We then compared the liquid chromatography tandem mass spectrometry-based proteomic profiles of CRISPR-edited ARK1 and ARK4 serous EC cells to matched parental cells. Results: Among distinct total and phosphorylated proteins that were significantly differentially expressed in FBXW7-mutant cell lines compared to matched parental lines, we identified increased PADI2 (peptidyl arginine deiminase 2) expression in all ARK1 and ARK4 CRISPR-edited FBXW7-mutant cell lines. We further confirmed the correlation between FBXW7 mutation and increased PADI2 expression in a third biological background, JHUEM-1 endometrioid EC cells. Finally, we established that PADI2 protein is expressed in primary serous endometrial tumors. Conclusion: Our findings provide novel insight into proteomic changes associated with FBXW7 mutation in serous ECs and identify PADI2 as a novel potential therapeutic target for these tumors.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 52%

Proteomic profiling of FBXW7‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

Urick

Bell

2020

Cancer Medicine

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“…What appeals to us is that despite participation in glucose metabolism, PYCR1 also plays a role in proline metabolism [39] and thus it's worth more comprehensive insights into its molecular functions. Different from PYCR1, whether UCHL1 is an oncogene or a tumor-suppressor depends on types of cancer [40][41][42][43][44]. However, similar to our findings, an article indicated that prognosis of renal cell carcinoma was associated with alterations of UCHL1 promoter methylation [44].…”

Section: Discussionsupporting

confidence: 83%

A signature of glucose metabolism and DNA methylation improves prognostic prediction for urinary bladder cancer

Liu

Sun

Zhang

et al. 2020

Preprint

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Background: Glucose metabolism and DNA methylation have been previously proved to play important roles in cancers. However, few studies have explored the potential connections between abnormal glucose metabolism and DNA methylation in tumor progression. In this study, we aimed to screen out glucose metabolism-related genes that were DNA methylation associated in order to establish a promising signature for the prognosis of bladder cancer (BLCA).Methods: With transcriptome data of BLCA samples from The Cancer Genome Atlas (TCGA) and methylation data downloaded from TCGA data base 450K microarray, glucose metabolism-related genes that were simultaneously methylation modulated and survival associated were obtained and a prognostic signature was established. Gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis (WGCNA) were performed for identification of gene and pathway enrichment. Two most methylation-related risky genes were selected to conduct functional validations. Results: 18 target genes were identified and the samples were survival-significantly divided into two groups by using the signature. Via multivariate Cox analysis, we considered the signature an independent prognostic factor. Several biological processes and signaling pathways were enriched in the high-risk group according to GSEA results and three modules of genes were identified by WGCNA. We demonstrated that UCHL1 and PYCR1 promoted proliferation, migration and invasion ability of bladder cancer cells. Conclusions: The signature based on the 18 target genes could serve as an independent prognostic factor for urinary bladder cancer patients.

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“…CRABP1 is a retinoic-acid-binding protein, the increased expression of which has already been associated with bad prognosis and increased proliferation in endometrioid endometrial carcinoma [40]. The product of the UCHL1 gene, ubiquitin C-terminal hydrolase L1, has been described as a key player in the metastases formation of tumors in most tumor types, thus also in endometrial carcinoma [41]. FOXB1 is a DNA-binding transcription factor protein the specific role of which has not yet been examined in the tumorigenesis of the endometrium [40,42].…”

Section: Discussionmentioning

confidence: 99%

Histological Grade of Endometrioid Endometrial Cancer and Relapse Risk Can Be Predicted with Machine Learning from Gene Expression Data

Gargya

Bálint

2021

Cancers

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The tumor grade of endometrioid endometrial cancer is used as an independent marker of prognosis and a key component in clinical decision making. It is reported that between grades 1 and 3, however, the intermediate grade 2 carries limited information; thus, patients with grade 2 tumors are at risk of both under- and overtreatment. We used RNA-sequencing data from the TCGA project and machine learning to develop a model which can correctly classify grade 1 and grade 3 samples. We used the trained model on grade 2 patients to subdivide them into low-risk and high-risk groups. With iterative retraining, we selected the most relevant 12 transcripts to build a simplified model without losing accuracy. Both models had a high AUC of 0.93. In both cases, there was a significant difference in the relapse-free survivals of the newly identified grade 2 subgroups. Both models could identify grade 2 patients that have a higher risk of relapse. Our approach overcomes the subjective components of the histological evaluation. The developed method can be automated to perform a prescreening of the samples before a final decision is made by pathologists. Our translational approach based on machine learning methods could allow for better therapeutic planning for grade 2 endometrial cancer patients.

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High Expression of Ubiquitin C-terminal Hydrolase L1 Is Associated With Poor Prognosis in Endometrial Cancer Patients

Abstract: The results of this study suggest that high UCHL1 expression is a strong marker of poor prognosis of endometrial cancer. Furthermore, we suggest that UCHL1 may be involved in the development of distant metastasis in endometrial cancer.

Cited by 10 publications

References 38 publications

Proteomic profiling of FBXW7‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

Proteomic profiling of FBXW7‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

A signature of glucose metabolism and DNA methylation improves prognostic prediction for urinary bladder cancer

Histological Grade of Endometrioid Endometrial Cancer and Relapse Risk Can Be Predicted with Machine Learning from Gene Expression Data

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