Multiproteomic and Transcriptomic Analysis of Oncogenic β-Catenin Molecular Networks

Ewing, Rob M.; Song, Jing; Gokulrangan, Giridharan; Bai, Sheldon; Bowler, Emily H; Bolton, Rachel; Skipp, Paul; Wang, Yihua; Wang, Benlian

doi:10.1021/acs.jproteome.8b00180

Cited by 7 publications

(7 citation statements)

References 47 publications

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“…This study speculated that the activation of CDKN2A expression in the stroma was influenced by cellular senescence and oncogene activation, and senescent fibroblasts prematurely accumulated in the stroma as a result of chronic inflammation and oxidative stress[ 24 ]. Moreover, CDKN2A participates in the development of CRC through the Wnt/β-catenin signaling pathway[ 13 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive proteomic signature and identification of CDKN2A as a promising prognostic biomarker and therapeutic target of colorectal cancer

Wang¹,

Zhou²,

Ge³

et al. 2022

WJCC

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BACKGROUND The carcinogenesis of colorectal cancer (CRC) involves many different molecules and multiple pathways, and the specific mechanism has not been elucidated until now. Existing studies on the proteomic signature profiles of CRC are relatively limited. Therefore, we herein aimed to provide a more comprehensive proteomic signature profile and discover new prognostic markers and therapeutic targets by performing proteomic analysis of CRC and paired normal tissues. AIM To investigate the proteomic signature and identify novel protein prognostic biomarkers of CRC. METHODS Cancer tissues and paired normal tissues were collected from 48 patients who underwent surgical removal at the China-Japan Friendship Hospital from January 2020 to June 2021. Data independent acquisition (DIA) quantitative proteomic analysis was performed using high-performance liquid chromatography–mass spectrometry/mass spectrometry (nano-UHPLC–MS/MS) to identify differentially expressed proteins, among which those with a P adj value ( t test, BH correction) < 0.05 and an absolute fold change (|log 2 FC|) > 2 were identified as potential markers. Differentially expressed proteins were selected by bioinformatics analysis and validated by immunohistochemical tissue microarrays, and their association with prognosis was further analyzed with the Gene Expression Profiling Interactive Analysis database to identify prognostic protein biomarkers of CRC. RESULTS Significantly differential protein expression was observed between cancer tissues and normal tissues. Compared with normal tissues, 1115 proteins were upregulated and 705 proteins were downregulated in CRC based on P adj < 0.05 and |log 2 FC| > 2, and bioinformatics analysis revealed that the differentially expressed proteins were involved in multiple biological processes associated with tumorigenesis, including ribosome biogenesis in eukaryotes, focal adhesion, extracellular matrix-receptor interactions and other tumor metabolism processes. Moreover, cyclin-dependent kinase inhibitor 2A (CDKN2A) expression was markedly upregulated in CRC, as validated by immunohistochemistry (0.228 vs 0.364, P = 0.0044), and was significantly enriched in tumor proliferation and signal transduction pathways such as the cell cycle and p53 signaling pathways. High CDKN2A expression was significantly correlated with poor prognosis ( P = 0.021). These results demonstrated that CDKN2A functions as a driver of CRC. CONCLUSION Our study provides a comprehensive proteomic signature of CRC and highlights CDKN2A as a potential powerful prognostic marker and precision therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Comprehensive proteomic signature and identification of CDKN2A as a promising prognostic biomarker and therapeutic target of colorectal cancer

Wang¹,

Zhou²,

Ge³

et al. 2022

WJCC

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“…There was evidence that the expression of CDKN2A protein was frequently silenced in tumors through promoter hypermethylation. This suggested that CpG methylation changes may be induced by oncogenic beta-catenin, where beta-catenin was found to have interacted with DNA methyltransferase I in a mutually stabilizing interaction in the nuclei of cancer cells [ 49 ]. Although, majority of CDKN2A mutations are inactivating mutations (i.e., loss-of-function mutations), an interesting study found an increased copy number of CDKN2A gene in a nonsyndromic case with cutaneous pilomatrical carcinosarcoma but mutation of exon 3 of the CTNNB1 gene was not detected in that case [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

No Evidence of Abnormal Expression of Beta-Catenin and Bcl-2 Proteins in Pilomatricoma as One Clinical Feature of Tetrasomy 9p Syndrome

Charalsawadi

Trongnit

Jaruthamsophon

et al. 2021

International Journal of Pediatrics

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Background. Little is currently known about the genetics of pilomatricoma. A number of studies have reported some evidence that this disease may have a genetic association with mutations of CTNNB1 gene or expression of the beta-catenin protein. In this study, we reviewed literatures involving 30 patients with various genetic syndromes that have been linked to pilomatricoma and found that somatic mutations of the CTNNB1 gene were reported in 67% of patients. Pilomatricoma has been reported in patients with chromosome 9 rearrangements, including 4 patients with tetrasomy 9p syndrome and one patient with partial trisomy 9. In addition to beta-catenin, the expression of bcl2 was observed in pilomatricoma. Objectives. To report an additional case of tetrasomy 9p syndrome with concurrent pilomatricoma and to examine whether abnormal protein expressions of the CTNNB1 and/or BCL2 genes were present. Methods. Cytogenetic analysis was carried out on peripheral blood, biopsied skin, and pilomatricoma tissue obtained from a patient with tetrasomy 9p syndrome. Immunohistochemical staining was performed on the pilomatricoma tissue, using beta-catenin and bcl2 monoclonal antibodies. Results. SNP microarray revealed nonmosaic gain of the short arm of chromosome 9. A nonmosaic isodicentric chromosome 9 was identified in the peripheral blood but this rearranged chromosome was detected in only 8.3% of the skin fibroblasts. Chromosomal abnormalities were not detected in the pilomatricoma nor expression of beta-catenin or bcl2 proteins in our patient. Conclusion. Pilomatricoma could be a new clinical feature associated with tetrasomy 9p syndrome; however, we found no evidence of tetrasomy 9p or abnormal beta-catenin or bcl2 proteins of the CTNNB1 and BCL2 genes in our pilomatricoma patient.

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“…All microarray data used in the present study were retrieved from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database () (21) using GEO accession numbers. The siRNA β-catenin and control treatment microarray dataset accession numbers were GSE44097 (10) for the DLD1 and SW480 cell lines, and GSE18560 (12) for Ls174T cells. The CRC dataset accession numbers were GSE68468 (22), GSE14333 (23), GSE17536 (24), GSE17537 (25), GSE24549 (26), GSE24550 (27), GSE31595 (28), GSE37892 (29) and GSE39582 (30).…”

Section: Methodsmentioning

confidence: 99%

“…The study then incorporated results from another study with a similar design, in which LS174T cells were treated with short hairpin RNA against β-catenin (11), and identified a total of 335 target genes. Recently, a multi-omics approach was used by Ewing et al (12) to decipher the oncogenic β-catenin network in HCT116 cells by comparing transcriptome, expression proteome and interactome data of wild type and β-catenin mutated samples. The results were subsequently integrated into a functional molecular network.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of β‑catenin target genes in colorectal cancer by interrogating gene fitness screening data

Zhao

Yin

et al. 2019

Oncol Lett

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β-catenin regulates its target genes which are associated with proliferation, differentiation, migration and angiogenesis, and the dysregulation of Wnt/β-catenin signaling facilitates hallmarks of colorectal cancer (CRC). Identification of β-catenin targets and their potential roles in tumorigenesis has gained increased interest. However, the number of identified targets remains limited. The present study implemented a novel strategy, interrogating gene fitness profiles derived from large-scale RNA interference and CRISPR-CRISPR associated protein 9 screening data to identify β-catenin target genes in CRC cell lines. Using these data sets, pair wise gene fitness similarities were determined which highlighted a total of 13 genes whose functions were highly correlated with β-catenin. It was further demonstrated that the expression of these genes were altered in CRC, illustrating their potential roles in the progression of CRC. The present study further demonstrated that these targets could be used to predict disease-free survival in CRC. In conclusion, the findings provided novel approaches for the identification of β-catenin targets, which may become prognostic biomarkers or drug targets for the management of CRC.

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Multiproteomic and Transcriptomic Analysis of Oncogenic β-Catenin Molecular Networks

Cited by 7 publications

References 47 publications

Comprehensive proteomic signature and identification of CDKN2A as a promising prognostic biomarker and therapeutic target of colorectal cancer

Comprehensive proteomic signature and identification of CDKN2A as a promising prognostic biomarker and therapeutic target of colorectal cancer

No Evidence of Abnormal Expression of Beta-Catenin and Bcl-2 Proteins in Pilomatricoma as One Clinical Feature of Tetrasomy 9p Syndrome

Identification of β‑catenin target genes in colorectal cancer by interrogating gene fitness screening data

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