Identification of Phosphorylated Cyclin-Dependent Kinase 1 Associated with Colorectal Cancer Survival Using Label-Free Quantitative Analyses (original) (raw)
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The role of protein tyrosine phosphatases in colorectal cancer
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2012
Colorectal cancer is one of the most common oncogenic diseases in the Western world. Several cancer associated cellular pathways have been identified, in which protein phosphorylation and dephosphorylation, especially on tyrosine residues, are one of most abundant regulatory mechanisms. The balance between these processes is under tight control by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Aberrant activity of oncogenic PTKs is present in a large portion of human cancers. Because of the counteracting role of PTPs on phosphorylation-based activation of signal pathways, it has long been thought that PTPs must act as tumor suppressors. This dogma is now being challenged, with recent evidence showing that dephosphorylation events induced by some PTPs may actually stimulate tumor formation. As such, PTPs might form a novel attractive target for anticancer therapy. In this review, we summarize the action of different PTPs, the consequences of their altered expression in colorectal cancer, and their potential as target for the treatment of this deadly disease.
Diabetes, 2022
Colorectal cancer (CRC) and diabetes are two of the most prevalent chronic diseases worldwide with dysregulated receptor tyrosine kinase signaling and strong co-occurrence correlation. Plasma autoantibodies represent a promising early diagnostic marker for both diseases before symptoms appear. In this study, we explore the value of autoantibodies against receptor-type tyrosine-protein phosphatase-like N (PTPRN; full-length or selected domains) as diagnostic markers using a cohort of individuals with type 2 diabetes (T2D), CRC, or both diseases or healthy individuals. We show that PTPRN autoantibody levels in plasma discriminated between patients with T2D with and without CRC. Consistently, high PTPRN expression correlated with decreased survival of patients with CRC. Mechanistically, PTPRN depletion significantly reduced invasiveness of CRC cells in vitro and liver homing and metastasis in vivo by means of a dysregulation of the epithelial-mesenchymal transition and a decrease of th...
Journal of Proteomics, 2015
Robust phosphopeptide enrichment methods with minimal fractionation are required to profile signaling network analysis in cancer cell lines and tissues. We assessed performance of single-shot LC-MS/MS label-free phosphoproteomics using TiOx-based phosphopeptide enrichment and report phosphopeptide identification reproducibility (75.8%), depth of identification (6014–6150 phosphopeptides) and reproducibility of label-free quantification (CV 17.8%). Subsequently, we have profiled the baseline global phosphorylation of 8 colorectal cancer (CRC) cell lines representing different CRC prognostic subtypes. Global single-shot phosphoproteomics can distinguish CRC subtypes previously identified by transcriptomics and identifies signaling proteins and processes associated with the CCS3 poor prognosis subtype. Data are available via ProteomeXchange with identifiers PXD001546 and PXD001550. This article is part of a Special Issue entitled: HUPO 2014. Biological significance: Label-free single-shot phosphoproteomics is a mature workflow that can be used for global quantitative profiling of biological cell lines and tissues to map signaling networks in comparative analyses. Here we show the feasibility of label-free profiling of CRC cell lines at sample input levels compatible with clinical samples such as tumor biopsies.
Biotechnology Reports, 2021
Introduction: Colorectal cancer (CRC) is one of the most cancer-related mortalities worldwide and remains a major public health issue. Despite several attempts to develop promising therapies for CRC, its survival rate decreases with metastasis. Cyclin-dependent kinases (CDKs) are a family of protein kinases with various regulatory activities including cell cycle, mRNA expression, transcription, and differentiation. Aside from their role in cell proliferation when mutated, abnormal expression of these genes has been reported in some human cancer subtypes. This study explored the roles and therapeutic potentials of CDK 1 and 4 as prognostic biomarkers in CRC. Methods: Bioinformatics analyses were carried out to demonstrate the expression and prognostic values of CDK-1 and CDK-4 with immune infiltrate in CRC. Discussion: CDK levels in CRC were remarkably higher than those in normal tissues (p < 0.05), and overexpression in CRC tissues was significantly related to nodal metastatic status (p < 0.05) and histological subtypes. Kaplan-Meier analyses showed that patients with CRC who exhibited CDK-1 overexpression had worse overall survival (OS) as against patients with CDK-4 overexpression. The alteration observed was a mutation while the mutation hotspots include E163* and R24A/C/H/L respectively for CDK-1 and CDK-4 on the Pkinase domain. Of the associated genes, AURKA and RB1 were predominantly altered. Furthermore, CDK-4 is positively correlated with tumor purity in both COAD and READ while CDK-1is only positively correlated in COAD. CDK-1 overexpression was significantly associated with poor prognosis as opposed to CDK-4. Conclusion: The expression and prognostic values of AURKA and RB1 may also be significant to CRC diagnosis. CDKs together with the co-expressed genes and their association with immune infiltrates may serve as target molecules for immunotherapy in CRC.
Immunoaffinity profiling of tyrosine phosphorylation in cancer cells
Nature Biotechnology, 2004
Tyrosine kinases play a prominent role in human cancer, yet the oncogenic signaling pathways driving cell proliferation and survival have been difficult to identify, in part because of the complexity of the pathways and in part because of low cellular levels of tyrosine phosphorylation. In general, global phosphoproteomic approaches reveal small numbers of peptides containing phosphotyrosine. We have developed a strategy that emphasizes the phosphotyrosine component of the phosphoproteome and identifies large numbers of tyrosine phosphorylation sites. Peptides containing phosphotyrosine are isolated directly from protease-digested cellular protein extracts with a phosphotyrosine-specific antibody and are identified by tandem mass spectrometry. Applying this approach to several cell systems, including cancer cell lines, shows it can be used to identify activated protein kinases and their phosphorylated substrates without prior knowledge of the signaling networks that are activated, a first step in profiling normal and oncogenic signaling networks.
Molecular Medicine Reports, 2019
The aim of the present study was to identify potential key genes associated with the progression and prognosis of colorectal cancer (crc). differentially expressed genes (deGs) between crc and normal samples were screened by integrated analysis of gene expression profile datasets, including the Gene expression omnibus (Geo) and The cancer Genome atlas. Gene ontology (Go) and Kyoto encyclopedia of Genes and Genomes (KeGG) pathway analysis was conducted to identify the biological role of deGs. in addition, a protein-protein interaction network and survival analysis were used to identify the key genes. The profiles of GSe9348, GSe22598 and GSe113513 were downloaded from the Geo database. a total of 405 common deGs were identified, including 236 down-and 169 upregulated. GO analysis revealed that the downregulated deGs were mainly enriched in 'detoxification of copper ion' [biological process, (BP)], 'oxidoreductase activity, acting on cH-oH group of donors, NAD or NADP as acceptor' [molecular function, (MF)] and 'brush border' [cellular component, (CC)]. Upregulated DEGs were mainly involved in 'nuclear division' (BP), 'snoRNA binding' (MF) and 'nucleolar part' (CC). KEGG pathway analysis revealed that deGs were mainly involved in 'mineral absorption', 'nitrogen metabolism', 'cell cycle' and 'caffeine metabolism'. A PPI network was constructed with 268 nodes and 1,027 edges. The top one module was selected, and it was revealed that module-related genes were mainly enriched in the GO terms 'sister chromatid segregation' (BP), 'chemokine activity' (MF), and 'condensed chromosome (CC)'. The KEGG pathway was mainly enriched in 'cell cycle', 'progesterone-mediated oocyte maturation', 'chemokine signaling pathway', 'IL-17 signaling pathway', 'legionellosis', and 'rheumatoid arthritis'. DNA topoisomerase II-α (ToP2a), mitotic arrest deficient 2 like 1 (MAD2L1), cyclin B1 (CCNB1), checkpoint kinase 1 (CHEK1), cell division cycle 6 (CDC6) and ubiquitin conjugating enzyme E2 C (UBE2C) were indicated as hub genes. Furthermore, survival analysis revealed that ToP2a, Mad2l1, cdc6 and cHeK1 may serve as prognostic biomarkers in crc. The present study provided insights into the molecular mechanism of crc that may be useful in further investigations.
Cancer, 2004
BACKGROUND. Low levels of p27 Kip1 are associated with high aggressiveness and poor prognosis in various malignancies, including colorectal carcinoma. The authors showed that S phase kinase protein 2 (Skp2), the specific ubiquitin ligase subunit that targets p27 Kip1 for degradation, was overexpressed and was inversely related to p27 Kip1 levels in patients with colorectal carcinoma. The essential role of cyclin kinase subunit 1 (Cks1) in Skp2-dependent p27 degradation was recently discovered, but its role in human malignancies is unknown.