Disturbed alternative splicing of FIR (PUF60) directed cyclin E overexpression in esophageal cancers

Ogura, Yukiko; Hoshino, Tyuji; Tanaka, Nobuko; Ailiken, Guzhanuer; Kobayashi, Sohei; Kïtamura, Kazuo; Rahmutulla, Bahityar; Kano, Masayuki; Murakami, Kentarou; Akutsu, Yasunori; Nomura, Fumio; Itoga, Sakae; Matsubara, Hisahiro; Matsushita, Hiroshi

doi:10.18632/oncotarget.25149

Cited by 13 publications

(29 citation statements)

References 37 publications

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“…The regulation of BRG1 by FBW7 has been studied that BRG1 is a substrate of FBW7 and was found to suppress E-cadherin through the FBW7/BRG1/Snai1 axis in gastric cancer 4 . Since FIRΔexon2 was co-immunoprecipitated with WDrepeat proteins 9 , a potential interaction was assessed between FIRΔexon2 and the WD-like motif in the degron pocket of FBW7 by three-dimension crystal analysis 22,23 . Finally, low molecular weight chemicals that bind to FIRΔexon2 were identified from natural chemical libraries (RIKEN, Wako, Saitama, Japan) and we investigated their effect on BRG1/Snai1 pathway for clinical applications.…”

Section: Introductionmentioning

confidence: 99%

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

et al. 2020

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Brahma-related gene 1 (BRG1), an ATPase subunit of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex controls multipotent neural crest formation by regulating epithelial-mesenchymal transition (EMT)-related genes with adenosine triphosphate-dependent chromodomain-helicase DNA-binding protein 7 (CHD7). The expression of BRG1 engages in pre-mRNA splicing through interacting RNPs in cancers; however, the detailed molecular pathology of how BRG1and CHD7 relate to cancer development remains largely unveiled. This study demonstrated novel post-transcriptional regulation of BRG1 in EMT and relationship with FIRΔexon2, which is a splicing variant of the far-upstream element-binding protein (FUBP) 1-interacting repressor (FIR) lacking exon 2, which fails to repress c-myc transcription in cancers. Previously, we have reported that FIR complete knockout mice (FIR −/− ) was embryonic lethal before E9.5, suggesting FIR is crucial for development. FIRΔexon2 acetylated H3K27 on promoter of BRG1 by CHIP-sequence and suppressed BRG1 expression post-transcriptionally; herein BRG1 suppressed Snai1 that is a transcriptional suppressor of E-cadherin that prevents cancer invasion and metastasis. Ribosomal proteins, hnRNPs, splicing-related factors, poly (A) binding proteins, mRNA-binding proteins, tRNA, DEAD box, and WD-repeat proteins were identified as co-immunoprecipitated proteins with FIR and FIRΔexon2 by redoing exhaustive mass spectrometry analysis. Furthermore, the effect of FIRΔexon2 on FGF8 mRNA splicing was examined as an indicator of neural development due to impaired CHD7 revealed in CHARGE syndrome. Expectedly, siRNA of FIRΔexon2 altered FGF8 pre-mRNA splicing, indicated close molecular interaction among FIRΔexon2, BRG1 and CHD7. FIRΔexon2 mRNA was elevated in human gastric cancers but not in non-invasive gastric tumors in FIR +/ mice (K19-Wnt1/C2mE x FIR +/− ). The levels of FIR family (FIR, FIRΔexon2 and PUF60), BRG1, Snai1, FBW7, E-cadherin, c-Myc, cyclin-E, and SAP155 increased in the gastric tumors in FIR +/− mice compared to those expressed in wild-type mice. FIR family, Snai1, cyclin-E, BRG1, and c-Myc showed trends toward higher expression in larger tumors than in smaller tumors in Gan-mice (K19-Wnt1/C2mE). The expressions of BRG1 and Snai1 were positively correlated in the gastric tumors of the Gan-mice. Finally, BRG1 is a candidate substrate of F-box and WD-repeat domain-containing 7 (FBW7) revealed by three-dimensional crystal structure analysis that the U2AF-homology motif (UHM) of FIRΔexon2 interacted with tryptophan-425 and asparate-399 (WD)-like motif in the degron pocket of FBW7 as a UHM-ligand motif. Together, FIRΔexon2 engages in multi-step post-transcriptional regulation of BRG1, affecting EMT through the BRG1/Snai1/E-cadherin pathway and promoting tumor proliferation and invasion of gastric cancers.

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Section: Introductionmentioning

confidence: 99%

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

et al. 2020

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“…Furthermore, AUC values greater than 0.700 were observed for FIRΔexon2 Abs in patients with ESCC. It is conceivable that FIRΔexon2 Abs are common markers for ESCCs …”

Section: Discussionmentioning

confidence: 99%

“…It is conceivable that FIRΔexon2 Abs are common markers for ESCCs. 23,31,32 The combined ROC analysis of candidate Abs with anti-p53…”

Section: Discussionmentioning

confidence: 99%

“…Anti‐PUF60 autoantibodies are reportedly detected in the sera of patients with autoimmune diseases such as dermatomyositis, Sjögren's syndrome, and idiopathic inflammatory myopathy . This suggests that the combination of anti‐FIR Abs with other clinically available tumor markers, such as anti‐p53 Abs, CEA, and CA19‐9, could increase the specificity and accuracy of diagnosis . The present study aimed to explore the presence and significance of anti‐FIRΔexon2 Abs in the sera of patients with ESCC and to determine its use as a potential candidate marker.…”

Section: Introductionmentioning

confidence: 97%

“…26,27 This suggests that the combination of anti-FIR Abs with other clinically available tumor markers, such as anti-p53 Abs, CEA, and CA19-9, could increase the specificity and accuracy of diagnosis. [28][29][30][31][32] The present study aimed to explore the presence and significance of anti-FIRΔexon2 Abs in the sera of patients with ESCC and to determine its use as a potential candidate marker.…”

Section: Introductionmentioning

confidence: 99%

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Anti‐FIRΔexon2, a splicing variant form of PUF60, autoantibody is detected in the sera of esophageal squamous cell carcinoma

et al. 2019

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Anti‐ PUF 60 autoantibodies are reportedly detected in the sera of patients with dermatomyositis and Sjögren's syndrome; however, little is known regarding its existence in the sera of cancer patients. FIR , a splicing variant of the PUF 60 gene, is a transcriptional repressor of c‐myc . In colorectal cancer, there is an overexpression of the dominant negative form of FIR , in which exon 2 is lacking ( FIR Δexon2). Previously, large‐scale SEREX (serological identification of antigens by recombinant cDNA expression cloning) screenings have identified anti‐ FIR autoantibodies in the sera of cancer patients. In the present study, we revealed the presence and significance of anti‐ FIR ( FIR / FIR Δexon2) Abs in the sera of patients with esophageal squamous cell carcinoma ( ESCC ). Our results were validated by an amplified luminescence proximity homogeneous assay using sera of patients with various cancer types. We revealed that anti‐ FIR Δexon2 Ab had higher sensitivity than anti‐ FIR Ab. Receiver operating characteristic (ROC) analysis was applied for evaluating the use of anti‐ FIR Δexon2 Ab as candidate markers such as anti‐p53 Ab and carcinoembryonic antigen, and the highest area under the ROC curve was observed in the combination of anti‐ FIR Δexon2 Ab and anti‐p53 Ab. In summary, our results suggest the use of anti‐ FIR Δexon2 Ab in combination with the anti‐p53 Ab as a predictive marker for ESCC . The area under the ROC curve was further increased in the advanced stage of ESCC . The value of anti‐ FIR Δexon2 autoantibody as novel clinical indicator against ESCC and as a companion diagnostic tool is discussed.

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Combinational antibody detection approach increases the clinical validity of colorectal cancer screening

Kobayashi,

Hiwasa,

Kitamura

et al. 2023

Clinical Laboratory Analysis

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BackgroundAt different stages of the disease, biomarkers can help to determine disease progression and recurrence and provide a personalized indicator of therapeutic effectiveness. The serological identification of antigens by recombinant cDNA expression cloning (SEREX) has identified five SEREX antigens.ResultsCompared with healthy donors, anti‐FIRΔexon2 and anti‐SOHLH antibodies (Abs) in the sera of patients with colorectal cancer (CRC) were markedly higher. Furthermore, no correlation was noted between five SEREX antigens and the three tumor markers (CEA, CA19‐9, and anti‐p53 Abs), indicating that anti‐FIRΔexon2 Abs are an independent candidate marker for patients with CRC. Generally, the levels of anti‐FIRΔexon2 Abs combined with clinically available tumor markers were determined to be significantly higher compared with CEA, CA19‐9. Moreover, in early‐stage CRC, the levels of anti‐FIRΔexon2 Abs combined with existing tumor markers were higher than those of CEA, CA19‐9.ConclusionDue to the highly heterogeneous nature of CRC, a single tumor marker is unlikely to become a standalone diagnostic test due to its commonly insufficient sensitivity and/or specificity. Using a combination antibody detection approach of tumor markers for CRC diagnosis has the potential to be an effective approach. Therefore, the use of serum protein biomarker candidates holds promise for the development of inexpensive, noninvasive, and inexpensive tests for the detection of CRC.

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Disturbed alternative splicing of FIR (PUF60) directed cyclin E overexpression in esophageal cancers

Cited by 13 publications

References 37 publications

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

Anti‐FIRΔexon2, a splicing variant form of PUF60, autoantibody is detected in the sera of esophageal squamous cell carcinoma

Combinational antibody detection approach increases the clinical validity of colorectal cancer screening

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