Anti‐<scp>FIR</scp>Δexon2, a splicing variant form of <scp>PUF</scp>60, autoantibody is detected in the sera of esophageal squamous cell carcinoma

Kobayashi, Sohei; Hiwasa, Takaki; Ishige, Takayuki; Rahmutulla, Bahityar; Kano, Masayuki; Hoshino, Tyuji; Minamoto, Toshinari; Shimada, Hideaki; Nomura, Fumio; Matsubara, Hisahiro; Matsushita, Hiroshi

doi:10.1111/cas.14024

Cited by 14 publications

(22 citation statements)

References 54 publications

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“…First, FIR and FIRΔexon2-binding proteins were revaluated among the data previously identified by exhaustive mass spectrometry analysis 9 . In fact, an autoantibody against FIRΔexon2 was detected in the sera of various cancer patients 10,11 , showing that FIRΔexon2 protein authentically expresses in cancers. Given that c-Myc activates ribosome protein synthesis, FIRΔexon2 is crucial for carcinogenesis in terms of ribosome protein synthesis in cancers.…”

Section: Introductionmentioning

confidence: 98%

“…The expressions of FIR family, Snai1, BRG1, E-cadherin, FBW7, c-Myc, cyclin-E, SAP155, and hnRNPA1 of wild-type, Gan-mice, and FIR +/− mice were examined. Frozen tissues samples of mice gastric tumors were obtained and proteins expression profiles examined by western blotting in three different genotypes: wild-type mouse(lanes 1-3), Gan-mice (gastric tumor wet weight < 0.5 g) (lanes 4-6), Gan-mice (gastric tumor wet weight > 2.0 g) (lanes 7-9) and FIR +/− mice (lanes[10][11][12]. c The extent of the signals detected by western blotting revealed inFig.…”

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confidence: 99%

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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: 98%

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confidence: 99%

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

et al. 2020

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“…This study revealed that the anti‐FIRΔexon2 Ab‐positive group exhibited markedly better OS than the anti‐FIRΔexon2 Ab‐negative group in GC patients. This study reported that anti‐FIRΔexon2 Ab in the sera is a novel diagnostic marker and predicted better survival for patients with GC identified by SEREX screening and AlphaLISA 21 . Compared with age‐matched HDs, anti‐FIRΔexon2, anti‐SNX15, and anti‐SOHLH Abs in the sera of patients with GC were markedly higher (Table 1 and Figure 1).…”

Section: Discussionmentioning

confidence: 83%

Anti‐FIRΔexon2 autoantibody as a novel indicator for better overall survival in gastric cancer

et al. 2021

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There is no clinically available biomarker for efficiently indicating the overall survival or therapy response of gastric cancer (GC). The autoantibodies (Abs) in the sera of anti‐far‐upstream element‐binding protein‐interacting repressor‐lacking exon2 (FIRΔexon2), anti‐sorting nexin 15, and anti‐spermatogenesis and oogenesis–specific basic helix–loop–helix 1 were markedly higher in GC patients than in healthy donors (HDs). These Abs were identified by large‐scale serological identification of antigens by recombinant cDNA expression cloning screenings and their expression levels were evaluated by amplified luminescence proximity homogeneous assay. In particular, compared with age‐matched HDs, the level of anti‐FIRΔexon2 Abs in GC patients was significantly higher (P < .001). The Spearman's rank correlation analysis between anti‐FIRΔexon2 Abs and clinically available tumor markers such as carcinoembryonic antigen (CEA) was statistically insignificant, indicating that FIRΔexon2 Abs is an independent biomarker. We performed receiver‐operating curve analysis to evaluate the anti‐FIRΔexon2 Ab as a candidate biomarker with CEA and carbohydrate antigen 19‐9 (CA19‐9). The overall survival of GC patients with high anti‐FIRΔexon2 Abs titer was significantly favorable (P = .04) than that of GC patients who were below detection level of anti‐FIRΔexon2 Abs. However, clinical stages were not apparently correlated with the levels of anti‐FIRΔexon2 Ab, CEA, and CA19‐9. In conclusion, anti‐FIRΔexon2 Abs detected in GC patients is a potential biomarker for monitoring a better prognosis. Hence, anti‐FIRΔexon2 Abs is a promising biomarker for indicating better overall survival of gastric cancer patients.

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“…The anti-p53 antibody is a typical antibody biomarker for cancer that has been put into practical use for diagnosing, monitoring, and predicting the prognosis of esophageal cancer (EC) and head and neck cancer [19,20]. Further application of the serological identi cation of antigens by cDNA expression cloning and the protein array method have identi ed autoantibodies against TACSTD2 [21], SLC2A1 [22], TRIM21 [23], myomegalin [24], makorin 1 [25], ECSA [26], cyclin L2 [27], and LRPAP1 [11] for EC; FIR/PUF60 for colorectal cancer (CRC) [28] and gastric cancer (GC) [29]; SH3GL1 [30] and lamin C [31] for glioma; EP300-interacting inhibitor of differentiation 3 for nonfunctional pancreatic neuroendocrine tumors [32]; and coatomer protein complex subunit epsilon/COPE [33], NBL1/DAN [34], and SNX16 [35] for obstructive sleep apnea syndrome (OSAS). Here, we report on serum antibodies against KIAA0513 (s-KIAA0513-Ab) as a broad-spectrum biomarker applicable to atherosclerosis-related diseases such as ischemic stroke, cardiovascular disease (CVD), chronic kidney disease (CKD), DM, and solid cancers.…”

Section: Introductionmentioning

confidence: 99%

Anti-KIAA0513 Antibody as a Broad-spectrum Biomarker of Mortal Atherosclerotic and Cancerous Diseases

Hiwasa¹,

Li²,

Kubota³

et al. 2021

Preprint

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Background: Numerous antibody biomarkers have been reported for cancer and atherosclerosis-related diseases. The major complications of atherosclerosis and diabetes mellitus (DM) are acute ischemic stroke (AIS), cardiovascular disease (CVD), and chronic kidney disease (CKD). Cancer development is accompanied by arterial disorders such as angiogenesis and atherosclerosis, and DM is a risk factor for certain cancers. Atherosclerosis-related diseases and cancers are therefore interrelated and could be detected by a common biomarker.Methods: We employed the protein array method for the initial screening of antigens and employed the amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) to evaluate antibody levels in serum samples.Results: The protein array identified KIAA0513 as an antigen recognized by serum IgG antibodies in the sera of patients with atherosclerosis. We then prepared recombinant glutathione S-transferase-fused KIAA0513 protein. AlphaLISA showed significantly higher serum antibody levels against KIAA0513 protein in patients with AIS, transient ischemic attack, DM, CVD, obstructive sleep apnea syndrome (OSAS), CKD, and solid cancers, such as esophageal, gastric, colon, lung, and breast cancer, than in healthy donors. A receiver operating characteristic (ROC) analysis revealed that the highest areas under the ROC curves of anti-KIAA0513 antibodies were for esophageal cancer, nephrosclerosis-type CKD, and DM. Spearman’s correlation analysis revealed that serum anti-KIAA0513 antibody levels were associated with maximum intima-media thickness and plaque score, which are indices of atherosclerosis and stenosis.Conclusion: Serum anti-KIAA0513 antibody markers appear to be useful for diagnosing AIS, TIA, DM, CVD, OSAS, CKD, and solid cancers and might reflect common arterial alterations leading to atherosclerotic and cancerous diseases.

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

Cited by 14 publications

References 54 publications

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

Anti‐FIRΔexon2 autoantibody as a novel indicator for better overall survival in gastric cancer

Anti-KIAA0513 Antibody as a Broad-spectrum Biomarker of Mortal Atherosclerotic and Cancerous Diseases

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