Identification of mesothelioma-specific sialylated epitope recognized with monoclonal antibody SKM9-2 in a mucin-like membrane protein HEG1

Matsuura, Rieko; Kaji, Hiroyuki; Tomioka, Azusa; Sato, Takashi; Narimatsu, Hisashi; Moriwaki, Yuji; Misawa, Hidemi; Imai, Kohzoh; Tsuji, Shoutaro

doi:10.1038/s41598-018-32534-8

Cited by 17 publications

(16 citation statements)

References 37 publications

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“…The core proteins of the mesothelial CL40-positive glycans are unknown. Several sialomucins are expressed in the mesothelium [ 51 , 52 ]. CL40-positive high molecular mass glycoproteins modified with O -linked glycans may be included in these mesothelial sialomucins.…”

Section: Resultsmentioning

confidence: 99%

Complementary Role of GlcNAc6ST2 and GlcNAc6ST3 in Synthesis of CL40-Reactive Sialylated and Sulfated Glycans in the Mouse Pleural Mesothelium

et al. 2022

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Sialyl 6-sulfo Lewis X (6-sulfo sLeX) and its derivative sialyl 6-sulfo N-acetyllactosamine (LacNAc) are sialylated and sulfated glycans of sialomucins found in the high endothelial venules (HEVs) of secondary lymphoid organs. A component of 6-sulfo sLeX present in the core 1-extended O-linked glycans detected by the MECA-79 antibody was previously shown to exist in the lymphoid aggregate vasculature and bronchial mucosa of allergic and asthmatic lungs. The components of 6-sulfo sLeX in pulmonary tissues under physiological conditions remain to be analyzed. The CL40 antibody recognizes 6-sulfo sLeX and sialyl 6-sulfo LacNAc in O-linked and N-linked glycans, with absolute requirements for both GlcNAc-6-sulfation and sialylation. Immunostaining of normal mouse lungs with CL40 was performed and analyzed. The contribution of GlcNAc-6-O-sulfotransferases (GlcNAc6STs) to the synthesis of the CL40 epitope in the lungs was also elucidated. Here, we show that the expression of the CL40 epitope was specifically detected in the mesothelin-positive mesothelium of the pulmonary pleura. Moreover, GlcNAc6ST2 (encoded by Chst4) and GlcNAc6ST3 (encoded by Chst5), but not GlcNAc6ST1 (encoded by Chst2) or GlcNAc6ST4 (encoded by Chst7), are required for the synthesis of CL40-positive glycans in the lung mesothelium. Furthermore, neither GlcNAc6ST2 nor GlcNAc6ST3 is sufficient for in vivo expression of the CL40 epitope in the lung mesothelium, as demonstrated by GlcNAc6ST1/3/4 triple-knock-out and GlcNAc6ST1/2/4 triple-knock-out mice. These results indicate that CL40-positive sialylated and sulfated glycans are abundant in the pleural mesothelium and are synthesized complementarily by GlcNAc6ST2 and GlcNAc6ST3, under physiological conditions in mice.

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Section: Resultsmentioning

confidence: 99%

Complementary Role of GlcNAc6ST2 and GlcNAc6ST3 in Synthesis of CL40-Reactive Sialylated and Sulfated Glycans in the Mouse Pleural Mesothelium

et al. 2022

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“…As mentioned above, this increase in R is responsible for the broad peak observed in the NMRD profiles at higher magnetic field strengths. Unfortunately, the intermediate/long M values (around 0.5 s), typical of Gd III -DOTA monoamide complexes, limit the r1 increase from mononuclear to binuclear complexes to only 40%, lower than that observed when the water residence lifetime is lower than 100 ns (fast exchange regime) [31].…”

Section: Relaxometric Characterizationsmentioning

confidence: 89%

“…Mesothelioma is the malignant neoplasm of the mesothelial cells and is a highly aggressive tumor lacking any significant therapies. Thus, it was decided to implement a binding test of (Gd III -DOTA-EN)2-F2PBA moles Gd/mg of total cell proteins A study that has recently been reported in the literature highlights that mesothelioma cells express a high amount of SA on their surface [31][32][33]. Mesothelioma is the malignant neoplasm of the mesothelial cells and is a highly aggressive tumor lacking any significant therapies.…”

Section: Determination Of the Binding Efficacymentioning

confidence: 99%

Towards Enhanced MRI Performance of Tumor-Specific Dimeric Phenylboronic Contrast Agents

et al. 2021

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It is known that phenylboronic acid (PBA) can target tumor tissues by binding to sialic acid, a substrate overexpressed by cancer cells. This capability has previously been explored in the design of targeting diagnostic probes such as Gd- and 68Ga-DOTA-EN-PBA, two contrast agents for magnetic resonance imaging (MRI) and positron emission tomography (PET), respectively, whose potential has already been demonstrated through in vivo experiments. In addition to its high resolution, the intrinsic low sensitivity of MRI stimulates the search for more effective contrast agents, which, in the case of small-molecular probes, basically narrows down to either increased tumbling time of the entire molecule or elevated local concentration of the paramagnetic ions, both strategies resulting in enhanced relaxivity, and consequently, a higher MRI contrast. The latter strategy can be achieved by the design of multimeric GdIII complexes. Based on the monomeric PBA-containing probes described recently, herein, we report the synthesis and characterization of the dimeric analogues (GdIII-DOTA-EN)2-PBA and (GdIII-DOTA-EN)2F2PBA. The presence of two Gd ions in one molecule clearly contributes to the improved biological performance, as demonstrated by the relaxometric study and cell-binding investigations.

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“…HEG1 is only one of the molecules in many complex networks related to cell proliferation, 11 , 27 metastasis, 21 and angiogenesis. 18 , 19 HEG1, Ki67, and P53 expression were investigated by H&E staining and immunohistochemistry in the tissues of patients with LUAD.…”

Section: Discussionmentioning

confidence: 99%

HEG1 as a novel potential biomarker for the prognosis of lung adenocarcinoma

et al. 2022

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Background Heart development protein with EGF‐like domains 1 (HEG1), generally related to angiogenesis and embryonic development, was reported to participate in the occurrence and progression of some tumors recently. However, the role of HEG1 in lung adenocarcinoma (LUAD) is unclear. Patients and Methods To explore the effect of HEG1 on LUAD, GEPIA platform and UALCAN database, as well as Kaplan–Meier plotter were adopted to analyze the association of HEG1 with clinicopathological characteristics and survival outcomes for LUAD firstly. And then the HEG1 in LUAD tissues, blood and cell lines were detected by qRT‐PCR, western blot, immunofluorescence, immunohistochemistry, and ELISA. Gene set enrichment analysis (GSEA) was conducted to identify pathways that might be affected by HEG1 in LUAD. Results In this study, HEG1 in lung tissues and cell lines of LUAD were significantly downregulated compared to benign pulmonary disease tissues and alveolar epithelial cells ( p < 0.05). Moreover, compared with other groups, patients with advanced tumor stage had lower HEG1 mRNA expression levels ( p = 0.025), which were negatively correlated with Ki67 index in tumor tissues ( r = −0.427, p = 0.033). On the other hand, the LUAD patients with lower HEG1 had shorter overall survival (OS) (HR = 0.51, 95% CI: 0.40–0.65, p < 0.001) according to Kaplan–Meier plotter. In addition, HEG1 in serum of LUAD patients was negatively associated with CEA ( r = −0.636, p < 0.001). GSEA showed that HEG1 was enriched in various metabolic‐related pathways, including glucose metabolism, lipid metabolism, and nucleotide metabolism signaling. Conclusions HEG1 was downregulated in LUAD patients and associated with poor prognosis, which indicating HEG1 may serve as a potential biomarker for diagnosis and prognosis of LUAD.

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Identification of mesothelioma-specific sialylated epitope recognized with monoclonal antibody SKM9-2 in a mucin-like membrane protein HEG1

Cited by 17 publications

References 37 publications

Complementary Role of GlcNAc6ST2 and GlcNAc6ST3 in Synthesis of CL40-Reactive Sialylated and Sulfated Glycans in the Mouse Pleural Mesothelium

Complementary Role of GlcNAc6ST2 and GlcNAc6ST3 in Synthesis of CL40-Reactive Sialylated and Sulfated Glycans in the Mouse Pleural Mesothelium

Towards Enhanced MRI Performance of Tumor-Specific Dimeric Phenylboronic Contrast Agents

HEG1 as a novel potential biomarker for the prognosis of lung adenocarcinoma

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