Identification of fucosylated haptoglobin‐producing cells in pancreatic cancer tissue and its molecular mechanism

Ito, Nami; Yamada, M.; Morishita, Koichi; Nojima, Satoshi; Motooka, Kei; Sakata, Natsumi; Asuka, Tatsuya; Otsu, Ryoji; Takamatsu, Shinji; Kamada, Y.; Mori, Soichiro; Akita, Hirofumi; Eguchi, Hidetoshi; Morii, Eiichi; Miyoshi, Eiji

doi:10.1007/s10719-020-09970-8

Cited by 8 publications

(10 citation statements)

References 16 publications

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Section: Discussionmentioning

confidence: 99%

“…Fucosylation is an oligosaccharide modification that plays a critical role in immune response and malignancy 12 , 19 – 21 . Recently, fucosylation was reported to be associated with different physiological and pathological processes depending on the tumour type, focusing on its roles in cancer cell proliferation, invasion, and metastasis and in tumour immune surveillance 12 , 22 . Furthermore, several studies have reported that fucosylation affects T cell-mediated tumour immune surveillance through core fucosylation of T cell receptors or PD-1 on T cells 23 – 25 .…”

Section: Discussionmentioning

confidence: 99%

“…In our previous studies, lectin-antibody enzyme-linked immunosorbent assay (ELISA) was used to measure serum fucosylated haptoglobin (Fut-Hp) levels and revealed significantly increased serum Fut-Hp levels in several types of cancer and inflammatory bowel diseases 8 – 10 . Recent studies have highlighted the importance of fucosylation in immune cell development and functional regulation and have significantly broadened the role of fucosylation in cancer immunity and inflammatory diseases 8 , 11 , 12 .…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of serum fucosylated pro-haptoglobin in advanced renal cell carcinoma patients treated with immune checkpoint inhibitors

Kato,

Morishita,

Tomiyama

et al. 2023

Sci Rep

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With the widespread use of immune checkpoint inhibitors (ICIs), identifying predictive biomarkers is critical. Recently, serum fucosylated haptoglobin (Fuc-Hp) was thought to play an important role in tumour immunity in several types of cancer. Therefore, evaluating serum Fuc-Hp in the peripheral blood can potentially identify non-invasive predictive biomarkers for the clinical efficacy of ICIs. In this study, 31 patients with advanced renal cell carcinoma (RCC) treated with nivolumab were enrolled and defined as responders or non-responders according to RECIST criteria. Serum samples were collected before and 1 month after treatment initiation, and an ELISA assay was performed using Aleuria Aurantia Lectin (AAL) and 10-7G monoclonal antibodies that recognise Fuc-mature Hp (Fuc-mHp) and Fuc-pro Hp (Fuc-pHp), respectively. We first measured AAL-haptoglobin (Fuc-mHp) and total haptoglobin levels before nivolumab and found that neither value could predict the clinical response. Notably, serum 10-7G levels were significantly lower in the responder group (p = 0.035). We also confirmed the use of serum 10-7G levels for predicting progressive disease after nivolumab (area under the curve, 0.816). Accordingly, low 10-7G levels were significantly correlated with better progression-free survival (p = 0.041). In conclusion, serum Fuc-pHp analysis may identify patients with advanced RCC who benefit from ICIs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of serum fucosylated pro-haptoglobin in advanced renal cell carcinoma patients treated with immune checkpoint inhibitors

Kato,

Morishita,

Tomiyama

et al. 2023

Sci Rep

Self Cite

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“…However, it is still unclear whether proHp exits in tumor tissues or microenvironment of hepatoma cancers, while the presence of proHp in the sera of patients with hepatic and pancreatic cancers has been shown [ 24 , 39 ]. A recent study demonstrated that immune cells, particularly macrophages, in pancreatic cancer microenvironment produce fucosylated proHp [ 40 ]. If in vivo evidences are accumulated for the proHp expression and its regulating functions on EMT in liver cancer microenvironment, proHp could be proposed as a candidate biomarker of HCC metastasis and progression.…”

Section: Discussionmentioning

confidence: 99%

Prohaptoglobin inhibits the transforming growth factor-β-induced epithelial-to-mesenchymal transition in vitro by increasing Smad1/5 activation and suppressing the Smad2/3 signaling pathway in SK-Hep1 liver cancer cells

Joo

Kim

2022

PLoS ONE

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Transforming growth factor-β (TGF-β) is an important inducer of the epithelial-to-mesenchymal transition (EMT) in various cancers. Our previous study demonstrated that prohaptoglobin (proHp) stimulates Smad1/5 activation via ALK1, a TGF-β type I receptor, in endothelial cells, suggesting that proHp plays a role in TGF-β signaling. However, the function of proHp in cellular events downstream of Smads remains unclear. The current study investigated the effects of proHp on TGF-β-mediated Smad-dependent EMT induction and cell invasion in vitro using proHp-overexpressing SK-Hep1 liver cancer cells. The results of Western blotting, quantitative real-time RT-PCR, and immunocytochemistry indicated that proHp downregulated expression of mesenchymal marker and EMT regulator such as N-cadherin, vimentin, and twist, and upregulated expression of the epithelial marker E-cadherin. Compared with control cells, proHp-overexpressing cells exhibited high levels of ALK1/2/3 receptors and markedly increased Smad1/5 phosphorylation. Interestingly, proHp attenuated TGF-β-induced expression of mesenchymal markers and Smad2/3 phosphorylation. It also significantly suppressed cell invasion and migration. Knockdown of Smad1/5 abolished the inhibitory effects of proHp on TGF-β-stimulated Smad2/3 phosphorylation and mesenchymal marker expression. These findings indicate that proHp suppresses the TGF-β-induced EMT and cell invasion in vitro by enhancing Smad1/5 activation via ALK1/2/3 receptors and thus suppressing the Smad2/3 signaling pathway in SK-Hep1 cells. This study suggests that proHp may prevent a de-differentiation of hepatic cells and induce a cell differentiation by regulating the Smad signaling pathway.

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“…Core-fucosylated αAFP, which is characteristically present in the serum of patients with hepatocellular carcinoma, is detected by combining the core fucose recognition lectin ( Lens culinaris agglutinin; LCA), with an anti-αAFP antibody ( 19 – 21 ). In addition, core-fucosylated haptoglobins are promising diagnostic marker candidates for pancreatic cancer ( 22 , 23 ).…”

Section: Introductionmentioning

confidence: 99%

Targeted O-glycoproteomics for the development of diagnostic markers for advanced colorectal cancer

et al. 2023

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Aberrant glycosylation is a prominent feature of cancer, that can be used as targets to improve the existing cancer biomarkers, and help to assess metastasis risks, and therapeutic effects. We developed a targeted O-glycoproteomics method using serum specimens, and evaluated its utility in identifying advanced colorectal cancer (CRC) markers. To this end, we combined consecutive lectin affinity purification using Maclura pomifera lectin (MPL), jacalin, and Sambucus nigra lectin, which have affinities for the following O-glycans, that have received attention as cancer-related antigens, Tn (GalNAc-Ser/Thr), Sialyl Tn (Siaα2-6GalNAc-Ser/Thr), T (Galβ1-3GalNAc-Ser/Thr), Sialyl T (Siaα2-3Galβ1-GalNAc-Ser/Thr), and di-Sialyl T (Siaα2-3Galβ1-3[Siaα2-6] GalNAc-Ser/Thr), with a unique O-glycoproteomics approach. A total of 2,068 O-glycoforms derived from 265 proteins were identified in healthy individuals and patients with advanced CRC, of which 44 CRC-specific O-glycoforms were extracted. Particularly, five glycoproteins with T, Sialyl T, and di-Sialyl T antigens in specific peptide regions were evaluated quantitatively and statistically. We found that fibulin-2 (FBLN2) (aa330-349)/T antigen (area under the curve [AUC] = 0.92); macrophage colony-stimulating factor 1 (CSF1) (aa370-395)/(T + di-Sialyl T) (AUC = 0.94); macrophage mannose receptor 1 (MRC1) (aa1083-1101 and aa1215-1229)/T (AUC = 0.96 and 0.99); fibrinogen alpha chain (FGA) (aa354-367, aa511-527 and aa559-573)/Sialyl T (AUC = 0.98, 0.90 and 0.94); and complement component C7 (C7) (aa692-701)/di-Sialyl T (AUC = 1.00), can have high diagnostic efficacy to strategically predict advanced CRC groups. Hence, they could be promising markers for detection of advanced CRC, and provide new clinical test indicators along with lectins, such as MPL and jacalin. Our O-glycoproteomics platform provides a novel tool and resource, for researchers and clinicians seeking to better understand and treat advanced CRC.

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Identification of fucosylated haptoglobin‐producing cells in pancreatic cancer tissue and its molecular mechanism

Cited by 8 publications

References 16 publications

Prognostic significance of serum fucosylated pro-haptoglobin in advanced renal cell carcinoma patients treated with immune checkpoint inhibitors

Prognostic significance of serum fucosylated pro-haptoglobin in advanced renal cell carcinoma patients treated with immune checkpoint inhibitors

Prohaptoglobin inhibits the transforming growth factor-β-induced epithelial-to-mesenchymal transition in vitro by increasing Smad1/5 activation and suppressing the Smad2/3 signaling pathway in SK-Hep1 liver cancer cells

Targeted O-glycoproteomics for the development of diagnostic markers for advanced colorectal cancer

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