Molecular Mechanism of Inhibition of Polysialyltransferase Domain (PSTD) by Heparin

: Polysialic acid (polySia) is a unique carbohydrate polymer produced on the neuronal cell adhesion molecule (NCAM) in many cancer cells. It strongly correlates with the migration and invasion of tumor cells and aggressive, metastatic disease, and poor clinical prognosis in the clinic. Its synthesis is catalyzed by two polysialyltransferases (polySTs), ST8SiaIV (PST) and ST8SiaII (STX). Therefore, selective inhibition of polySTs presents a therapeutic opportunity to inhibit tumor invasion and metastasis due to NCAM polysialylation. It has been proposed that NCAM polysialylation could be inhibited by two types of heparin inhibitors, low molecular heparin (LMWH) and heparin tetrasaccharide (DP4). This review summarizes the interactions between Polysialyltransferase Domain (PSTD) in ST8SiaIV and CMP-Sia, and between the PSTD and polySia; and how LMWH and DP4 inhibit these interactions. Our NMR studies indicate that LMWH is a more effective inhibitor than DP4 for inhibition of NCAM polysialylation. The NMR identification of heparin-binding sites in the PSTD may provide insight into the design of specific inhibitors of polysialylation.

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The Inhibition of Polysialyltranseferase ST8SiaIV Through Heparin Binding to Polysialyltransferase Domain (PSTD)

Medicinal Chemistry ◽

10.2174/1573406415666181218101623 ◽

2019 ◽

Vol 15 (5) ◽

pp. 486-495 ◽

Cited By ~ 7

Author(s):

Li-Xin Peng ◽

Xue-Hui Liu ◽

Bo Lu ◽

Si-Ming Liao ◽

Feng Zhou ◽

...

Keyword(s):

Fluorescence Quenching ◽

Polysialic Acid ◽

Neuronal Cell ◽

Cd Spectroscopy ◽

Migration And Invasion ◽

Heparin Binding ◽

Clinical Prognosis ◽

Quenching Analysis ◽

Different Types ◽

Α Helix

Background:The polysialic acid (polySia) is a unique carbohydrate polymer produced on the surface Of Neuronal Cell Adhesion Molecule (NCAM) in a number of cancer cells, and strongly correlates with the migration and invasion of tumor cells and with aggressive, metastatic disease and poor clinical prognosis in the clinic. Its synthesis is catalyzed by two polysialyltransferases (polySTs), ST8SiaIV (PST) and ST8SiaII (STX). Selective inhibition of polySTs, therefore, presents a therapeutic opportunity to inhibit tumor invasion and metastasis due to NCAM polysialylation. Heparin has been found to be effective in inhibiting the ST8Sia IV activity, but no clear molecular rationale. It has been found that polysialyltransferase domain (PSTD) in polyST plays a significant role in influencing polyST activity, and thus it is critical for NCAM polysialylation based on the previous studies.Objective:To determine whether the three different types of heparin (unfractionated hepain (UFH), low molecular heparin (LMWH) and heparin tetrasaccharide (DP4)) is bound to the PSTD; and if so, what are the critical residues of the PSTD for these binding complexes?Methods:Fluorescence quenching analysis, the Circular Dichroism (CD) spectroscopy, and NMR spectroscopy were used to determine and analyze interactions of PSTD-UFH, PSTD-LMWH, and PSTD-DP4.Results:The fluorescence quenching analysis indicates that the PSTD-UFH binding is the strongest and the PSTD-DP4 binding is the weakest among these three types of the binding; the CD spectra showed that mainly the PSTD-heparin interactions caused a reduction in signal intensity but not marked decrease in α-helix content; the NMR data of the PSTD-DP4 and the PSTDLMWH interactions showed that the different types of heparin shared 12 common binding sites at N247, V251, R252, T253, S257, R265, Y267, W268, L269, V273, I275, and K276, which were mainly distributed in the long α-helix of the PSTD and the short 3-residue loop of the C-terminal PSTD. In addition, three residues K246, K250 and A254 were bound to the LMWH, but not to DP4. This suggests that the PSTD-LMWH binding is stronger than the PSTD-DP4 binding, and the LMWH is a more effective inhibitor than DP4.Conclusion:The findings in the present study demonstrate that PSTD domain is a potential target of heparin and may provide new insights into the molecular rationale of heparin-inhibiting NCAM polysialylation.

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The value of miR-510 in the prognosis and development of colon cancer

Open Medicine ◽

10.1515/med-2021-0251 ◽

2021 ◽

Vol 16 (1) ◽

pp. 795-804

Author(s):

Junjie Hang ◽

Feifei Wei ◽

Zhiying Yan ◽

Xianming Zhang ◽

Kequn Xu ◽

...

Keyword(s):

Colon Cancer ◽

Cell Proliferation ◽

Cultured Cells ◽

Malignant Tumors ◽

Prognostic Indicator ◽

Tumor Promoter ◽

Migration And Invasion ◽

Clinical Prognosis ◽

Normal Tissues ◽

Novel Therapeutic Strategies

Abstract Purpose Colon cancer is one of the malignant tumors that threatens human health. miR-510 was demonstrated to play roles in the progression of various cancers; its dysregulation was speculated to be associated with the development of colon cancer. Methods One hundred and thirteen colon cancer patients participated in this research. With the help of RT-qPCR, the expression of miR-510 in collected tissues and cultured cells was analyzed. The association between miR-510 expression level and clinical features and prognosis of patients was evaluated. Moreover, the effects of miR-510 on cell proliferation, migration, and invasion of colon cancer were assessed by CCK8 and Transwell assay. Results miR-510 significantly upregulated in colon cancer tissues and cell lines relative to the adjacent normal tissues and colonic cells. The expression of miR-510 was significantly associated with the TNM stage and poor prognosis of patients, indicating miR-510 was involved in the disease progression and clinical prognosis of colon cancer. Additionally, the upregulation of miR-510 significantly promoted cell proliferation, migration, and invasion of colon cancer, while its knockdown significantly inhibited these cellular processes. SRCIN 1 was the direct target of miR-510 during its promoted effect on the development of colon cancer. Conclusion The upregulation of miR-510 acts as an independent prognostic indicator and a tumor promoter by targeting SRCIN 1 in colon cancer, which provides novel therapeutic strategies for colon cancer.

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Selective inhibition of platelet macroaggregate formation by a recombinant heparin-binding domain of human thrombospondin.

Arteriosclerosis and Thrombosis A Journal of Vascular Biology ◽

10.1161/01.atv.14.11.1784 ◽

1994 ◽

Vol 14 (11) ◽

pp. 1784-1791 ◽

Cited By ~ 22

Author(s):

C Legrand ◽

V Morandi ◽

S Mendelovitz ◽

H Shaked ◽

J R Hartman ◽

...

Keyword(s):

Selective Inhibition ◽

Binding Domain ◽

Heparin Binding ◽

Heparin Binding Domain

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Association of the neuronal cell adhesion molecule (NRCAM) gene variants with autism

The International Journal of Neuropsychopharmacology ◽

10.1017/s1461145708009127 ◽

2008 ◽

Vol 12 (01) ◽

pp. 1 ◽

Cited By ~ 45

Author(s):

Tetsuya Marui ◽

Ikuko Funatogawa ◽

Shinko Koishi ◽

Kenji Yamamoto ◽

Hideo Matsumoto ◽

...

Keyword(s):

Cell Adhesion ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Neuronal Cell ◽

Gene Variants ◽

Neuronal Cell Adhesion Molecule

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Downexpression of HSD17B6 correlates with clinical prognosis and tumor immune infiltrates in hepatocellular carcinoma

Cancer Cell International ◽

10.1186/s12935-020-01298-5 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Lei Lv ◽

Yujia Zhao ◽

Qinqin Wei ◽

Ye Zhao ◽

Qiyi Yi

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Immune Responses ◽

Cancer Cells ◽

Negative Regulator ◽

Functional Enrichment ◽

Migration And Invasion ◽

Relative Reduction ◽

Clinical Prognosis ◽

Liver Cancer Cells

Abstract Background Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6), a key protein involved in synthetizing dihydrotestosterone, is abundant in the liver. Previous studies have suggested a role for dihydrotestosterone in modulating progress of various malignancies, and HSD17B6 dysfunction was associated with lung cancer and prostate cancer. However, little is known about the detailed role of HSD17B6 in hepatocellular carcinoma (HCC). Methods Clinical implication and survival data related to HSD17B6 expression in patients with HCC were obtained through TCGA, ICGC, ONCOMINE, GEO and HPA databases. Survival analysis plots were drawn with Kaplan–Meier Plotter. The ChIP-seq data were obtained from Cistrome DB. Protein–Protein Interaction and gene functional enrichment analyses were performed in STRING database. The correlations between HSD17B6 and tumor immune infiltrates was investigated via TIMER and xCell. The proliferation, migration and invasion of liver cancer cells transfected with HSD17B6 were evaluated by the CCK8 assay, wound healing test and transwell assay respectively. Expression of HSD17B6, TGFB1 and PD-L1 were assessed by quantitative RT-PCR. Results HSD17B6 expression was lower in HCC compared to normal liver and correlated with tumor stage and grade. Lower expression of HSD17B6 was associated with worse OS, PFS, RFS and DSS in HCC patients. HNF4A bound to enhancer and promoter regions of HSD17B6 gene, activating its transcription, and DNA methylation of HSD17B6 promoter negatively controlled the expression. HSD17B6 and its interaction partners were involved in androgen metabolism and biosynthesis in liver. HSD17B6 inhibited tumor cell proliferation, migration and invasion in liver cancer cells and low expression of HSD17B6 correlated with high immune cells infiltration, relative reduction of immune responses and multiple immune checkpoint genes expression in HCC, probably by regulating the expression of TGFB1. Conclusions This study indicate that HSD17B6 could be a new biomarker for the prognosis of HCC and an important negative regulator of immune responses in HCC.

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