Roles of chitinase 3-like 1 in the development of cancer, neurodegenerative diseases, and inflammatory diseases

Yeo, In Jun; Lee, Chong-Kil; Han, Sang‐Bae; Yun, Jaesuk; Hong, Jin Tae

doi:10.1016/j.pharmthera.2019.107394

Cited by 100 publications

(113 citation statements)

References 264 publications

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“…Little is known about how CHI3L1 functions in the in ammatory response, but it plays an critical role in exacerbating the process of in ammation [45]. In the brain, the activated microglia due to neuroin ammation produce CHI3L1 [46]. San lippo et al discussed that the secretion of CHI3L1 by microglia and astrocytes could lead to peripheral immune cell in ltration including monocyte and macrophage to brain and consequently could increase neuronal death [22].…”

Section: Discussionmentioning

confidence: 99%

K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

Ham

Lee

Yun

et al. 2020

Preprint

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Background Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms. We have previously demonstrated that the 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), the inhibitor of CHI3L1, has an inhibitory effect on memory impairment in Αβ infusion mouse model and on LPS-induced neuroinflammation in the murine BV-2 microglia and primary cultured astrocyte. Methods In the present study, we investigated that the inhibitory effect of K284-6111 on memory dysfunction and neuroinflammation in Tg2576 transgenic mice, and more detailed correlation of CHI3L1 and AD. To investigate the effects of K284-6111 on memory dysfunction, we administered K284-6111 (3 mg/kg, p.o.) daily for four weeks to Tg2576, followed by behavioral tests of water maze test, probe test, and passive avoidance test.Results Administration of K284-6111 alleviated memory impairment in Tg2576 mice and had the effect of reducing accumulation of Aβ and neuroinflammatory responses in the mouse brain. K284-6111 treatment also selectively inactivated ERK and NF-κB pathways, which were activated when CHI3L1 was overexpressed, in mouse brain and in BV-2 cells. Web-based gene network analysis and our results of gene expression level in BV-2 cells showed that CHI3L1 is closely correlated with PTX3. Our result revealed that knockdown of PTX3 has inhibitory effect on the production of inflammatory proteins and cytokines, and on the phosphorylation of ERK and IκBα.Conclusion These results suggest that K284-6111 could improve memory dysfunction by alleviating neuroinflammation through inhibiting CHI3L1 through blocking ERK dependent PTX3 pathway.

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Section: Discussionmentioning

confidence: 99%

K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

Ham

Lee

Yun

et al. 2020

Preprint

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“…Although the CNS was previously considered an immuneprivileged site, it is now evident that neuroimmune interactions within the brain and between brain and circulating immune cells and molecules are important both in disease and normal brain function (39). IL-6 and YKL-40 are both involved in complex immune modulatory systems, cancer propagation, and regulate each other's expression (5,9,18,40,41). In the present study we evaluated the correlation between IL-6 plasma levels, YKL-40 plasma levels, CHI3L1 rs4950928 SNP genotype, and survival of newly diagnosed and recurrent GBM.…”

Section: Discussionmentioning

confidence: 99%

“…IL-6 and YKL-40 regulate each other's transcription levels along with a range of other mediators (9,18) and IL-6 infusion increased YKL-40 secretion in plasma in healthy volunteers (19). High or increasing levels of circulating IL-6 or YKL-40 have been associated with decreased survival of patients with glioma either alone or in combination with other biomarkers (12,(20)(21)(22)(23)(24), although not consistently (25)(26)(27)(28)(29)(30) (Supplementary File 1).…”

Section: Introductionmentioning

confidence: 99%

Systemic Immune Modulation in Gliomas: Prognostic Value of Plasma IL-6, YKL-40, and Genetic Variation in YKL-40

et al. 2020

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Background: Complex local and systemic immune dysfunction in glioblastoma (GBM) may affect survival. Interleukin (IL)-6 and YKL-40 are pleiotropic biomarkers present in the tumor microenvironment and involved in immune regulation. We therefore analyzed plasma IL-6, YKL-40, and genetic variation in YKL-40 and explored their ability to distinguish between glioma subtypes and predict survival in GBM. Methods: One hundred fifty-eight patients with glioma WHO grade II-IV were included in the study. Plasma collected at surgery was analyzed for IL-6 and YKL-40 (CHI3L1) by ELISA. CHI3L1 rs4950928 genotyping was analyzed on whole-blood DNA. Results: Neither plasma IL-6 nor YKL-40 corrected for age or rs4950928 genotype could differentiate GBM from lower grade gliomas. GC and GG rs4950928 genotype were associated with lower plasma YKL-40 levels (CC vs. GC, p = 0.0019; CC vs. GG, p = 0.01). Only 10 and 14 out of 94 patients with newly diagnosed GBM had elevated IL-6 or YKL-40, respectively. Most patients received corticosteroid treatment at time of blood-sampling. Higher pretreatment plasma IL-6 was associated with short overall survival (OS) [HR = 1.19 (per 2-fold change), p = 0.042] in univariate analysis. The effect disappeared in multivariate analysis. rs4950928 genotype did not associate with OS [HR = 1.30, p = 0.30]. In recurrent GBM, higher YKL-40 [HR = 2.12 (per 2fold change), p = 0.0005] but not IL-6 [HR = 0.99 (per 2-fold change), p = 0.92] were associated with short OS in univariate analysis. Conclusion: In recurrent GBM high plasma YKL-40 may hold promise as a prognostic marker. In newly diagnosed GBM perioperative plasma IL-6, YKL-40, and genetic variation in YKL-40 did not associate with survival. Corticosteroid use may complicate interpretation of results.

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“…YKL-40, also known as chitinase 3-like 1 (Chi3L1), is a 40 kDa secreted glycoprotein belonging to the family of chitinase-like proteins (CLPs) [ 1 ]. It is a highly conserved chitin-binding protein and its crystallographic three-dimensional structures reveal the typical fold of the chitinase family protein but lacks chitinase activity due to mutation of an essential amino acid residue in its catalytic domain [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is a highly conserved chitin-binding protein and its crystallographic three-dimensional structures reveal the typical fold of the chitinase family protein but lacks chitinase activity due to mutation of an essential amino acid residue in its catalytic domain [ 2 ]. YKL-40 is overexpressed in cancers and tumor-associated macrophages, and its serum levels are elevated in patients with metastatic cancers and in various chronic inflammatory diseases, implicating pathological role of YKL-40 in cancer progression, metastasis, and inflammation [ 1 , 3 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Selection and Characterization of YKL-40-Targeting Monoclonal Antibodies from Human Synthetic Fab Phage Display Libraries

Kang

Kim

Lee

et al. 2020

IJMS

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YKL-40, also known as chitinase-3-like 1 (CHI3L1), is a glycoprotein that is expressed and secreted by various cell types, including cancers and macrophages. Due to its implications for and upregulation in a variety of diseases, including inflammatory conditions, fibrotic disorders, and tumor growth, YKL-40 has been considered as a significant therapeutic biomarker. Here, we used a phage display to develop novel monoclonal antibodies (mAbs) targeting human YKL-40 (hYKL-40). Human synthetic antibody phage display libraries were panned against a recombinant hYKL-40 protein, yielding seven unique Fabs (Antigen-binding fragment), of which two Fabs (H1 and H2) were non-aggregating and thermally stable (75.5 °C and 76.5 °C, respectively) and had high apparent affinities (KD = 2.3 nM and 4.0 nM, respectively). Reformatting the Fabs into IgGs (Immunoglobulin Gs) increased their apparent affinities (notably, for H1 and H2, KD = 0.5 nM and 0.3 nM, respectively), presumably due to the effects of avidity, with little change to their non-aggregation property. The six anti-hYKL-40 IgGs were analyzed using a trans-well migration assay in vitro, revealing that three clones (H1, H2, and H4) were notably effective in reducing cell migration from both A549 and H460 lung cancer cell lines. The three clones were further analyzed in an in vivo animal test that assessed their anti-cancer activities, demonstrating that the tumor area and the number of tumor nodules were significantly reduced in the lung tissues treated with H1 (IgG). Given its high affinity and desirable properties, we expect that the H1 anti-hYKL-40 mAb will be a suitable candidate for developing anti-cancer therapeutics.

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Roles of chitinase 3-like 1 in the development of cancer, neurodegenerative diseases, and inflammatory diseases

Cited by 100 publications

References 264 publications

K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

Systemic Immune Modulation in Gliomas: Prognostic Value of Plasma IL-6, YKL-40, and Genetic Variation in YKL-40

Selection and Characterization of YKL-40-Targeting Monoclonal Antibodies from Human Synthetic Fab Phage Display Libraries

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