Chitinase 3 like 1 (CHI3L1) promotes vasculogenic mimicry formation in cervical cancer

Ngernyuang, Nipaporn; Shao, Rong; Suwannarurk, Komsun; Limpaiboon, Temduang

doi:10.1016/j.pathol.2017.09.015

Cited by 20 publications

(18 citation statements)

References 35 publications

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“…Chi3L1 do not possess chitinase activity and fails to degrade chitin due to amino acid mutations within the proposed catalytic site (conserved sequence: DXXDXDXE; YKL-40 sequence: DGLDLAWL) although Chi3L1 has homologous sequence to bacterial and fungal chitinases [11,38]. High expression of Chi3L1 is found in pathological conditions [20][21][22][23][24][25][26][27][28][29][30][31], but the clinical implications and function of Chi3L1 are still elusive. In these experiments, we generated Chi3L1 KO(−/−) mice using CRISPR/ Cas9 system and found that the Chi3L1 KO(−/−) mice significantly reduced lung tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Chitinase 3-like-1 (Chi3L1), also called a breast regression protein 39 (BRP-39) in mouse and YKL-40 in human, is known as a secreted glycoprotein and prototypic mammalian chitinase like protein [11,12]. Increased expression of Chi3L1 protein and mRNA have been shown in various disease models and states including rheumatoid arthritis schizophrenics, inflammatory bowel disease, chronic obstructive pulmonary disease, asthma, diabetes, and atherosclerosis [13][14][15][16][17][18][19], Especially, Chi3L1 expression has been found in a variety of cancer cells such as breast, lung, prostate, colon, rectum, ovary, kidney, breast, glioblastomas, and malignant melanoma [20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis

et al. 2020

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Background: Chitinase 3 like 1 protein (Chi3L1) is expressed in several cancers, and a few evidences suggest that the secreted Chi3L1 contributes to tumor development. However, the molecular mechanisms of intracellular Chi3L1 are unknown in the lung tumor development. Methods: In the present study, we generated Chi3L1 knockout mice (Chi3L1 KO(−/−) ) using CRISPR/Cas9 system to investigate the role of Chi3L1 on lung tumorigenesis. Results:We established lung metastasis induced by i.v. injections of B16F10 in Chi3L1 KO(−/−) . The lung tumor nodules were significantly reduced in Chi3L1 KO(−/−) and protein levels of p53, p21, BAX, and cleaved-caspase 3 were significantly increased in Chi3L1 KO(−/−) , while protein levels of cyclin E1, CDK2, and phsphorylation of STAT3 were decreased in Chi3L1 KO(−/−) . Allograft mice inoculated with B16F10 also suppressed tumor growth and increased p53 and its target proteins including p21 and BAX. In addition, knockdown of Chi3L1 in lung cancer cells inhibited lung cancer cell growth and upregulated p53 expression with p21 and BAX, and a decrease in phosphorylation of STAT3. Furthermore, we found that intracellular Chi3L1 physically interacted and colocalized with p53 to inhibit its protein stability and transcriptional activity for target genes related with cell cycle arrest and apoptosis. In lung tumor patient, we clinically found that Chi3L1 expression was upregulated with a decrease in p53 expression, as well as we validated that intracellular Chi3L1 was colocalized, reversely expressed, and physically interacted with p53, which results in suppression of the expression and function of p53 in lung tumor patient.Conclusions: Our studies suggest that intracellular Chi3L1 plays a critical role in the lung tumorigenesis by regulating its novel target protein, p53 in both an in vitro and in vivo system.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis

et al. 2020

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“…In particular, phage display is a powerful tool that has been proved to be highly effective for the selection of human antibodies through diverse human phage display libraries, mostly in either a naïve format generated from human peripheral blood mononuclear cells (PBMCs) or a semi-synthetic format constructed on a selected VH and VL scaffold by randomizing their CDRs [ 31 , 32 , 33 , 34 ]. Given the increased therapeutic value of YKL-40, many studies employing antibodies targeting hYKL-40 have been performed and reported that the antibodies are effective to modulate the biological processes that YKL-40 is involved, such as growth, differentiation, and metastasis of cancer cells [ 23 , 24 , 25 ] but most of the studies were performed with antibodies from mouse hybridoma and thus this is believed to be the first report of human antibodies targeting hYKL-40 identified from a human synthetic antibody phage display library. Moreover, human antibodies had desirable biophysical properties in terms of affinity, thermal stability, and non-aggregation, which are essential for the development of therapeutics.…”

Section: Discussionmentioning

confidence: 99%

“…K284-6111, a YKL-40 inhibitor, reduces the expression of neuroinflammatory genes such as COX-2, iNOS, and GFAP in AD animal model through downregulation of NF-kB pathway, resulting in attenuation of memory dysfunction [ 22 ]. In addition to YKL-40-inhibiting small compounds, anti-YKL-40 antibodies were also found to attenuate angiogenesis via inhibition of tumor vascularization in brain and breast cancers [ 23 , 24 , 25 ].…”

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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“…Therefore, the identification and comprehensive understanding of novel molecules in the detailed roles of intracellular pathways in OS progression may represent promising therapeutic strategies for the treatment of patients with this malignancy. Recently, chitinase 3 like 1 (Chi3L1) expression has been found in a variety of cancer cells such as breast, lung, prostate, colon, rectum, ovary, kidney, glioblastomas, and malignant melanoma (14)(15)(16)(17)(18)(19)(20). We also previously selected 20 chemicals as candidate compounds for the ligand of Chi3L1 by using 3D chemical database analysis with X-ray structure-based virtual screening (21), and G721-0282 was obtained from ChemiDiv Inc. (http://www.chemdiv.com).…”

Section: Ivyspringmentioning

confidence: 99%

G721-0282 inhibits cell growth and induces apoptosis in human osteosarcoma through down-regulation of the STAT3 pathway

Park¹,

Yun²,

Hong³

2020

Int. J. Biol. Sci.

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Osteosarcoma (OS) is considered the most common type of primary malignant bone tumor, which has an urgent need for more effective treatment. Recently, chitinase 3 like 1 (Chi3L1) expression has been found in a variety of cancer cells. However it is not known whether Chi3L1 regulates the STAT3 pathway in OS cells. Herein, we examined the effects of the G721-0282, a ligand of Chi3L1, in vitro and in vivo against OS cells. G721-0282 inhibited the proliferation of OS cells and induced apoptosis. This apoptosis was accompanied by upregulation of apoptotic proteins (PARP and procaspase-3), but downregulation of anti-apoptotic proteins (Survivin and Bcl-2). G721-0282 induced the inactivation of mitogen-activated protein kinases (MAPKs) with a decrease in the phosphorylation of Src and STAT3 in OS cells. Importantly, overexpression of Chi3L1 potentiated the effects of G721-0282, while knockdown of Chi3L1 attenuated the effects of G721-0282. Docking model study also showed that G721-0282 interacted with Chi3L1. In addition, G721-0282 inhibited cell migration, invasion, and colony formation. Furthermore, the anti-tumor effects of G721-0282 were observed in an xenograft in vivo model in association with the reduced expression of Chi3L1, PCNA, Cyclin D1, p-STAT3, as well as the increased expression of Chi3L1 was correlated with the p-STAT3 level in human bone tumor tissues. Taken together, a Chi3L1 ligand, G721-0282 may be an attractive therapeutic strategy for OS, especially in vitro and in vivo anti-proliferative effects against OS cells through the inhibition of the STAT3 pathway, and suggest the potentially therapeutic application of G721-0282 in the treatment of OS.

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Chitinase 3 like 1 (CHI3L1) promotes vasculogenic mimicry formation in cervical cancer

Cited by 20 publications

References 35 publications

Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis

Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis

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

G721-0282 inhibits cell growth and induces apoptosis in human osteosarcoma through down-regulation of the STAT3 pathway

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