YKL-40/CHI3L1 drives inflammation on the road of tumor progression.
Libreros Stephania,Iragavarapu-Charyulu Vijaya
Journal of leukocyte biology
Inflammation plays a vital role at different stages of tumor progression. The development of tumors is affected by inflammatory mediators produced by the tumor and the host. YKL-40/chitinase-3-like-1 protein is often up-regulated in inflammation-associated diseases. With the use of chronic inflammatory disease systems, we describe the role of YKL-40/chitinase-3-like-1 protein in enhancing the inflammatory response and its implications in tumorigenesis. We also discuss how pre-existing inflammation enhances tumor growth and metastasis. In this mini-review, we highlight the effect of YKL-40/chitinase-3-like-1 protein-associated inflammation in promoting tumor progression.
High Endogenous Expression of Chitinase 3-Like 1 and Excessive Epithelial Proliferation with Colonic Tumor Formation in MOLF/EiJ Mice.
Low Daren,DeGruttola Arianna K,Poltrak Alexander,Mizoguchi Atsushi,Mino-Kenudson Mari,Mizoguchi Emiko
Colorectal cancer (CRC) development is mediated by uncontrolled survival and proliferation of tumor progenitor cells. Using animal models to identify and study host-derived factors that underlie this process can aid interventions in preventing tumor expansion and metastasis. In healthy steady states in humans and mice (e.g. C57BL/6 strain), colonic Chitinase 3-like 1 (CHI3L1) gene expression is undetectable. However, this expression can be induced during intestinal inflammation and tumorigenesis where CHI3L1 plays an important role in tissue restitution and cell proliferation. Here, we show that a wild-derived mouse strain MOLF/EiJ expresses high levels of colonic epithelial CHI3L1 at the steady state due to several nucleotide polymorphisms in the proximal promoter regions of the CHI3L1 gene. Interestingly, these mice spontaneously developed polypoid nodules in the colon with signs of immune cell infiltrations at steady state. The CHI3L1 positive colonic epithelial cells were highly proliferative and exhibited malignant transformation and expansion when exposed in vivo to azoxymethane, one of the well-known colonic carcinogens.
Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9.
Low Daren,Subramaniam Renuka,Lin Li,Aomatsu Tomoki,Mizoguchi Atsushi,Ng Aylwin,DeGruttola Arianna K,Lee Chun Geun,Elias Jack A,Andoh Akira,Mino-Kenudson Mari,Mizoguchi Emiko
Many host-factors are inducibly expressed during the development of inflammatory bowel disease (IBD), each having their unique properties, such as immune activation, bacterial clearance, and tissue repair/remodeling. Dysregulation/imbalance of these factors may have pathogenic effects that can contribute to colitis-associated cancer (CAC). Previous reports showed that IBD patients inducibly express colonic chitinase 3-like 1 (CHI3L1) that is further upregulated during CAC development. However, little is known about the direct pathogenic involvement of CHI3L1 in vivo. Here we demonstrate that CHI3L1 (aka Brp39) knockout (KO) mice treated with azoxymethane (AOM)/dextran sulphate sodium (DSS) developed severe colitis but lesser incidence of CAC as compared to that in wild-type (WT) mice. Highest CHI3L1 expression was found during the chronic phase of colitis, rather than the acute phase, and is essential to promote intestinal epithelial cell (IEC) proliferation in vivo. This CHI3L1-mediated cell proliferation/survival involves partial downregulation of the pro-apoptotic S100A9 protein that is highly expressed during the acute phase of colitis, by binding to the S100A9 receptor, RAGE (Receptor for Advanced Glycation End products). This interaction disrupts the S100A9-associated expression positive feedback loop during early immune activation, creating a CHI3L1hi S100A9low colonic environment, especially in the later phase of colitis, which promotes cell proliferation/survival of both normal IECs and tumor cells.
CHI3L1 regulates PD-L1 and anti-CHI3L1-PD-1 antibody elicits synergistic antitumor responses.
Ma Bing,Akosman Bedia,Kamle Suchitra,Lee Chang-Min,He Chuan Hua,Koo Ja Seok,Lee Chun Geun,Elias Jack A
The Journal of clinical investigation
Evasion of the immune response is a hallmark of cancer, and programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) are major mediators of this immunosuppression. Chitinase 3-like 1 (CHI3L1) is induced in many cancers, where it portends a poor prognosis and contributes to tumor metastasis and spread. However, the mechanism(s) that CHI3L1 uses in metastasis have not been defined. Here we demonstrate that CHI3L1 regulates the expression of PD-L1, PD-L2, PD-1, LAG3, and TIM3 and plays a critical role in melanoma progression and lymphatic spread. CHI3L1 also contributed to IFN-γ-stimulated macrophage PD-L1 expression, and RIG-like helicase innate immunity suppressed CHI3L1, PD-L1, and melanoma progression. Individual antibodies against CHI3L1 or PD-1 had discrete antitumor effects and additive antitumor responses in metastasis models and T cell-tumor cell cocultures when administered simultaneously. Synergistic cytotoxic tumor cell death was seen in T cell-tumor cell cocultures, and significantly enhanced antitumor responses were seen in in vivo tumor models treated with bispecific antibodies that simultaneously target CHI3L1 and PD-1. CHI3L1 contributes to tumor progression by stimulating the PD-1/PD-L1 axis and other checkpoint molecules. The simultaneous targeting of CHI3L1 and the PD-1/PD-L1 axis with individual and, more powerfully, with bispecific antibodies represents a promising therapy for pulmonary metastasis and progression.
Faecal chitinase 3-like 1 is a reliable marker as accurate as faecal calprotectin in detecting endoscopic activity in adult patients with inflammatory bowel diseases.
Buisson A,Vazeille E,Minet-Quinard R,Goutte M,Bouvier D,Goutorbe F,Pereira B,Barnich N,Bommelaer G
Alimentary pharmacology & therapeutics
BACKGROUND:Faecal biomarkers are emerging tools in the assessment of mucosal healing in inflammatory bowel diseases (IBDs). AIM:To evaluate the accuracy of faecal chitinase 3-like 1(CHI3L1) compared to calprotectin in detecting endoscopic activity in IBD. METHODS:Overall, 86 IBD adults underwent colonoscopy consecutively and prospectively, with Crohn's disease Endoscopic Index of Severity (CDEIS) or Mayo endoscopic subscore calculation for ulcerative colitis, and stool collection. Faecal calprotectin was measured using quantitative immunochromatographic testing. Faecal CHI3L1 was quantified by ELISA. CHI3L1 cut-off value was determined using a receiver-operating curve. RESULTS:In 54 Crohn's disease patients, faecal CHI3L1 (ρ = 0.70, P < 0.001) and calprotectin (ρ = 0.74, P < 0.001) levels correlated with CDEIS and were significantly increased in patients with endoscopic ulceration. In patients with ileal Crohn's disease, faecal CHI3L1 seemed to be better correlated with CDEIS than faecal calprotectin (ρ = 0.78 vs. ρ = 0.62, P < 0.001 for both). CHI3L1 > 15 ng/g detected endoscopic ulceration in Crohn's disease with a sensitivity of 100% and a specificity of 63.6%, compared to faecal calprotectin > 250 μg/g showing a sensitivity of 90.5% and a specificity of 59.1%. In 32 ulcerative colitis patients, faecal CHI3L1 and calprotectin levels correlated with Mayo endoscopic subscore (ρ = 0.44 and 0.61, respectively, P < 0.001 for both) and were significantly increased in ulcerative colitis patients with endoscopic activity. In ulcerative colitis patients, faecal CHI3L1 > 15 ng/g predicted endoscopic activity with a sensitivity of 81.8% and a specificity of 80.0%, compared to faecal calprotectin>250 μg/g showing a sensitivity of 86.4% and a specificity of 80.0%. CONCLUSION:Faecal CHI3L1 is a reliable biomarker in detecting endoscopic activity in IBD.
Clinical significance of serum YKL-40 in Behçet disease.
Seo J,Ahn Y,Zheng Z,Kim B O,Choi M J,Bang D,Kim D Y
The British journal of dermatology
BACKGROUND:Serum YKL-40 is an inflammatory biomarker of endothelial dysfunction and may play a role in the inflammatory process of Behçet disease (BD). OBJECTIVES:Serum YKL-40 levels were evaluated in patients with BD in order to identify associations with other inflammatory cytokines and establish laboratory parameters. Serum YKL-40 levels were also compared with BD clinical features and disease activity. METHODS:In total, 112 patients with BD and 45 age- and sex-matched healthy volunteers were included. Disease activity was assessed with BD Current Activity Form score and Electronic Medical Record-based Activity Index (EMRAI) score. RESULTS:Serum YKL-40 levels were significantly higher in patients with BD (median 41·88, range 12·52-171·30 ng mL(-1) ) than in healthy volunteers (median 20·92, range 5·01-64·20 ng mL(-1) ; P < 0·01). The cut-off value for YKL-40 (30·005 ng mL(-1) ) was determined from the receiver operating characteristic curve. EMRAI scores and the proportion of patients in the active phase of BD presenting with two or more major criteria were significantly higher in patients with elevated YKL-40 levels (P = 0·04 and P = 0·04, respectively). A statistically significant elevation in YKL-40 levels was observed in patients with active BD compared with patients with inactive BD (P = 0·05). Serum YKL-40 values were positively correlated with interleukin-6 and EMRAI scores (both P = 0·04), indicating that serum YKL-40 levels are increased in patients with BD and positively correlate with disease activity. CONCLUSIONS:YKL-40 may play a role in the pathophysiology of BD and provide a useful marker for monitoring patients with BD.
The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review.
International journal of biological sciences
YKL-40, a chitinase-3-like protein 1 (CHI3L1) or human cartilage glycoprotein 39 (HC gp-39), is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells and vascular smooth muscle cells. Its biological function is not well elucidated, but it is speculated to have some connection with inflammatory reactions and autoimmune diseases. Although having important biological roles in autoimmunity, there were only attempts to elucidate relationships of YKL-40 with a single or couple of diseases in the literature. Therefore, in order to analyze the relationship between YKL-40 and the overall diseases, we reviewed 51 articles that discussed the association of YKL-40 with rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Behçet disease and inflammatory bowel disease. Several studies showed that YKL-40 could be assumed as a marker for disease diagnosis, prognosis, disease activity and severity. It is also shown to be involved in response to disease treatment. However, other studies showed controversial results particularly in the case of Behçet disease activity. Therefore, further studies are needed to elucidate the exact role of YKL-40 in autoimmunity and to investigate its potential in therapeutics.
CHI3L1 promotes proliferation and improves sensitivity to cetuximab in colon cancer cells by down-regulating p53.
Liu Kaitai,Jin Ming,Ye Shuang,Yan Senxiang
Journal of clinical laboratory analysis
BACKGROUND:Chitinase 3-like protein 1 (CHI3L1) is most likely a malignant tumor metastasis-associated gene. However, the functions of CHI3L1 in colon cancer cell proliferation and its cetuximab sensitivity are still unclear. We aimed to investigate the mechanism of CHI3L1 in promoting colon cancer cell proliferation and its sensitivity to cetuximab. METHODS:The expression of CHI3L1 in colon cancer and adjacent tissues were detected by immunohistochemistry. CHI3L1 was overexpressed in colon cancer cell lines by lentiviral technology. Cell proliferation and sensitivity to cetuximab were measured by MTT assay, cell cycle was analyzed by flow cytometry, and expression of cell cycle-related proteins was analyzed by immunoblotting. RESULTS:The results showed that the level of CHI3L1 in colon cancer tissue was significantly higher than that in adjacent tissue, which was also correlated with overall survival. The cell proliferation rate was significantly increased after overexpression of CHI3L1, and the sensitivity to cetuximab was significantly increased. The expression of p53 was down-regulated while the EGFR was up-regulated significantly in CHI3L1 overexpressed cells. When rescued the expression of p53 in HCT116-CHI3L1 cells, the cell proliferation and sensitivity to cetuximab could be restored. CONCLUSION:High levels of CHI3L1 are associated with poor prognosis and accelerate the proliferation of colon cancer cells and increase the sensitivity to cetuximab. Its mechanism of increasing the cell proliferation and sensitivity to cetuximab may be explained by down-regulating p53 expression and then, up-regulating the expression of EGFR.
Increased expression and possible role of chitinase 3-like-1 in a colitis-associated carcinoma model.
Ma Jia-Yi,Li Run-Hua,Huang Kun,Tan Gao,Li Chen,Zhi Fa-Chao
World journal of gastroenterology
AIM:To investigate the possible role of chitinase 3-like-1 (CHI3L1) in the progression of colitis-associated carcinoma (CAC). METHODS:Thirty-four Balb/c mice were randomly assigned to five groups, including the control, CAC control, CAC + caffeine, colitis control and colitis + caffeine. Three animals were sacrificed every two weeks for blinded macroscopic inspection, histological analysis, and total RNA extraction. An immunofluorescent assay was performed using specimens from the colitis control and colitis + caffeine groups to investigate whether the protective effect of caffeine was associated with less oxidative DNA damage. In vitro, HT29 cells pre-stimulated with different concentrations of recombinant CHI3L1 protein and H2O2 were loaded with the DCFH-DA fluorescent probe to determine the effect of CHI3L1 on intracellular reactive oxygen species production. RESULTS:CHI3L1 mRNA was increased during the progression of colon carcinogenesis. Tumors were mostly located in the distal end of the colon where the expression of CHI3L1 was higher than in the proximal colon. Caffeine-treated mice developed fewer tumors and milder inflammation than untreated mice. CHI3L1 protein increased reactive oxygen species in HT29 cells when exposed to H2O2. CONCLUSION:Caffeine reduces tumor incidence by decreasing oxidative DNA damage. CHI3L1 may contribute to CAC by increasing reactive oxygen species production.
The loss of tolerance to CHI3L1 - A putative role in inflammatory bowel disease?
Deutschmann Claudia,Roggenbuck Dirk,Schierack Peter
Clinical immunology (Orlando, Fla.)
The incidence of inflammatory bowel disease (IBD) is steadily increasing. IBD is characterized by chronic inflammation of the gastrointestinal tract and is divided into the two main entities Crohn's disease (CD) and ulcerative colitis (UC). Genetic predispositions, environmental factors and a dysregulated immune response are known to be involved at the beginning of IBD. However, their etiopathogenesis is not yet fully understood. Over the last ten years, there has been increasing evidence of the involvement of the member of the 18-glycosylhydrolase family chitinase-3-like protein 1 (CHI3L1) in IBD. CHI3L1 is associated with various diseases such as cancer and chronic inflammatory diseases including rheumatoid arthritis or IBD as well as neurological diseases where it can act as a chemoattractant, mitogen or growth factor. This review will focus on the role of autoimmunity to CHI3L1 in IBD in the context of its expression in inflamed colonic epithelia and interaction with intestinal microbiota. Further, it will provide insights into the interaction of CHI3L1 with different mechanisms of the innate and adaptive immune response in IBD.
Identification of Chitinase-3-Like Protein 1 as a Novel Neutrophil Antigenic Target in Crohn's Disease.
Deutschmann Claudia,Sowa Mandy,Murugaiyan Jayaseelan,Roesler Uwe,Röber Nadja,Conrad Karsten,Laass Martin W,Bogdanos Dimitrios,Sipeki Nora,Papp Maria,Rödiger Stefan,Roggenbuck Dirk,Schierack Peter
Journal of Crohn's & colitis
BACKGROUND AND AIMS:There is an increasing incidence of inflammatory bowel disease [IBD]. Autoimmune responses are involved in the pathophysiology of IBD, but their underlying pathways and target antigens have not yet been fully elucidated. METHODS:Autoantigenic targets in IBD were identified after separation of whole cell proteins isolated from neutrophils using two-dimensional electrophoresis and matrix assisted laser desorption ionization - time of flight mass spectrometry-based protein identification of the spots that displayed Western blotting signals with anti-neutrophil cytoplasmic antibody-positive sera. The prevalence of IgG, IgA and secretory IgA [sIgA] to chitinase 3-like protein 1 [CHI3L1] was analysed by enzyme-linked immunosorbent assays using recombinant CHI3L1 in 110 patients with Crohn's disease [CD], 95 with ulcerative colitis [UC], 126 with coeliac disease [CeD] and 86 healthy controls [HCs]. RESULTS:The 18-glycosylhydrolase family member CHI3L1 was identified as a neutrophil autoantigenic target. CD patients displayed significantly higher levels of IgG to CHI3L1 than patients with UC and CeD (p < 0.0001, respectively). IgA and sIgA to CHI3L1 was significantly higher in CD than in UC, CeD and HCs [p < 0.0001, respectively]. IgA and sIgA to CHI3L1 demonstrated the highest prevalence in CD [25.5%, 28/110; and 41.8%%, 46/110] compared to HCs [2.3%, 2/86; and 4.7%%, 4/86; p = 0.0015 and p < 0.0001] and are associated with a more complicated progression of CD. CONCLUSION:CHI3L1 is a novel neutrophil autoantigenic target in CD. IgA and sIgA to CHI3L1 may serve as novel markers for CD and may facilitate the serological diagnosis of IBD.