CHI3L1 promotes tumor progression by activating TGF-β signaling pathway in hepatocellular carcinoma (original) (raw)
Related papers
Immunologic Research, 2013
Elevated serum levels of a glycoprotein known as chitinase-3-like protein 1 (CHI3L1) have been correlated with poor prognosis and shorter survival of patients with cancer and inflammatory diseases. The biological and physiological functions of CHI3L1 in cancer have not yet been completely elucidated. In this review, we describe the role of CHI3L1 in inducing pro-inflammatory/pro-tumorigenic and angiogenic factors that could promote tumor growth and metastasis.
Research Square (Research Square), 2024
Chitinase-like proteins have multiple biological functions that promote tumor growth, angiogenesis and metastasis. Expression of CHI3L2, which is similar in structure to CHI3L1, is detected in glioma cells and tumor-associated macrophages (TAMs) in glioma and breast cancer. However, its exact role remains unclear. Methods We analyzed the expression of CHI3L2 in 74 invasive ductal breast carcinoma (IDC) tumors, breast cancer and macrophages cell cultures using immunohistochemistry, immuno uorescence, Western blot and PCR methods. Clinicopathologic data were included in the analysis. Results The results obtained show that CHI3L2 expression decreases with increasing degree of tumor grade and negative status of estrogen (ER) and progesterone receptors (PR). Furthermore, CHI3L2 is signi cantly and positively correlated with phosphorylation of STAT-3 and ERK1/2 signaling pathways, but negatively correlated with macrophage in ltration. Furthermore, CHI3L2 is expressed both in the cytoplasm of cancer cells and in macrophages. Analysis of the clinicopathologic data revealed that CHI3L2 levels had no effect on patient survival. Discussion CHI3L2 expression may be speci c for cancer cells in IDC and involved in cross-talk with the tumor microenvironment. Our study has shown that IDC cancer cells express the CHI3L2 protein, possibly indicating a novel function of this protein.
RIG-like Helicase Regulation of Chitinase 3-like 1 Axis and Pulmonary Metastasis
Scientific Reports, 2016
Chi3l1 is induced by a variety of cancers where it portends a poor prognosis and plays a key role in the generation of metastasis. However, the mechanisms that Chi3l1 uses to mediate these responses and the pathways that control Chi3l1-induced tumor responses are poorly understood. We characterized the mechanisms that Chi3l1 uses to foster tumor progression and the ability of the RIG-like helicase (RLH) innate immune response to control Chi3l1 elaboration and pulmonary metastasis. Here we demonstrate that RLH activation inhibits tumor induction of Chi3l1 and the expression of receptor IL-13Rα2 and pulmonary metastasis while restoring NK cell accumulation and activation, augmenting the expression of IFN-α/β, chemerin and its receptor ChemR23, p-cofilin, LIMK2 and PTEN and inhibiting BRAF and NLRX1 in a MAVS-dependent manner. These studies demonstrate that Chi3l1 is a multifaceted immune stimulator of tumor progression and metastasis whose elaboration and tissue effects are abrogated by RLH innate immune responses. The prototypic chitinase-like protein (CLP), Chitinase 3-like-1 (Chi3l1) (also called as YKL-40 in humans and BRP-39 in rodents) is a member of the 18 glycosyl hydrolase (GH 18) gene family, which binds to but does not degrade chitin 1. The retention of GH 18 moieties over species and evolutionary time has led to the belief that these moieties play essential roles in biology 2,3. In support of this speculation, recent studies from our laboratory and others demonstrated that Chi3l1 plays a major role in anti-pathogen, antigen and oxidant-induced inflammatory, repair and remodeling responses by regulating a variety of essential biologic processes including oxidant injury, apoptosis, pyroptosis, inflammasome activation, Th1/Th2 cytokine balance, M2 macrophage differentiation, TGF-β 1 elaboration, dendritic cell accumulation and activation, fat accumulation and the activation of MAPK, Akt and Wnt/β-catenin signaling 4-11. Studies from our laboratory and others have demonstrated that Chi3l1 is expressed by a variety of cells including macrophages, and epithelial cells and is stimulated by a number of mediators including IL-13, IL-6, IL-1β , and IFN-γ 7,8. These studies also identified significant correlations between dysregulated Chi3l1 and the development, severity and/or progression of a number of diseases including asthma, pulmonary fibrosis and obesity (as reviewed in references 1,12). Chi3l1 dysregulation is particularly striking in solid tumors with the levels of circulating Chi3l1/YKL-40 being increased in patients with cancers of the lung, prostate, colon, rectum, ovary, kidney, breast, glioblastomas and malignant melanoma where they correlate directly with disease progression and inversely with disease free interval and patient survival 12-21. These studies strongly suggest that Chi3l1 plays an important role(s) in the biology that underlies these malignancies. However, the mechanisms that Chi3l1 uses to contribute to tumor progression have not been adequately defined. Metastatic spread is an ominous prognostic event in cancer biology. This can be readily appreciated in malignant melanoma where there is a good chance of recovery if the primary lesion is detected early and the 5 year survival is less than 10% in patients with distant melanoma metastases (stages III and IV) 22. Malignant melanoma is one of the most aggressive forms of cancer, accounts for 80% of skin cancer deaths and is increasing faster than any other malignancy 22,23. Patients with malignant melanoma have increased levels of circulating Chi3l1/ YKL-40 which have been shown to be a risk factor for disease progression 17,20. Recent studies from our laboratory also demonstrated that the induction of Chi3l1 is a critical event in the generation of a metastasis permissive
YKL-40/CHI3L1 drives inflammation on the road of tumor progression
Journal of Leukocyte Biology, 2015
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 upregulated 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.
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2016
YKL-40, a chitinase-like glycoprotein, is expressed at a high level in cancer patients. Its exact function is unknown and is the subject of current investigation. Here, we report the correlation of plasma YKL-40 levels with clinicopathological features of cholangiocarcinoma (CCA), a lethal bile duct cancer, particularly prevalent in Northeastern Thailand. Statistical analysis of plasma YKL-40 concentrations in 57 CCA patients and 41 normal healthy subjects gave a median value of 169.5 ng/mL for CCA patients compared with 46.9 ng/mL for the control subjects (P < 0.0001). There was no significant association of plasma YKL-40 levels with patient age, tumor grade, or histology type. However, Kaplan-Meier analysis suggested that the elevated plasma YKL-40 level was particularly associated with short survival in CCA patients (P = 0.038). Immunohistochemical examination of 34 CCA tissues revealed low expression of YKL-40 in CCA cells, but high expression in adjacent intratumoral stroma,...
Oncotarget, 2015
We propose CHI3L1 as a prognostic biomarker for patients with epithelial ovarian carcinoma (EOC) and also suggest possible biological functions of CHI3L1. We measured CHI3L1 expression with quantitative real time-polymerase chain reaction (qRT-PCR) in 180 women with EOC and evaluated correlations between CHI3L1 expression, clinicopathological characteristics, and the outcomes of the patients. The expression of CHI3L1 was higher in cancerous tissues than in normal tissues. The expression of CHI3L1 was also higher in patients with a serous histological type, advanced stage, and chemoresistance. Patients with high CHI3L1 expression had a shorter progression-free survival (p < 0.001)and overall survival (p < 0.001). Patients with high CHI3L1 expression also had a high risk of recurrence (p < 0.001)and death (p < 0.001). In vitro studies showed that CHI3L1 up-regulated the expression of anti-apoptotic Mcl-1 protein and hampered paclitaxel-induced apoptosis of ovarian cancer c...
Gene Encoding Chitinase 3-Like 1 Protein (CHI3L1) is a Putative Oncogene
International journal of biomedical science : IJBS, 2011
An important task in understanding oncogenesis is the identification of those genes whose copy number and expression increase during tumorigenesis. Previously, in an effort to identify genes which could be used as molecular markers for glial tumors, we compared gene expression in glioblastoma to the normal brain cells. Among the genes with the most pronounced increased expression in tumors there was CHI3L1, encoding the secreted chitinase 3-like 1 protein (also known as HC gp-39 or YKL-40). Expression of CHI3L1 was found increased significantly in various tumors in comparison with corresponding normal tissues. Here we show that CHI3L1 can decrease the doubling time of 293 cells. We have also demonstrated that CHI3L1 allows the anchorage-independent growth in soft agar and, in addition, stable CHI3L1 expression made 293 cells tumorigenic: these cells stimulate the initiation of tumors after their xenograft transplantation into the Wistar rat brains. Thus, the overexpression of CHI3L1 is likely to be critical in the development of some tumors and when we gain more information about mechanisms of CHI3L1 oncogenicity, it could be used as one of the potential targets for anticancer therapy. (Int J Biomed Sci 2011; 7 (3): 230-237)
bioRxiv (Cold Spring Harbor Laboratory), 2022
Chitinase-like proteins (CLPs) are associated with tissue-remodelling and inflammation but also with several disorders, including fibrosis, atherosclerosis, allergies, and cancer. However, the CLP's role in tumors is far from clear. Here, we utilize Drosophila melanogaster to investigate the function of CLPs (imaginal disc growth factors; Idgf's) in Ras V12 dysplastic salivary glands (SGs). We find one of the Idgf's members, Idgf3, to be transcriptionally induced in a tissue-and cell-autonomously manner in a Drosophila hypertrophic model for early tumor progression. Induction involves non-canonical JNK-signaling via a positive feedback loop mediated by reactive oxygen species (ROS). Moreover, Idgf3 accumulates in enlarged vesicles (EnVs) that promote tumor progression by disrupting cytoskeletal organization, independent of Rab5 and Rab11. The process is mediated via Rac1 and the downstream component, αSpectrin, which localizes to the EnVs. Similar to Idgf3, expression of two human members of the CLP family in Drosophila SGs aggravates tumor-related phenotypes. Our data provide new insight into a phylogenetically conserved tissue-autonomous CLP function in tumors and identify specific targets for tumor control. Introduction: Chitinase-like protein (CLPs), including human Ch3L2 (YKL-39) and Ch3L1 (YKL-40) are released in various inflammatory conditions, including tumors. These proteins are secreted amongst others by immune cells, are often associated with a poor prognosis, and may promote tumor growth through interaction with the tumor microenvironment (Roslind and Johansen 2009, Shao, Hamel et al. 2009). CLPs are upregulated in patients with ductal tumors, including tumors in the lung, the breast and the pancreas (Johansen, Jensen et al. 2006, Uhlen, Zhang et al. 2017). The discovery of the human Rat sarcoma (Ras) oncogene more than 40 years ago has led to a substantial improvement of our understanding of cancer biology. The oncogene is mutated or dysregulated in a large number of non-physiological contexts, including pancreatitis. CC-BY-NC-ND 4.
Journal of experimental & clinical cancer research : CR, 2018
Enzymatically inactive chitinase-like protein CHI3L1 drives inflammatory response and promotes tumor progression. However, its role in gastric cancer (GC) tumorigenesis and metastasis has not yet been fully elucidated. We determined the significance of CHI3L1 expression in patients with GC. We also explored an as-yet unknown receptor of CHI3L1 and investigated the involved signaling in GC metastasis. CHI3L1 expression was evaluated by immunoblotting, tissue microarray-based immunohistochemistry analysis (n = 100), and enzyme linked immunosorbent assay (ELISA) (n = 150). The interactions between CD44 and CHI3L1 or Interleukin-13 receptor alpha 2 (IL-13Rα2) were analyzed by co-immunoprecipitation, immunofluorescence co-localization assay, ELISA, and bio-layer interferometry. The roles of CHI3L1/CD44 axis in GC metastasis were investigated in GC cell lines and experimental animal model by gain and loss of function. CHI3L1 upregulation occurred during GC development, and positively corr...
Role of chitinase-like proteins in cancer
Biological Chemistry, 2016
Chitinase-like proteins (CLPs) are lectins combining properties of cytokines and growth factors. Human CLPs include YKL-40, YKL-39 and SI-CLP that are secreted by cancer cells, macrophages, neutrophils, synoviocytes, chondrocytes and other cells. The best investigated CLP in cancer is YKL-40. Serum and plasma levels of YKL-40 correlate with poor prognosis in breast, lung, prostate, liver, bladder, colon and other types of cancers. In combination with other circulating factors YKL-40 can be used as a predictive biomarker of cancer outcome. In experimental models YKL-40 supports tumor initiation through binding to RAGE, and is able to induce cancer cell proliferation via ERK1/2-MAPK pathway. YKL-40 supports tumor angiogenesis by interaction with syndecan-1 on endothelial cells and metastatic spread by stimulating production of pro-inflammatory and pro-invasive factors MMP9, CCL2 and CXCL2. CLPs induce production of pro- and anti-inflammatory cytokines and chemokines, and are potential...