Gene Summary

Gene:CHI3L1; chitinase 3-like 1 (cartilage glycoprotein-39)
Aliases: GP39, ASRT7, GP-39, YKL40, CGP-39, YKL-40, YYL-40, HC-gp39, HCGP-3P, hCGP-39
Summary:Chitinases catalyze the hydrolysis of chitin, which is an abundant glycopolymer found in insect exoskeletons and fungal cell walls. The glycoside hydrolase 18 family of chitinases includes eight human family members. This gene encodes a glycoprotein member of the glycosyl hydrolase 18 family. The protein lacks chitinase activity and is secreted by activated macrophages, chondrocytes, neutrophils and synovial cells. The protein is thought to play a role in the process of inflammation and tissue remodeling. [provided by RefSeq, Sep 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:chitinase-3-like protein 1
Source:NCBIAccessed: 25 June, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CHI3L1 (cancer-related)

Koev IG, Feodorova YN, Kazakova MH, et al.
Glioblastoma multiforme classified as mesenchymal subtype.
Folia Med (Plovdiv). 2014 Jul-Sep; 56(3):215-9 [PubMed] Related Publications
INTRODUCTION: Recently, researchers have been considering as adverse prognostic factors in primary glioblastomas not only clinical indicators but also various cellular, genetic and immunological markers. The aim of the present article was to report a case of primary glioblastoma multiforme with poor survival in a patient after surgical intervention, and to determine the unfavorable prognostic markers.
CASE REPORT: We present a 71-year-old man with histologically verified glioblastoma multiforme and a postoperative survival of 48 days. The patient did not receive any radiotherapy and adjuvant therapy with temozolomide because of the short survival. Serum and transcription levels of TNF-α, CD44, YKL-40 and IL-6 were determined by molecular-biological and immunological analyses. We found very high transcription levels of the genes CD44, YKL-40 and IL-6, increased gene expression of TNF-α, and elevated serum concentrations of TNF-α, YKL-40 and IL-6 and reduced serum concentration of CD44.
CONCLUSION: Molecular-biological and immunological analyses support the hypothesis that glioblastoma multiforme is presented by a heterogeneous group of glial tumors with different clinical course and prognosis. The high expression levels of TNF-α, CD44, YKL-40, and IL-6 indicate that the tumor can be categorized as mesenchymal subtype of glioblastoma multiforme, which accounts for the rapid clinical course and lethal outcome of the condition.

Wang XW, Cai CL, Xu JM, et al.
Increased expression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesis.
Tumour Biol. 2015; 36(2):901-7 [PubMed] Related Publications
Increasing evidence demonstrated that chitinase 3-like 1 (CHI3L1) was highly expressed and tightly associated with human tumor development and progression. However, its precise role in non-small cell lung cancer (NSCLC) remains to be delineated. The aim of this study was to examine CHI3L1 expression in patients with NSCLC and explore the relationship of CHI3L1 protein with clinicopathologic factors, tumor angiogenesis, and prognosis. CHI3L1 protein and intratumoral microvessels were examined by immunohistochemical staining in 95 NSCLC patients. Intratumoral microvessel density (MVD) was measured by counting CD34-positive immunostained endothelial cells. Quantitative real-time PCR (qRT-PCR) analyses were used to investigate the CHI3L1 expression status in tissues. Our result showed that CHI3L1 was significantly up-regulated in NSCLC tissues. In addition, univariate and multivariate analysis demonstrated that CHI3L1 protein overexpression and high MVD were significantly associated with tumor relapse. Although CHI3L1 overexpression and high MVD indicated poor overall survival (P < 0.05), multivariate analysis suggested that only CHI3L1 overexpression was an independent prognostic marker for unfavorable overall survival in patients with NSCLC (P < 0.05). The current results demonstrated that CHI3L1 may be a promising biomarker to identify individuals with poor prognostic potential and a possible target for anti-angiogenic therapy in patients with early stage NSCLC.

Lin YS, Liu YF, Chou YE, et al.
Correlation of chitinase 3-like 1 single nucleotide polymorphisms and haplotypes with uterine cervical cancer in Taiwanese women.
PLoS One. 2014; 9(9):e104038 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study aimed to investigate the relationships of chitinase 3-like 1 (CHI3L1) single nucleotide polymorphisms (SNPs) and haplotypes with the development of uterine cervical cancer in Taiwanese women. The SNPs frequencies and haplotypes were also correlated with the clinicopathologic variables of cervical cancer, cancer recurrence, and patient survival.
METHODOLOGY AND PRINCIPAL FINDINGS: Ninety-nine patients with invasive cancer and 61 with pre-cancerous lesions of the uterine cervix were compared to 310 healthy control subjects. Three SNPs rs6691378 (-1371, G/A), rs10399805 (-247, G/A) and rs4950928 (-131, C/G) in the promoter region, and one SNP rs880633 (+2950, T/C) in exon 5 were analyzed by real time polymerase chain reaction and genotyping. The results showed that the mutant homozygous genotype AA of CHI3L1 SNP rs6691378 and AA of rs10399805, and haplotypes AACC and AACT increased the risk of developing pre-cancerous lesions and invasive cancer. The patients with these risk haplotypes had higher than stage I tumors, larger tumors, and vaginal invasion. In logistic regression model, they also tended to have poor survival event [p = 0.078; odds ratio (OR): 2.99, 95% confidence interval (CI): 0.89-10.08] and a higher probability of recurrence event (p = 0.081; OR: 3.07, 95% CI: 0.87-10.81). There was a significant association between the CHI3L1 risk haplotypes and probability of recurrence (p = 0.002; hazard ratio: 6.21, 95% CI: 1.90-20.41), and a marginal association between the risk haplotypes and overall survival (p = 0.051; hazard ratio: 3.76, 95% CI: 0.99-14.29) in the patients with SCC, using Cox proportional hazard model.
CONCLUSION: The CHI3L1 SNPs rs6691378 and rs10399805 and CHI3L1 haplotypes all correlated with the development of cervical pre-cancerous lesions and invasive cancer. The cervical cancer patients with the CHI3L1 haplotypes AACC or AACT had poor clinicopathologic characteristics and poor recurrence and survival events. These risk haplotypes were associated with higher recurrence, especially in the patients with SCC.

Zhang JP, Yuan HX, Kong WT, et al.
Increased expression of Chitinase 3-like 1 and microvessel density predicts metastasis and poor prognosis in clear cell renal cell carcinoma.
Tumour Biol. 2014; 35(12):12131-7 [PubMed] Related Publications
Increasing evidence demonstrated that Chitinase 3-like 1 (hereafter termed CHI3L1 or YKL-40) was highly expressed and tightly associated with human tumor development and progression. However, its precise role in clear cell renal cell carcinoma (hereafter termed RCC) remains to be delineated. In the present study, we investigated the relationship between CHI3L1 expression and microvessel density (MVD), a reflection of angiogenesis, with metastasis and prognosis in patients with clear cell renal cell carcinoma (RCC). Formalin-fixed, paraffin-embedded tissue sections of clear cell RCC from 73 patients who had undergone radical nephrectomy were stained immunohistochemically with specific antibodies against CHI3L1 and CD34. CHI3L1 immunostaining was semi-quantitatively estimated based on the proportion (percentage of positive cells) and intensity. MVD was determined with CD34-stained slides. The expression pattern of CHI3L1 and MVD was compared with the clinicopathological variables. Twenty patients had either synchronous or metachronous metastases and 12 died during the follow-up. CHI3L1 intensity was significantly correlated with tumor size (P = 0.005), TNM stage (P = 0.027), M stage (P = 0.011), grade (P = 0.014), and metastasis (synchronous or metachronous; P < 0.001). The CHI3L1 proportion (P = 0.038) and MVD (P = 0.012) were significantly correlated with metastasis. MVD was correlated with CHI3L1 intensity (r = 0.376, P = 0.001) and CHI3L1 proportion (r = 0.364, P = 0.002). There was no difference in the expression of CHI3L1 and MVD between primary and metastatic sites. The survival of patients with higher CHI3L1 intensity was significantly worse than that of patients with lower CHI3L1 intensity. Multivariate analyses indicated that only M stage was an independent prognostic factor for cancer-specific survival and CHI3L1 expression was not an independent factor. Taken altogether, increased expression of CHI3L1 and MVD is associated with metastasis and a worse prognosis in clear cell RCC. CHI3L1 expression is correlated with MVD. The results suggest that CHI3L1 may be important in the progression and angiogenesis of clear cell RCC and CHI3L1 might be a novel strategy for therapy of the patients with RCC.

Zheng X, Xing S, Liu XM, et al.
Establishment of using serum YKL-40 and SCCA in combination for the diagnosis of patients with esophageal squamous cell carcinoma.
BMC Cancer. 2014; 14:490 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Elevated serum YKL-40 levels have been observed in various cancers. We evaluated the diagnostic performance of serum YKL-40 alone or in combination with the CEA, CYFRA21-1 and SCCA tumor markers for patients with esophageal squamous cell carcinoma (ESCC).
METHODS: YKL-40 was detected in ESCC cell lines and tissues by real-time RT-PCR, Western blotting and ELISA. YKL-40 protein expression was determined in 20 ESCC tumor tissues using immunohistochemistry. Serum YKL-40 was measured by ELISA in 126 healthy donors, 59 patients with benign esophageal diseases and 150 patients with ESCC. Serum CEA, CYFRA21-1 and SCCA were determined by electrochemiluminescence.
RESULTS: YKL-40 mRNA and protein were observed in ESCC cancer cell lines, tissues and cell culture media, respectively. YKL-40 expression was observed in 17 of 20 ESCC samples (85%). Serum YKL-40 concentration was significantly elevated in patients with ESCC (Range: 6.95-502.10 ng/ml) compared with patients with benign diseases (Range: 1.21-429.30 ng/ml; P = 0.038) and healthy controls (Range: 2.56-132.26 ng/ml; P < 0.001). ROC curves demonstrated that serum YKL-40 has a sensitivity of 72.70%, a specificity of 84.13% and an AUC of 0.874 for the diagnosis of ESCC, which was superior to CEA (Sen: 8.00%; Spe: 96.80%, AUC = 0.652), CYFRA21-1 (Sen: 40.00%; Spe: 92.06%, AUC = 0.746) and SCCA (Sen: 32.67%; Spe: 94.44%, AUC = 0.789). The YKL-40 and SCCA combination was better for diagnosing ESCC (Sen: 82.00%, Spe: 79.37%, PPV: 82.55 and NPV: 78.74; AUC = 0.917) than the YKL-40 and CEA combination (Sen: 74.00%, Spe: 83.20%, PPV: 84.09 and NPV: 72.73; AUC = 0.877), the YKL-40 and CYFRA21-1 combination (Sen: 82.00%, Spe: 77.78%, PPV: 81.46% and NPV: 78.40%; AUC = 0.897) or the CEA, CYFRA21-1 and SCCA combination (Sen: 56.67%, Spe: 84.80%, PPV: 81.73 and NPV: 61.99; AUC = 0.831). Associations between serum YKL-40 levels and the clinic characteristics of ESCC were not significant, with the exception of age (p = 0.001).
CONCLUSIONS: ESCC tumor cells and tissues express YKL-40. Serum YKL-40 may be a potential biomarker for ESCC. Serum YKL-40 in combination with SCCA significantly increases the sensitivity of detecting ESCC.

Jeet V, Tevz G, Lehman M, et al.
Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells.
Endocr Relat Cancer. 2014; 21(5):723-37 [PubMed] Free Access to Full Article Related Publications
Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in tumours from patients with advanced stage cancers, including prostate cancer (PCa). The exact function of YKL40 is poorly understood, but it has been shown to play an important role in promoting tumour angiogenesis and metastasis. The therapeutic value and biological function of YKL40 are unknown in PCa. The objective of this study was to examine the expression and function of YKL40 in PCa. Gene expression analysis demonstrated that YKL40 was highly expressed in metastatic PCa cells when compared with less invasive and normal prostate epithelial cell lines. In addition, the expression was primarily limited to androgen receptor-positive cell lines. Evaluation of YKL40 tissue expression in PCa patients showed a progressive increase in patients with aggressive disease when compared with those with less aggressive cancers and normal controls. Treatment of LNCaP and C4-2B cells with androgens increased YKL40 expression, whereas treatment with an anti-androgen agent decreased the gene expression of YKL40 in androgen-sensitive LNCaP cells. Furthermore, knockdown of YKL40 significantly decreased invasion and migration of PCa cells, whereas overexpression rendered them more invasive and migratory, which was commensurate with an enhancement in the anchorage-independent growth of cells. To our knowledge, this study characterises the role of YKL40 for the first time in PCa. Together, these results suggest that YKL40 plays an important role in PCa progression and thus inhibition of YKL40 may be a potential therapeutic strategy for the treatment of PCa.

Akiyama Y, Ashizawa T, Komiyama M, et al.
YKL-40 downregulation is a key factor to overcome temozolomide resistance in a glioblastoma cell line.
Oncol Rep. 2014; 32(1):159-66 [PubMed] Related Publications
The frequent recurrence of glioblastoma multiforme (GBM) after standard treatment with temozolomide (TMZ) is a crucial issue to be solved in the clinical field. O6‑methylguanine‑DNA methyltransferase (MGMT) is considered one of the major mechanisms involved in TMZ resistance. However, some important mechanisms for TMZ resistance other than MGMT have recently been identified. In the present study, we established a TMZ-resistant (TMZ-R) U87 glioblastoma cell line in vitro and in vivo and investigated novel targeting molecules other than MGMT in those cells. The TMZ-R U87 glioblastoma cell line was established in vitro and in vivo. TMZ-R U87 cells showed a more invasive activity and a shorter survival time in vivo. Gene expression analysis using DNA microarray and quantitative PCR (qPCR) demonstrated that YKL‑40, MAGEC1 and MGMT mRNA expression was upregulated 100-, 83- and 6-fold, respectively in the TMZ-R U87 cell line. Western blot analysis and qPCR demonstrated that STAT3 phosphorylation, STAT3 target genes and stem cell and mesenchymal marker genes were upregulated to a greater extent in the TMZ‑resistant cell line. Notably, short hairpin (sh)RNA‑based inhibition against the YKL‑40 gene resulted in moderate growth inhibition in the resistant cells in vitro and in vivo. Additionally, YKL‑40 gene inhibition exhibited significant suppression of the invasive activity and particularly partially restored the sensitivity to TMZ. Therefore, YKL‑40 may be a novel key molecule in addition to MGMT, that is responsible for TMZ resistance in glioblastoma cell lines and could be a new target to overcome TMZ resistance in recurrent glioblastomas in the future.

Ashizawa T, Akiyama Y, Miyata H, et al.
Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line.
Int J Oncol. 2014; 45(1):411-8 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is one of the most malignant and aggressive tumors and has a very poor prognosis, with a median survival time of less than 2 years. Once recurrence develops, there are few therapeutic approaches to control the growth of glioblastoma. In particular, temozolomide (TMZ)-resistant (TMZ-R) GBM is very difficult to treat, and a novel approach to overcome resistance is eagerly awaited. Previously, we reported a novel small molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. In the current study, the efficacy of STX-0119 was evaluated against our established TMZ-resistant U87 cell line using quantitative PCR-based gene expression analysis, in vitro assay and animal experiments. The growth inhibitory effect of STX-0119 on U87 and TMZ-R U87 cells was moderate (IC₅₀, 34 and 45 µM, respectively). In particular, STX-0119 did not show significant inhibition of U87 tumor growth; however, it suppressed the growth of the TMZ-R U87 tumor in nude mice by more than 50%, and prolonged the median survival time compared to the control group. Quantitative PCR revealed that YKL-40, MAGEC1, MGMT, several EMT genes, mesenchymal genes and STAT3 target genes were upregulated, but most of those genes were downregulated by STX-0119 treatment. Furthermore, the invasive activity of TMZ-R U87 cells was significantly inhibited by STX-0119. YKL-40 levels in TMZ-R U87 cells and their supernatants were significantly decreased by STX-0119 administration. These results suggest that STX-0119 is an efficient therapeutic to overcome TMZ resistance in recurrent GBM tumors, and could be the next promising compound leading to survival prolongation, and YKL-40 may be a possible surrogate marker for STAT3 targeting.

Tschirdewahn S, Reis H, Niedworok C, et al.
Prognostic effect of serum and tissue YKL-40 levels in bladder cancer.
Urol Oncol. 2014; 32(5):663-9 [PubMed] Related Publications
OBJECTIVES: YKL-40 is a novel inflammatory serum protein shown to be associated with the presence and prognosis of several malignancies. However, its prognostic relevance has not yet been analyzed in bladder cancer (BC). Therefore, the aim of this study was to assess the tissue, serum, and urinary levels of YKL-40 and their prognostic value in BC.
METHODS AND MATERIALS: YKL-40 gene expression levels were analyzed in frozen tissue samples of 91 patients with BC; YKL-40 concentrations were measured in 120 serum (101 patients with BC and 19 controls) and 154 urine samples (125 patients with BC and 29 controls). In 16 cases, corresponding serum samples collected before and after radical cystectomy were analyzed for YKL-40. Results were correlated with clinicopathological parameters and follow-up data.
RESULTS: YKL-40 gene expressions and serum concentrations were higher in patients with BC compared with controls; however, urinary YKL-40 levels remained under the detection limit in both patients and controls. Higher tissue gene expressions and serum concentrations were associated with poor patients' survival in the univariable analysis (P = 0.037 and 0.022, respectively), but only high YKL-40 serum levels proved to be independent prognostic factors in BC (hazard ratio = 1.755, 95% CI: 1.014-3.039, P = 0.045). We found no significant difference between preoperative and postoperative serum concentrations of YKL-40.
CONCLUSIONS: YKL-40 serum levels are associated with the presence of BC and poor patients' survival. The independent prognostic relevance of YKL-40 is of particular interest in patients with muscle-invasive BC treated with radical surgery. Our data suggest that BC tissue is not the main source of serum YKL-40 levels.

He CH, Lee CG, Dela Cruz CS, et al.
Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor α2.
Cell Rep. 2013; 4(4):830-41 [PubMed] Free Access to Full Article Related Publications
Members of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.

Francescone R, Ngernyuang N, Yan W, et al.
Tumor-derived mural-like cells coordinate with endothelial cells: role of YKL-40 in mural cell-mediated angiogenesis.
Oncogene. 2014; 33(16):2110-22 [PubMed] Free Access to Full Article Related Publications
Tumor neo-vasculature is characterized by spatial coordination of endothelial cells with mural cells, which delivers oxygen and nutrients. Here, we explored a key role of the secreted glycoprotein YKL-40, a mesenchymal marker, in the interaction between endothelial cells and mesenchymal mural-like cells for tumor angiogenesis. Xenotransplantation of tumor-derived mural-like cells (GSDCs) expressing YKL-40 in mice developed extensive and stable blood vessels covered with more GSDCs than those in YKL-40 gene knockdown tumors. YKL-40 expressed by GSDCs was associated with increased interaction of neural cadherin/β-catenin/smooth muscle alpha actin; thus, mediating cell-cell adhesion and permeability. YKL-40 also induced the interaction of vascular endothelial cadherin/β-catenin/actin in endothelial cells (HMVECs). In cell co-culture systems, YKL-40 enhanced both GSDC and HMVEC contacts, restricted vascular leakage, and stabilized vascular networks. Collectively, the data inform new mechanistic insights into the cooperation of mural cells with endothelial cells induced by YKL-40 during tumor angiogenesis, and also enhance our understanding of YKL-40 in both mural and endothelial cell biology.

Makki FM, Taylor SM, Shahnavaz A, et al.
Serum biomarkers of papillary thyroid cancer.
J Otolaryngol Head Neck Surg. 2013; 42:16 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To identify serum biomarkers of papillary thyroid cancer.
METHODS: Prospective analysis was performed of banked tumor and serum specimens from 99 patients with thyroid masses. Enzyme-linked immunosorbent assay (ELISA) was employed to measure levels of five serum proteins previously demonstrated to be up-regulated in papillary thyroid cancer (PTC): angiopoietin-1 (Ang-1), cytokeratin 19 (CK-19), tissue inhibitor of metalloproteinase-1 (TIMP-1), chitinase 3 like-1 (YKL-40), and galectin-3 (GAL-3). Serum levels were compared between patients with PTC and those with benign tumors.
RESULTS: A total of 99 patients were enrolled in the study (27 men, 72 women), with a median age of 54 years. Forty-three patients had PTC and 58 cases were benign tumors. There were no statistically significant differences when comparing all five different biomarkers between PTC and other benign thyroid tumors. The p-values were 0.94, 0.48, 0.72, 0.48, and 0.90 for YKL-40, Gal-3, CK19, TIMP-1, and Ang-1, respectively.
CONCLUSION: Serum levels of four of the five proteins were elevated in patients with thyroid masses relative to normal values. However, the difference between benign and PTC was not significant. Two of the markers (Gal-3 & TIMP-1) displayed a greater potential difference, which may warrant further investigation. This study suggests that other serum markers should be sought. This is the first study to investigate potential serum biomarkers based on over-expressed proteins in thyroid cancer versus benign pathology.

Yan C, Ding X, Wu L, et al.
Stat3 downstream gene product chitinase 3-like 1 is a potential biomarker of inflammation-induced lung cancer in multiple mouse lung tumor models and humans.
PLoS One. 2013; 8(4):e61984 [PubMed] Free Access to Full Article Related Publications
Over-activation of the signal transducers and activators of the transcription 3 (Stat3) pathway in lung alveolar type II (AT II) epithelial cells induces chronic inflammation and adenocarcinoma in the lung of CCSP-rtTA/(tetO)7-CMV-Stat3C bitransgenic mice. One of Stat3 downstream genes products, chitinase 3-like 1 (CHI3L1) protein, showed increased concentration in both bronchioalveolar lavage fluid (BALF) and blood of doxycycline-treated CCSP-rtTA/(tetO)7-CMV-Stat3C bitransgenic mice. When tested in other inflammation-induced lung cancer mouse models, the CHI3L1 protein concentration was also highly increased in BALF and blood of these models with tumors. Immunohistochemical staining showed strong staining of CHI3L1 protein around tumor areas in these mouse models. Analysis of normal objects and lung cancer patients revealed a significant elevation of CHI3L1 protein concentration in human serum samples from all categories of lung cancers. Furthermore, recombinant CHI3L protein stimulated proliferation and growth of Lewis lung cancer cells. Therefore, secretory CHI3L1 plays an important role in inflammation-induced lung cancer formation and potentially serve as a biomarker for lung cancer prediction. Based on our previous publication and this work, this is the first animal study linking overexpression of CHI3L1 to various lung tumor mouse models. These models will facilitate identification of additional biomarkers to predict and verify lung cancer under various pathogenic conditions, which normally cannot be done in humans.

Pan JJ, Ge YS, Xu GL, et al.
The expression of chitinase 3-like 1: a novel prognostic predictor for hepatocellular carcinoma.
J Cancer Res Clin Oncol. 2013; 139(6):1043-54 [PubMed] Related Publications
OBJECTIVES: Chitinase 3-like 1 (CHI3L1) is associated with poor prognosis of various human cancers. However, the clinical and prognostic significance of CHI3L1 in hepatocellular carcinoma (HCC) is largely unknown. The aim of the present study is to investigate the expression of CHI3L1 in human HCC cell lines, clinical HCC specimens and its association with expressions of phosphorylated-Akt (p-Akt), E-cadherin and prognostic significance.
METHODS: The protein level of CHI3L1 in HCC cell lines was evaluated by western blot. The mRNA and protein levels of CHI3L1 in 19 self-paired HCC specimens were assessed by RT-PCR and western blot assays. The clinical and prognostic significance of CHI3L1 in 70 cases of HCC patients was determined by immunohistochemistry. In addition, expressions of p-Akt and E-cadherin were also assessed.
RESULTS: The protein level of CHI3L1 paralleled with increased malignant potential of HCC cell lines (P < 0.05). The mRNA and protein levels of CHI3L1 in HCC tissues were up-regulated compared with those in adjacent peritumoral tissues and further increased in tumors with metastasis (P < 0.05). Clinicopathological analysis showed that positive CHI3L1 expression was significantly associated with larger tumor size, capsular invasion, advanced TNM stages and status of metastasis (P = 0.035, 0.003, 0.023 and 0.003, respectively). Furthermore, CHI3L1 expression was positively correlated with high level of p-Akt (r = 0.293, P = 0.014), but inversely correlated with expression of E-cadherin (r = -0.267, P = 0.026). Additionally, Kaplan-Meier survival analysis showed that HCC patients with positive CHI3L1 expression had a worse overall survival and disease-free survival compared with those with negative CHI3L1 expression (P < 0.001, respectively). Multivariate analysis identified CHI3L1 as an independent prognostic predictor for overall survival and disease-free survival of HCC patients (P = 0.044 and 0.031, respectively).
CONCLUSIONS: CHI3L1 plays an essential role in HCC malignancies and may be served as a valuable prognostic biomarker for HCC patients.

Sarris EG, Syrigos KN, Saif MW
Pancreatic cancer: updates on translational research and future applications.
JOP. 2013; 14(2):145-8 [PubMed] Related Publications
Pancreatic cancer is one of the most lethal malignancies with a mortality rate almost equal to its incidence. It is ranked as the fourth leading cause of cancer-related deaths in the United States, and despite intensive basic and clinical research over the last few years, the survival benefit for the majority of patients with pancreatic cancer is still disappointing. Due to the absence of specific symptoms and the lack of early detection tests, pancreatic cancer is usually diagnosed at an advanced inoperrable stage and palliative chemotherapy with the purine analogue gemcitabine in combination with the targeted agent erlotinib, remains the mainstay method in the management of these patients. Therefore, there is an imperative need for new findings in the translational research field with prognostic, predictive and therapeutic value. In this paper we summarize five most interesting research abstracts as presented at the 2013 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. In particular, we focus on Abstract #141 which investigates the interaction between liver and pancreatic organ damage in patients with pancreatic cancer and the potential contribution of the patatin-like phospholipase domain containing 3 (PNPLA3) gene variation in pancreatic cancer development and on Abstract #149, in which, the prognostic and predictive role of SWI/SNF complex, a chromatin-remodeling complex, is examined. The key role of pharmacogenomics, in terms of predicting response and resistance to chemotherapy in pancreatic cancer patients, is analyzed in Abstract #142 and the contribution of circulating tumor cell detection in the early diagnosis of pancreatic cancer, allowing the avoidance of more invasive procedures like EUS-FNA, is discussed in Abstract #157. Lastly, in Abstract #164, the diagnostic utility of YKL-40 and IL-6 in pancreatic cancer patients is investigated.

Lee DW, Ramakrishnan D, Valenta J, et al.
The NF-κB RelB protein is an oncogenic driver of mesenchymal glioma.
PLoS One. 2013; 8(2):e57489 [PubMed] Free Access to Full Article Related Publications
High-grade gliomas, such as glioblastomas (GBMs), are very aggressive, invasive brain tumors with low patient survival rates. The recent identification of distinct glioma tumor subtypes offers the potential for understanding disease pathogenesis, responses to treatment and identification of molecular targets for personalized cancer therapies. However, the key alterations that drive tumorigenesis within each subtype are still poorly understood. Although aberrant NF-κB activity has been implicated in glioma, the roles of specific members of this protein family in tumorigenesis and pathogenesis have not been elucidated. In this study, we show that the NF-κB protein RelB is expressed in a particularly aggressive mesenchymal subtype of glioma, and loss of RelB significantly attenuated glioma cell survival, motility and invasion. We find that RelB promotes the expression of mesenchymal genes including YKL-40, a marker of the MES glioma subtype. Additionally, RelB regulates expression of Olig2, a regulator of cancer stem cell proliferation and a candidate marker for the cell of origin in glioma. Furthermore, loss of RelB in glioma cells significantly diminished tumor growth in orthotopic mouse xenografts. The relevance of our studies for human disease was confirmed by analysis of a human GBM genome database, which revealed that high RelB expression strongly correlates with rapid tumor progression and poor patient survival rates. Thus, our findings demonstrate that RelB is an oncogenic driver of mesenchymal glioma tumor growth and invasion, highlighting the therapeutic potential of inhibiting the noncanonical NF-κB (RelB-mediated) pathway to treat these deadly tumors.

Qin W, Zhang K, Kliethermes B, et al.
Differential expression of cancer-associated proteins in breastmilk.
Breastfeed Med. 2013; 8(1):120-6 [PubMed] Related Publications
Breast cancer that develops during or shortly after pregnancy is frequently more aggressive than cancer diagnosed at other times in a woman's life. To better understand the patterns of cancer-related protein expression in the breasts of lactating women, we determined the differences in total and individual protein expression in milk based on (a) three time points during lactation (early, mid, and late), (b) length of lactation, and (c) parity. Breastmilk was collected from 72 healthy lactating women within 10 days of starting lactation (transitional [T]), 2 months after lactation started, and during breast weaning (W). Sixteen proteins whose expression is altered in breast cancer (11 kallikreins [KLKs], basic fibroblast growth factor [bFGF], YKL-40, neutrophil gelatinase-associated lipocalin, and transforming growth factor [TGF] β1 and β2) were evaluated. The concentration of total milk protein decreased over time (p<0.01 at 2 months and W compared with T). After we controlled for total protein, KLK6 and TGFβ2 significantly increased, and bFGF decreased from T to W. Neither length of nursing nor parity significantly influenced individual protein expression at the W time point. On the other hand, length of nursing did influence the difference in KLK6, -7, and -8 expression between the W and T time points. Total milk protein concentration is lower in the mid and late phases of nursing. Biomarker differences between T and W milk samples in KLK6, TGFβ2, and bFGF are consistent with a protective effect of nursing.

Galamb O, Wichmann B, Sipos F, et al.
Dysplasia-carcinoma transition specific transcripts in colonic biopsy samples.
PLoS One. 2012; 7(11):e48547 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The early molecular detection of the dysplasia-carcinoma transition may enhance the strength of diagnosis in the case of colonic biopsies. Our aims were to identify characteristic transcript sets in order to develop diagnostic mRNA expression patterns for objective classification of benign and malignant colorectal diseases and to test the classificatory power of these markers on an independent sample set.
METHODOLOGY/PRINCIPAL FINDINGS: Colorectal cancer (CRC) and adenoma specific transcript sets were identified using HGU133plus2 microarrays and 53 biopsies (22 CRC, 20 adenoma and 11 normal). Ninety-four independent biopsies (27 CRC, 29 adenoma and 38 normal) were analyzed on microarrays for testing the classificatory power of the discriminatory genes. Array real-time PCR validation was done on 68 independent samples (24 CRC, 24 adenoma and 20 normal). A set of 11 transcripts (including CXCL1, CHI3L1 and GREM1) was determined which could correctly discriminate between high-grade dysplastic adenoma and CRC samples by 100% sensitivity and 88.9% specificity. The discriminatory power of the marker set was proved to be high on independent samples in both microarray and RT-PCR analyses. 95.6% of original and 94.1% of cross-validated samples was correctly classified in discriminant analysis.
CONCLUSIONS/SIGNIFICANCE: The identified transcripts could correctly characterize the dysplasia-carcinoma transition in biopsy samples, also on a large independent sample set. These markers can establish the basis of gene expression based diagnostic classification of colorectal cancer. Diagnostic RT-PCR cards can become part of the automated routine procedure.

Floyd DH, Kefas B, Seleverstov O, et al.
Alpha-secretase inhibition reduces human glioblastoma stem cell growth in vitro and in vivo by inhibiting Notch.
Neuro Oncol. 2012; 14(10):1215-26 [PubMed] Free Access to Full Article Related Publications
The Notch pathway is dysregulated and a potential target in glioblastoma multiforme (GBM). Currently available Notch inhibitors block γ-secretase, which is necessary for Notch processing. However, Notch is first cleaved by α-secretase outside the plasma membrane, via a disintegrin and metalloproteinase-10 and -17. In this work, we used a potent α-secretase inhibitor (ASI) to test inhibition of glioblastoma growth and inhibition of Notch and of both novel and known Notch targets. Featured in this study are luciferase reporter assays and immunoblot, microarray analysis, chromatin immunoprecipitation (ChIP), quantitative real-time PCR, cell number assay, bromodeoxyuridine incorporation, plasmid rescue, orthotopic xenograft model, and local delivery of treatment with convection-enhanced delivery using nanoparticles, as well as survival, MRI, and ex vivo luciferase assay. A CBF1-luciferase reporter assay as well as an immunoblot of endogenous Notch revealed Notch inhibition by the ASI. Microarray analysis, quantitative real-time PCR, and ChIP of ASI and γ-secretase inhibitor (GSI) treatment of GBM cells identified known Notch pathway targets, as well as novel Notch targets, including YKL-40 and leukemia inhibitory factor. Finally, we found that local nanoparticle delivery of ASIs but not GSIs increased survival time significantly in a GBM stem cell xenograft treatment model, and ASI treatment resulted in decreased tumor size and Notch activity. This work indicates α-secretase as an alternative to γ-secretase for inhibition of Notch in GBM and possibly other cancers as well, and it identifies novel Notch targets with biologic relevance and potential as biomarkers.

Ma X, Yoshimoto K, Guan Y, et al.
Associations between microRNA expression and mesenchymal marker gene expression in glioblastoma.
Neuro Oncol. 2012; 14(9):1153-62 [PubMed] Free Access to Full Article Related Publications
The subclassification of glioblastoma (GBM) into clinically relevant subtypes using microRNA (miRNA)- and messenger RNA (mRNA)-based integrated analysis has been attempted. Because miRNAs regulate multiple gene-signaling pathways, understanding miRNA-mRNA interactions is a prerequisite for understanding glioma biology. However, such associations have not been thoroughly examined using high-throughput integrated analysis. To identify significant miRNA-mRNA correlations, we selected and quantified signature miRNAs and mRNAs in 82 gliomas (grade II: 14, III: 16, IV: 52) using real-time reverse-transcriptase polymerase chain reaction. Quantitative expression data were integrated into a single analysis platform that evaluated the expression relationship between miRNAs and mRNAs. The 21 miRNAs include miR-15b, -21, -34a, -105, -124a, -128a, -135b, -184, -196a-b, -200a-c, -203, -302a-d, -363, -367, and -504. In addition, we examined 23 genes, including proneural markers (DLL3, BCAN, and OLIG2), mesenchymal markers (YKL-40, CD44, and Vimentin), cancer stem cell-related markers, and receptor tyrosine kinase genes. Primary GBM was characterized exclusively by upregulation of mesenchymal markers, whereas secondary GBM was characterized by significant downregulation of mesenchymal markers, miR-21, and -34a, and by upregulation of proneural markers and miR-504. Statistical analysis showed that expression of miR-128a, -504, -124a, and -184 each negatively correlated with the expression of mesenchymal markers in GBM. Our functional analysis of miR-128a and -504 as inhibitors demonstrated that suppression of miR-128a and -504 increased the expression of mesenchymal markers in glioblastoma cell lines. Mesenchymal signaling in GBM may be negatively regulated by miR-128a and -504.

Li ML, Zhang JC, Li SG, et al.
Characteristic gene expression profiles in the progression from normal gastric epithelial cells to moderate gastric epithelial dysplasia and to gastric cancer.
Chin Med J (Engl). 2012; 125(10):1777-83 [PubMed] Related Publications
BACKGROUND: Gastric cancer ranks high among the most common causes of cancer-related death worldwide. This study was designed to explore key genes involved in the progression of normal gastric epithelial cells to moderate gastric epithelial dysplasia (mGED) and to gastric cancer.
METHODS: Twelve pairs of mGED tissues, gastric cancer tissues, and normal gastric tissues were collected by gastroscopy. Total RNA was then extracted and purified. After the addition of fluorescent tags, hybridization was carried out on a Gene chip microarray slide. Significance analysis of microarrays was performed to determine significant differences in gene expression between the different tissue types.
RESULTS: Microarray data analysis revealed totally 34 genes that were expressed differently: 18 highly expressed (fold change > 2; P < 0.01) and 16 down-regulated (fold change > 2; P < 0.01). Of the 34 genes, 24 belonged to several different functional categories such as structural molecule activity, extracellular regions, structural formation, cell death, biological adhesion, developmental processes, locomotion, and biological regulation that were associated with cancer. The remaining 10 genes were not involved in cancer research. Of these genes, the expression levels of Matrix metalloproteinase-12 (MMP12), Caspase-associated recruitment domain 14 (CARD14), and Chitinase 3-like 1 (CHI3L1) were confirmed by semi-quantitative RT-PCR. A two-way clustering algorithm divided the 36 samples into three categories and the overall correct classification efficiency was 80.6% (29/36). Almost all of these genes (31/34) showed constant changes in the process of normal gastric epithelial cells to mGED to gastric cancer.
CONCLUSIONS: The results of this study provided global gene expression profiles during the development and progression from normal gastric epithelial cells to mGED to gastric cancer. These data may provide new insights into the molecular pathology of gastric cancer which may be useful for the detection, diagnosis, and treatment.

Salvati M, Pichierri A, Piccirilli M, et al.
Extent of tumor removal and molecular markers in cerebral glioblastoma: a combined prognostic factors study in a surgical series of 105 patients.
J Neurosurg. 2012; 117(2):204-11 [PubMed] Related Publications
OBJECT: In this paper, the authors' goal was to evaluate the prognostic value of YKL-40 expression as a prognostic factor for glioblastomas and to compare its validity to the already known MGMT.
METHODS: Between January 2002 and January 2007, 105 patients were treated for cerebral glioblastoma. The extent of removal was classified in 4 groups. YKL-40 expression was evaluated by a semiquantitative immunohistochemical staining scale (0, no staining; 1, mild expression; and 2, strong expression). MGMT promoter methylation status was analyzed with methylation-specific polymerase chain reaction. All patients received adjuvant radiotherapy and chemotherapy. Kaplan-Meier curves were used to analyze progression-free survival (PFS) and overall survival (OS), and to compare these parameters between the subgroups stratified by extent of surgical removal, MGMT methylation, and YKL-40 expression. The log-rank test was used to determine statistical significance. A multivariate regression analysis was applied to extent of removal, YKL-40 expression, and MGMT status to check their specific statistical power and to test the independence of the variables.
RESULTS: There were 55 men and 50 women with a mean age of 58 years. Extent of surgical removal is reported. The MGMT promoter was methylated in 48 patients and nonmethylated in 57. Analysis of YKL-40 expression is reported. The median PFS was 10.7 months (14.9 months in the gross-total removal subgroup) (p < 0.0001), and the median OS was 12.5 months (17.4 months in the gross-total removal group) (p < 0.0001). In the univariate analysis, OS was significantly correlated to the extent of resection (p < 0.0001), MGMT status (p < 0.0001), and YKL-40 (p < 0.0001). Multivariate analysis showed that all 3 factors reached statistical significance with respect to patient survival. In particular, surgical removal contributed more than the 2 other factors to the survival prediction (β = -0.6254). Interestingly, YKL-40 (β = -0.3867) contributed more than MGMT (β = -0.1705) to the predicted survival.
CONCLUSIONS: The extent of removal is the most important factor influencing the OS of patients harboring glioblastomas. When biological aggressiveness is taken into account, YKL-40 expression was found to be an independent prognostic factor that predicts OS better than MGMT status.

Desantis SM, Houseman EA, Coull BA, et al.
Supervised Bayesian latent class models for high-dimensional data.
Stat Med. 2012; 31(13):1342-60 [PubMed] Free Access to Full Article Related Publications
High-grade gliomas are the most common primary brain tumors in adults and are typically diagnosed using histopathology. However, these diagnostic categories are highly heterogeneous and do not always correlate well with survival. In an attempt to refine these diagnoses, we make several immunohistochemical measurements of YKL-40, a gene previously shown to be differentially expressed between diagnostic groups. We propose two latent class models for classification and variable selection in the presence of high-dimensional binary data, fit by using Bayesian Markov chain Monte Carlo techniques. Penalization and model selection are incorporated in this setting via prior distributions on the unknown parameters. The methods provide valid parameter estimates under conditions in which standard supervised latent class models do not, and outperform two-stage approaches to variable selection and parameter estimation in a variety of settings. We study the properties of these methods in simulations, and apply these methodologies to the glioma study for which identifiable three-class parameter estimates cannot be obtained without penalization. With penalization, the resulting latent classes correlate well with clinical tumor grade and offer additional information on survival prognosis that is not captured by clinical diagnosis alone. The inclusion of YKL-40 features also increases the precision of survival estimates. Fitting models with and without YKL-40 highlights a subgroup of patients who have glioblastoma (GBM) diagnosis but appear to have better prognosis than the typical GBM patient.

Qin W, Zhang K, Kliethermes B, et al.
Differential expression of cancer associated proteins in breast milk based on age at first full term pregnancy.
BMC Cancer. 2012; 12:100 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: First full term pregnancy (FFTP) completed at a young age has been linked to low long term breast cancer risk, whereas late FFTP pregnancy age confers high long term risk, compared to nulliparity. Our hypothesis was that proteins linked to breast cancer would be differentially expressed in human milk collected at three time points during lactation based on age at FFTP.
METHODS: We analyzed breast milk from 72 lactating women. Samples were collected within 10 days of the onset of lactation (baseline-BL), two months after lactation started and during breast weaning (W). We measured 16 proteins (11 kallikreins (KLKs), basic fibroblast growth factor, YKL-40, neutrophil gelatinase-associated lipocalin and transforming growth factor (TGF) β-1 and -2) associated with breast cancer, most known to be secreted into milk.
RESULTS: During lactation there was a significant change in the expression of 14 proteins in women < 26 years old and 9 proteins in women > = 26 at FFTP. The most significant (p < .001) changes from BL to W in women divided by FFTP age (< 26 vs. > = 26) were in KLK3,6, 8, and TGFβ2 in women < 26; and KLK6, 8, and TGFβ2 in women > = 26. There was a significant increase (p = .022) in KLK8 expression from BL to W depending on FFTP age. Examination of DNA methylation in the promoter region of KLK6 revealed high levels of methylation that did not explain the observed changes in protein levels. On the other hand, KLK6 and TGFβ1 expression were significantly associated (r2 = .43, p = .0050).
CONCLUSIONS: The expression profile of milk proteins linked to breast cancer is influenced by age at FFTP. These proteins may play a role in future cancer risk.

Avdieiev S, Savinska L, Filonenko V, Kavsan V
Chitinase 3-like 2 protein monoclonal antibodies.
Hybridoma (Larchmt). 2012; 31(1):32-9 [PubMed] Related Publications
Chitinase 3-like 2 (CHI3L2) is one of the most overexpressed genes in glioblastoma. Despite this, both the CHI3L2 gene and its protein product CHI3L2 are poorly characterized. Here we report the generation and characterization of monoclonal antibodies to CHI3L2 protein (CHI3L2 MAbs). Bacterially expressed 6 His-tagged full-length CHI3L2 was used as antigen. Spleen cells from immunized mice were collected and fused with SP2/0 myeloma cells. Hybridoma clones 2D3 and 4D2 producing high titer CHI3L2 MAbs were identified by enzyme-linked immunosorbent assay (ELISA) and further examined for their activity with the CHI3L2 protein by Western blot analysis and immunoprecipitation. The 2D3 clone was chosen for mouse inoculation and ascites formation. Antibodies derived from the ascitic fluid specifically recognized the recombinant CHI3L2 protein and strongly interacted with CHI3L2 in glioblastoma tissue lysate, as determined by Western blot analysis. The antibodies generated may be useful as a tool in various aspects of CHI3L2 investigation.

Xiao XQ, Hassanein T, Li QF, et al.
YKL-40 expression in human hepatocellular carcinoma: a potential biomarker?
Hepatobiliary Pancreat Dis Int. 2011; 10(6):605-10 [PubMed] Related Publications
BACKGROUND: YKL-40 is a new biomarker with diagnostic value in many different cancers. Whether it may serve as a biomarker for hepatocellular carcinoma (HCC) is still unclear. This study aimed to examine the expression of YKL-40 in the serum and liver tissues of HCC patients and in HCC cell lines, in comparison with that in non-HCC liver disease patients and non-tumor hepatic cell lines, respectively.
METHODS: Immunohistochemical staining was used to detect YKL-40 protein expression in liver biopsy specimens from 8 HCC patients. ELISA was used to assess the serum YKL-40 level in 90 HCC patients, 90 inactive HBsAg carrier (IHC) patients with normal liver functions, and 90 liver cirrhosis patients. Real-time PCR was used to determine the YKL-40 mRNA expression in three HCC cell lines and two non-tumor hepatic cell lines.
RESULTS: Immunohistochemical staining of liver biopsy specimens from HCC patients showed that the YKL-40 protein expression in tumor tissue was higher than that in adjacent normal tissues. ELISA revealed that the YKL-40 serum level in the HCC group was significantly higher than that in the IHC group, but not significantly different from that in the cirrhosis group. Real-time PCR showed that YKL-40 mRNA levels in HCC cell lines were significantly higher than those in non-tumor hepatic cells.
CONCLUSIONS: YKL-40 is highly expressed in HCC at the molecular, cellular and tissue levels. However, it may not serve as a serum biomarker for HCC because measurement of the serum YKL-40 level cannot distinguish HCC from cirrhosis.

Kawada M, Seno H, Kanda K, et al.
Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer.
Oncogene. 2012; 31(26):3111-23 [PubMed] Free Access to Full Article Related Publications
Chitinase 3-like 1 (CHI3L1), one of the mammalian members of the chitinase family, is expressed in several types of human cancer, and elevated serum level of CHI3L1 is suggested to be a biomarker of poor prognosis in advanced cancer patients. However, the overall biological function of CHI3L1 in human cancers still remains unknown. Studies were performed to characterize the role of CHI3L1 in cancer pathophysiology utilizing human colorectal cancer samples and human cell lines. Plasma protein and tissue mRNA expression levels of CHI3L1 in colorectal cancer were strongly upregulated. Immunohistochemical analysis showed that CHI3L1 was expressed in cancer cells, and CHI3L1 expression had a significant association with the number of infiltrated macrophages and microvessel density (MVD). By utilizing transwell migration and tube-formation assays, overexpression of CHI3L1 in SW480 cells (human colon cancer cells) enhanced the migration of THP-1 cells (human macrophage cells) and HUVECs (human endothelial cells), and the tube formation of HUVECs. The knockdown of CHI3L1 by RNA interference or the neutralization of CHI3L1 by anti-CHI3L1 antibody displayed strong suppression of CHI3L1-induced migration and tube formation. Cell proliferation assay showed that CHI3L1 overexpression significantly enhanced the proliferation of SW480 cells. Enzyme-linked immunosorbent assay (ELISA) analysis showed that CHI3L1 increased the secretion of inflammatory chemokines, IL-8 and monocyte chemoattractant protein-1 (MCP-1), from SW480 cells through mitogen-activated protein kinase (MAPK) signaling pathway. Both neutralization of IL-8 or MCP-1 and inhibition or knockdown of MAPK in SW480 cells significantly inhibited CHI3L1-induced migration and tube formation. In a xenograft mouse model, overexpression of CHI3L1 in HCT116 cells (human colon cancer cells) enhanced the tumor growth as well as macrophage infiltration and MVD. In conclusion, CHI3L1 expressed in colon cancer cells promotes cancer cell proliferation, macrophage recruitment and angiogenesis. Thus, the inhibition of CHI3L1 activity may be a novel therapeutic strategy for human colorectal cancer.

Liu Y, Ye F, Yamada K, et al.
Autocrine endothelin-3/endothelin receptor B signaling maintains cellular and molecular properties of glioblastoma stem cells.
Mol Cancer Res. 2011; 9(12):1668-85 [PubMed] Free Access to Full Article Related Publications
Glioblastoma stem cells (GSC) express both radial glial cell and neural crest cell (NCC)-associated genes. We report that endothelin 3 (EDN3), an essential mitogen for NCC development and migration, is highly produced by GSCs. Serum-induced proliferative differentiation rapidly decreased EDN3 production and downregulated the expression of stemness-associated genes, and reciprocally, two glioblastoma markers, EDN1 and YKL-40 transcripts, were induced. Correspondingly, patient glioblastoma tissues express low levels of EDN3 mRNA and high levels of EDN1 and YKL-40 mRNA. Blocking EDN3/EDN receptor B (EDNRB) signaling by an EDNRB antagonist (BQ788), or EDN3 RNA interference (siRNA), leads to cell apoptosis and functional impairment of tumor sphere formation and cell spreading/migration in culture and loss of tumorigenic capacity in animals. Using exogenous EDN3 as the sole mitogen in culture does not support GSC propagation, but it can rescue GSCs from undergoing cell apoptosis. Molecular analysis by gene expression profiling revealed that most genes downregulated by EDN3/EDNRB blockade were those involved in cytoskeleton organization, pause of growth and differentiation, and DNA damage response, implicating the involvement of EDN3/EDNRB signaling in maintaining GSC migration, undifferentiation, and survival. These data suggest that autocrine EDN3/EDNRB signaling is essential for maintaining GSCs. Incorporating END3/EDNRB-targeted therapies into conventional cancer treatments may have clinical implication for the prevention of tumor recurrence.

Antonelli M, Massimino M, Morra I, et al.
Expression of pERK and pAKT in pediatric high grade astrocytomas: correlation with YKL40 and prognostic significance.
Neuropathology. 2012; 32(2):133-8 [PubMed] Related Publications
The Ras signaling pathway, consisting of mitogen-activated protein kinase (MAPK) and PI3K/AKT signaling, is a prominent oncogenic pathways in adult diffuse gliomas, but few studies have evaluated such pathways in pediatric malignant gliomas. We investigated by immunohistochemistry MAPK and AKT signaling in a series of 28 pediatric high-grade gliomas (WHO grade III and IV). We sought a possible association of phospho-ERK (p-ERK) and phospho-AKT (p-AKT) with expression of other proteins involved in the Ras pathway, that is, YKL40, epidermal growth factor receptor (EGFR), EGFR vIII and c-Met. Moreover we correlated the expression of p-ERK and p-AKT with prognosis. No cases showed expression for c-Met and EGFR, and only one case was positive for EGFR vIII. YKL-40 protein was expressed in 43% of cases. We detected expression of p-ERK and p-AKT in 61% and 57%, respectively, of pediatric high grade gliomas. Statistical analysis comparing the two groups in term of high and low p-ERK and p-AKT expression showed a trend toward worse overall survival in patients with high expression of p-AKT. The activation of ERK and AKT suggest a possible role of this protein in inducing activation of the Ras signaling pathway in pediatric high-grade gliomas. Moreover high levels of p-AKT are associated with worse overall survival.

Singh SK, Bhardwaj R, Wilczynska KM, et al.
A complex of nuclear factor I-X3 and STAT3 regulates astrocyte and glioma migration through the secreted glycoprotein YKL-40.
J Biol Chem. 2011; 286(46):39893-903 [PubMed] Free Access to Full Article Related Publications
Nuclear factor I-X3 (NFI-X3) is a newly identified splice variant of NFI-X that regulates expression of several astrocyte-specific markers, such as glial fibrillary acidic protein. Here, we identified a set of genes regulated by NFI-X3 that includes a gene encoding a secreted glycoprotein YKL-40. Although YKL-40 expression is up-regulated in glioblastoma multiforme, its regulation and functions in nontransformed cells of the central nervous system are widely unexplored. We find that expression of YKL-40 is activated during brain development and also differentiation of neural progenitors into astrocytes in vitro. Furthermore, YKL-40 is a migration factor for primary astrocytes, and its expression is controlled by both NFI-X3 and STAT3, which are known regulators of gliogenesis. Knockdown of NFI-X3 and STAT3 significantly reduced YKL-40 expression in astrocytes, whereas overexpression of NFI-X3 dramatically enhanced YKL-40 expression in glioma cells. Activation of STAT3 by oncostatin M induced YKL-40 expression in astrocytes, whereas expression of a dominant-negative STAT3 had a suppressive effect. Mechanistically, NFI-X3 and STAT3 form a complex that binds to weak regulatory elements in the YKL-40 promoter and activates transcription. We propose that NFI-X3 and STAT3 control the migration of differentiating astrocytes as well as migration and invasion of glioma cells via regulating YKL-40 expression.

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