CHI3L1 (YKL‐40) is expressed in human gliomas and regulates the invasion, growth and survival of glioma cells

Ku, Bo Mi; Lee, Yeon Kyung; Ryu, Jinhyun; Jeong, Joo; Choi, Jungil; Eun, Keyoung Mi; Shin, Hye Young; Kim, Dong Gyu; Hwang, Eun Mi; Yoo, Jae Cheal; Park, Jae Yong; Roh, Gu Seob; Kim, Hyun Joon; Cho, Gyeong Jae; Choi, Wan Sung; Paek, Sun Ha; Kang, Sang Soo

doi:10.1002/ijc.25466

Cited by 100 publications

(105 citation statements)

References 38 publications

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“…Notably, among these 12 genes, 5 (ARG2, CHI3L1, FAM134B, KRT17, and CD6) have prosurvival functions and/or are associated with transformation and poorer clinical outcome in human cancers. [43][44][45][46][47][48][49] Next, we confirmed that a subset of these genes is dependent on HIF1-a for hypoxia-induced upregulation. As shown in Figure 7B, knockdown of HIF1-a resulted in abrogation of the hypoxia-induced upregulation of ARG2, BNIP3, SULF2, and NEDD9.…”

supporting

confidence: 55%

Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition

Manjeri

Lee

et al. 2014

Blood

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• Hypoxia mediates TKI resistance.• Hypoxia enhances CML stem cell maintenance.C-abl oncogene 1, nonreceptor tyrosine kinase (ABL1) kinase inhibitors such as imatinib mesylate (imatinib) are effective in managing chronic myeloid leukemia (CML) but incapable of eliminating leukemia stem cells (LSCs), suggesting that kinase-independent pathways support LSC survival. Given that the bone marrow (BM) hypoxic microenvironment supports hematopoietic stem cells, we investigated whether hypoxia similarly contributes to LSC persistence. Importantly, we found that although breakpoint cluster region (BCR)-ABL1 kinase remained effectively inhibited by imatinib under hypoxia, apoptosis became partially suppressed. Furthermore, hypoxia enhanced the clonogenicity of CML cells, as well as their efficiency in repopulating immunodeficient mice, both in the presence and absence of imatinib. Hypoxia-inducible factor 1 a (HIF1-a), which is the master regulator of the hypoxia transcriptional response, is expressed in the BM specimens of CML individuals. In vitro, HIF1-a is stabilized during hypoxia, and its expression and transcriptional activity can be partially attenuated by concurrent imatinib treatment. Expression analysis demonstrates at the whole-transcriptome level that hypoxia and imatinib regulate distinct subsets of genes. Functionally, knockdown of HIF1-a abolished the enhanced clonogenicity during hypoxia. Taken together, our results suggest that in the hypoxic microenvironment, HIF1-a signaling supports LSC persistence independent of BCR-ABL1 kinase activity. Thus, targeting HIF1-a and its pathway components may be therapeutically important for the complete eradication of LSCs. (Blood. 2014;123(21):3316-3326)

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supporting

confidence: 55%

Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition

Manjeri

Lee

et al. 2014

Blood

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“…Many of the mucins, which are frequently mutated or overexpressed in cancers (43), were up-regulated, especially Muc5B, Muc13, and Muc3a. Finally, Chitinase 3-like 1 (CHI3L1), which is also expressed in human gliomas (44) and promotes angiogenesis in colorectal cancer (45), is increased. PKA.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic characterization of fibrolamellar hepatocellular carcinoma

Simon

Freije

Farber

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

113

174

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Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a deletion of ∼400 kb in chromosome 19, resulting in a fusion of the genes for the heat shock protein, DNAJ (Hsp40) homolog, subfamily B, member 1, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA. The resulting chimeric transcript produces a fusion protein that retains kinase activity. No other recurrent genomic alterations have been identified. Here we characterize the molecular pathogenesis of FLHCC with transcriptome sequencing (RNA sequencing). Differential expression (tumor vs. adjacent normal tissue) was detected for more than 3,500 genes (log2 fold change ≥1, false discovery rate ≤0.01), many of which were distinct from those found in hepatocellular carcinoma. Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples. These and other dysregulated genes may serve as potential targets for therapeutic intervention.

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“…Interestingly, CHI3L1 (Chitinase 3-like 1), a secreted glycoprotein, which has been implicated in invasion and cell matrix adhesion (62), was observed at higher levels in the secretome of U87 cells (58,59) and was present at lower levels in the EGFR-and EGFRvIII-expressing cell lines compared with U87 parental, ϩPE-and ϩPTEN-expressing cells. For the ϩPE cell line, 32 proteins were detected and CTSL1 protein; an endopeptidase inhibitor was present at the highest level.…”

Section: Pten-and Pe-expressing Cell Lines Had Low Abundance Of Invasmentioning

confidence: 99%

“…CHI3L1 is a secreted glycoprotein highly expressed in gliomas that has been shown to increase invasion (59), and elevated levels of CHI3L1 in serum have been associated with poor prognosis (62,106). All glioma cell lines secreted CHI3L1 protein and surprisingly, both ϩPE and ϩPTEN secreted high levels of the glycoprotein indicating PTEN's influence on secretion of CHI3L1.…”

Section: Proteins Involved In the Epithelial-mesenchymal Transition (mentioning

confidence: 99%

Quantitative Proteomic Analysis Reveals Effects of Epidermal Growth Factor Receptor (EGFR) on Invasion-promoting Proteins Secreted by Glioblastoma Cells

Sangar

Funk

Kusebauch

et al. 2014

Molecular & Cellular Proteomics

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Glioblastoma multiforme is a highly invasive and aggressive brain tumor with an invariably poor prognosis. The overexpression of epidermal growth factor receptor (EGFR) is a primary influencer of invasion and proliferation in tumor cells and the constitutively active EGFRvIII mutant, found in 30 -65% of Glioblastoma multiforme, confers more aggressive invasion. To better understand how EGFR contributes to tumor aggressiveness, we investigated the effect of EGFR on the secreted levels of 65 rationally selected proteins involved in invasion. We employed selected reaction monitoring targeted mass spectrometry using stable isotope labeled internal peptide standards to quantity proteins in the secretome from five GBM (U87) isogenic cell lines in which EGFR, EGFRvIII, and/or PTEN were expressed. Our results show that cell lines with EGFR overexpression and constitutive EGFRvIII expression differ remarkably in the expression profiles for both secreted and intracellular signaling proteins, and alterations in EGFR signaling result in reproducible changes in concentrations of secreted proteins. Furthermore, the EGFRvIII-expressing mutant cell line secretes the majority of the selected invasion-promoting proteins at higher levels than other cell lines tested. Additionally, the intracellular and extracellular protein measurements indicate elevated oxidative stress in the EGFRvIIIexpressing cell line. In conclusion, the results of our study demonstrate that EGFR signaling has a significant effect on the levels of secreted invasion-promoting proteins, likely contributing to the aggressiveness of Glioblastoma multiforme. Further characterization of these proteins may provide candidates for new therapeutic strategies and targets as well as biomarkers for this aggressive disease. Molecular & Cellular

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CHI3L1 (YKL‐40) is expressed in human gliomas and regulates the invasion, growth and survival of glioma cells

Cited by 100 publications

References 38 publications

Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition

Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition

Transcriptomic characterization of fibrolamellar hepatocellular carcinoma

Quantitative Proteomic Analysis Reveals Effects of Epidermal Growth Factor Receptor (EGFR) on Invasion-promoting Proteins Secreted by Glioblastoma Cells

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