Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: A systematic expression analysis

Hamm, Alexander; Veeck, Jürgen; Bektas, Nuran; Wild, Peter J.; Hartmann, Arndt; Heindrichs, U.; Kristiansen, Glen; Werbowetski-Ogilvie, Tamra E.; Maestro, Rolando Del; Knuechel, Ruth; Dahl, Edgar

doi:10.1186/1471-2407-8-25

Cited by 181 publications

(201 citation statements)

References 57 publications

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“…HC5 plays a role in tumor suppression with dysregulated or reduced expression of HC5 directly linked to tumor development (22,40,41) and its overexpression leading to suppression of cell migration and colony spreading (42). A recent study also found that HC5 was the major heavy chain expressed in skin, predominantly due to its production by dermal fibroblasts (43).…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation

Martin

Midgley

Meran

et al. 2016

Journal of Biological Chemistry

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Fibroblasts are central to wound healing and fibrosis through TGF␤1-triggered differentiation into contractile, ␣-smooth muscle actin (␣-SMA)-positive myofibroblasts. This is mediated by accumulation of a pericellular matrix of hyaluronan (HA) and the HA-dependent co-localization of CD44 with the epidermal growth factor receptor (EGFR). Interactions of HA with hyaladherins, such as inter-␣-inhibitor (I␣I) and tumor necrosis factor-stimulated gene-6 (TSG-6), are also essential for differentiation. This study investigated the mechanisms involved. TSG-6 and ␣-SMA had different kinetics of induction by TGF␤1, with TSG-6 peaking before ␣-SMA. Si CD44 or EGFR inhibition prevented differentiation but had no effect on TSG-6 expression. TSG-6 was essential for differentiation, and mAb A38 (preventing I␣I heavy chain (HC) transfer), HA-oligosaccharides, cobalt, or Si bikunin prevented TSG-6 activity, preventing differentiation. A38 also prevented the EGFR/CD44 association. This suggested that TSG-6/I␣I HC interaction was necessary for the effect of TSG-6 and that HC stabilization of HA initiated the CD44/EGFR association. The newly described HC5 was shown to be the principal HC expressed, and its cell surface expression was prevented by siRNA inhibition of TSG-6 or bikunin. HC5 was released by hyaluronidase treatment, confirming its association with cell surface HA. Finally, HC5 knockdown by siRNA confirmed its role in myofibroblast differentiation. The current study describes a novel mechanism linking the TSG-6 transfer of the newly described HC5 to the HA-dependent control of cell phenotype. The interaction of HC5 with cell surface HA was essential for TGF␤1-dependent differentiation of fibroblasts to myofibroblasts, highlighting its importance as a novel potential therapeutic target.The fibroblast is the most abundant cell type in normal connective tissues. It plays a central role in the synthesis, degradation, and remodeling of extracellular matrix both in health and in disease. At sites of tissue damage and in the context of wound healing, activated fibroblasts, termed myofibroblasts, with a contractile phenotype, characterized by the expression of the smooth muscle isoform of ␣-actin (␣-SMA), 3 are essential for the synthesis of a collagen-rich scar, providing the force for wound contraction (1). During a healing response, myofibroblasts are a transient cell population (2). Myofibroblasts are also the major effectors of fibrosis; their persistent presence has been established as the best marker of numerous types of progressive organ dysfunction, such as that seen in chronic renal failure of various etiologies (3-7), liver disease (8), and pulmonary fibrosis (9).The cytokine TGF␤1 is a well recognized mediator of progressive tissue fibrosis, and in vitro and in vivo evidence suggests that it is the primary driving force in fibroblast-myofibroblast phenotypic activation (10, 11). The sequence of events leading up to this transformation is being increasingly characterized at a molecular level in an attempt to understan...

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Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation

Martin

Midgley

Meran

et al. 2016

Journal of Biological Chemistry

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“…The combined data also favorably ranks some relevant genes that are not ranked favorably in individual datasets. For example, ITIH3 (Singh rank=25, Chandran rank=326, combined rank=6) and CHD5 (Singh rank=165, Chandran rank=95, combined rank=7) have both been linked to human cancer [28,29].…”

Section: Interpretation Of Selected Genesmentioning

confidence: 99%

Combining multiple microarray studies using bootstrap meta-analysis

Barrett

Phan

Wang

2008

2008 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society

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Microarray technology has enabled us to simultaneously measure the expression of thousands of genes. Using this high-throughput technology, we can examine subtle genetic changes between biological samples and build predictive models for clinical applications. Although microarrays have dramatically increased the rate of data collection, sample size is still a major issue when selecting features. Previous methods show that combining multiple microarray datasets improves feature selection using simple methods such as fold change. We propose a wrapper-based gene selection technique that combines bootstrap estimated classification errors for individual genes across multiple datasets and reduces the contribution of datasets with high variance. We use the bootstrap because it is an unbiased estimator of classification error that is also effective for small sample data. Coupled with data combination across multiple datasets, we show that our metaanalytic approach improves the biological relevance of gene selection using prostate and renal cancer microarray data.

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“…However, a few of these proteins listed in Table 3 are related to pro-cancer or anti-cancer properties to cancer cells [65][66][67][68][69][70][71][72][73][74]. The molecular nature and functions of these captured human serum proteins remain to be explored in the future [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68].…”

Section: Human Serum Proteins Recognized Separately By Ca215 and Ciggmentioning

confidence: 99%

Dual Differential Roles of Cancerous Immunoglobulins as Suggested by Interactions with Human Serum Proteins

Lee¹

2015

J Clin Cell Immunol

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In search of functional roles of immunoglobulins expressed by cancer cells, molecular interactions between cancerous immunoglobulins and human serum proteins or protein fragments were investigated by using RP215 monoclonal antibody as the unique probe. RP215 was initially generated against OC-3-VGH ovarian cancer cell extract and shown to react with carbohydrate-associated epitope located mainly on the variable regions of immunoglobulin heavy chains and others expressed by cancer cells which are designated in general as CA215. CA215 and cancerous immunoglobulins (cIgG) were affinity isolated from the shed medium of cultured cancer cells. Furthermore, by using purified CA215 and cIgG as the respective affinity ligands, the serum proteins or components were affinity isolated and subject to analysis by LCMS/MS methods. The results of such analysis suggest that as many as 80-86% of the isolated human serum proteins were identical in those purified by either affinity column. They are generally classified as pro-cancer and anti-cancer protein components. Among the known pro-cancer protein components recognized by cancerous immunoglobulins are C4 binding proteins α-chain, complement C3, complement factor H, serotransferrin and vitronectin, etc. On the other hand, inter-α-trypsin inhibitor heavy chain 4, anastellin, apolipoprotein A1, fibrinogen β-chain and keratin type 1 cytoskeletal 9 or autoimmune IgG were considered to be anti-cancer proteins from human serum. Based on these observations, dual functional roles of cancerous immunoglobulins are hypothesized. It has been demonstrated in this study that cancerous immunoglobulins are capable of serving as specific binding protein-like immunoglobulins to capture serum proteins to promote growth of cancer cells. At the same time, they can neutralize those with anti-cancer properties in human circulations.

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Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: A systematic expression analysis

Cited by 181 publications

References 57 publications

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor β1 (TGFβ1)-dependent Fibroblast to Myofibroblast Differentiation

Combining multiple microarray studies using bootstrap meta-analysis

Dual Differential Roles of Cancerous Immunoglobulins as Suggested by Interactions with Human Serum Proteins

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