Expression of T‐Cadherin (CDH13, H‐Cadherin) in Human Brain and Its Characteristics as a Negative Growth Regulator of Epidermal Growth Factor in Neuroblastoma Cells

Takeuchi, Tamotsu; Misaki, Akiko; Liang, Sheng‐Ben; Tachibana, Akiko; Hayashi, Nakanobu; Shinmoto, Hiroshi; Ohtsuki, Yuji

doi:10.1046/j.1471-4159.2000.0741489.x

Cited by 163 publications

(160 citation statements)

References 16 publications

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“…31 A variety of studies have demonstrated the functional role of CDH13 in cell proliferation, the cell cycle, and epigenetic silencing in cancer, and CDH13 is now recognized as a tumor suppressor gene. CDH13 is believed to suppress the development of neural cells 31 and induce G2 (premiotic phase) arrest in astrocytomas via p21.…”

Section: Discussionmentioning

confidence: 99%

“…Among those that fulfilled both of these criteria, we chose 251 probes that showed remarkably high expression only in fluorescentnegative tumors (median intensity of expression signal > 1.0). We then selected 68 cancer-related genes (80 probes) as functionally annotated by the Ingenuity Pathways Analysis Knowledge Base, and finally pinpointed CDH13, known as a tumor suppressor gene, 31 as the most likely determinant of a 5-ALA-induced fluorescence signal in glioma. In general, a tumor suppressor gene is related to the malignancy of a tumor, which is believed to be corre-lated with a positive rate of 5-ALA-induced fluorescence signal.…”

Section: Selection Of Genes Related To 5-ala-induced Tumor Fluorescenmentioning

confidence: 99%

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Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Suzuki¹,

Wada

Eguchi

et al. 2013

JNS

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Object Gliomas contain aggressive malignant cancer, and resection rate remains an important factor in treatment. Currently, fluorescence-guided resection using orally administered 5-aminolevulinic acid (5-ALA) has proved to be beneficial in improving the prognosis of patients with gliomas. 5-ALA is metabolized to protoporphyrin IX (PpIX) that accumulates selectively in the tumor and exhibits strong fluorescence upon excitation, but glioma cells do not always respond to 5-ALA, which can result in incomplete or excessive resection. Several possible mechanisms for this phenomenon have been suggested, but they remain poorly understood. To clarify the probable mechanisms underlying the variable induction of fluorescence and to improve fluorescence-guided surgery, the authors searched for key negative regulators of fluorescent signal induced by 5-ALA. Methods A comprehensive gene expression analysis was performed using microarrays in 11 pairs of tumor specimens, fluorescence-positive and fluorescence-negative tumors, and screened genes overexpressed specifically in fluorescence-negative tumors as the possible candidates for key negative regulators of 5-ALA–induced fluorescence. The most possible candidate was selected through annotation analysis in combination with a comparison of expression levels, and the relevance of expression of the selected gene to 5-ALA–induced fluorescence in tumor tissues was confirmed in the quantified expression levels. The biological significance of an identified gene in PpIX accumulation and 5-ALA–induced fluorescence was evaluated by in vitro PpIX fluorescence intensity analysis and in vitro PpIX fluorescence molecular imaging in 4 human glioblastoma cell lines (A1207, NMCG1, U251, and U373). Knockdown analyses using a specific small interfering RNA in U251 cells was also performed to determine the mechanisms of action and genes working as partners in the 5-ALA metabolic pathway. Results The authors chose 251 probes that showed remarkably high expression only in fluorescent-negative tumors (median intensity of expression signal > 1.0), and eventually the cadherin 13 gene (CDH13) was selected as the most possible determinant of 5-ALA–induced fluorescent signal in gliomas. The mean expression level of CDH13 in the fluorescence-negative gliomas was statistically higher than that in positive ones (p = 0.027), and knockdown of CDH13 expression enhanced the fluorescence image and increased the amount of PpIX 13-fold over controls (p < 0.001) in U251 glioma cells treated with 5-ALA. Comprehensive gene expression analysis of the CDH13-knockdown U251 cells demonstrated another two genes possibly involved in the PpIX biosynthesis: ATP-binding cassette transporter (ABCG2) significantly decreased in the CDH13 knockdown, while oligopeptide transporter 1 (PEPT1) increased. Conclusions The cadherin 13 gene might play a role in the PpIX accumulation pathway and act as a negative regulator of 5-ALA–induced fluorescence in glioma cells. Although further studies to clarify the mechanisms of action in the 5-ALA metabolic pathway would be indispensable, the results of this study might lead to a novel fluorescent marker able to overcome the obstacles of existing fluorescence-guided resection and improve the limited resection rate.

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Section: Discussionmentioning

confidence: 99%

Section: Selection Of Genes Related To 5-ala-induced Tumor Fluorescenmentioning

confidence: 99%

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Suzuki¹,

Wada

Eguchi

et al. 2013

JNS

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“…A second possibility is that APN might have other signal transduction pathways in addition to AdipoR1 and ‐R2. For instance, it will be interesting to determine if T‐cadherin, which is abundantly expressed in brain52 and is known to bind APN,53 might affect expression of APN.…”

Section: Apn May Promote Neurodegeneration In Ad Through Novel Mechanmentioning

confidence: 99%

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

Waragai

Ho²,

Takamatsu

et al. 2017

Ann Clin Transl Neurol

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A recent study suggested that insulin resistance may play a central role in the pathogenesis of Alzheimer's disease (AD). In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD. These results are unanticipated because AD has been linked to type II diabetes and other metabolic disorders in which hypoadiponectinemia has been firmly established, and because APN ameliorated neuropathological features in a mouse model of neurodegeneration. Therefore, the objective of this study is to discuss the possible mechanisms underlying the biological actions of APN in the context of AD. Given that insulin receptor signaling is required for normal function of the nervous system, we predict that APN may be upregulated to compensate for compromised activity of the insulin receptor signaling pathway. However, increased APN might be sequestered by tau in the brain, leading to neurotoxic protein aggregation in AD. Alternatively, misfolding of APN may result in downregulation of the insulin/APN signal transduction network, leading to decreased neuroprotective and neurotrophic activities. Thus, it is possible that both ‘gain of function’ and ‘loss of function’ of APN may underlie synaptic dysfunction and neuronal cell death in AD. Such a unique biological mechanism underlying APN function in AD may require a novel therapeutic strategy that is distinct from previous treatment for metabolic disorders.

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“…This cellular proliferation is blocked by virusmediated adiponectin expression (34). Interestingly, T-cadherin can regulate growth of cells in the nervous system (35). Tcadherin suppressed the growth of astrocytes and was reduced in a glioblastoma cell line (36), and reexpression of T-cadherin in this cell line induced growth arrest, which depended on p21 (CIP1͞WAF1) expression.…”

Section: Divalent Cations Are Required For Adiponectin Binding To T-cmentioning

confidence: 99%

T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin

Hug

Wang

Ahmad

et al. 2004

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

770

589

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Acrp30͞adiponectin is reduced in the serum of obese and diabetic individuals, and the genetic locus of adiponectin is linked to the metabolic syndrome. Recombinant adiponectin, administered to diet-induced obese mice, induced weight loss and improved insulin sensitivity. In muscle and liver, adiponectin stimulates AMP-activated protein kinase activation and fatty acid oxidation. To expression-clone molecules capable of binding adiponectin, we transduced a C2C12 myoblast cDNA retroviral expression library into Ba͞F3 cells and panned infected cells on recombinant adiponectin linked to magnetic beads. We identified T-cadherin as a receptor for the hexameric and high-molecular-weight species of adiponectin but not for the trimeric or globular species. Only eukaryotically expressed adiponectin bound to T-cadherin, implying that posttranslational modifications of adiponectin are critical for binding. An adiponectin mutant lacking a conserved N-terminal cysteine residue required for formation of hexamer and high-molecularweight species did not bind T-cadherin in coimmunoprecipitation studies. Although lacking known cellular functions, T-cadherin is expressed in endothelial and smooth muscle cells, where it is positioned to interact with adiponectin. Because T-cadherin is a glycosylphosphatidylinositol-anchored extracellular protein, it may act as a coreceptor for an as-yet-unidentified signaling receptor through which adiponectin transmits metabolic signals.A dipose tissue is not only a storage depot for lipid but also a regulator of metabolism, through hormones known as adipokines. One adipokine is adiponectin (also denoted Acrp30, for adipocyte complement-related protein of 30 kDa), a molecule secreted exclusively by differentiated adipocytes (1). Adiponectin, which has homology to C1q, is found in the serum as three distinct oligomers, namely trimer, hexamer, and a highmolecular-weight (HMW) species (2). Adiponectin levels are decreased in the serum of obese and diabetic people (3) and animal models of obesity and diabetes. Replenishment by any of several methods induces weight loss and correction of insulin resistance (4-6). The mechanisms by which adiponectin influences metabolism are not fully understood but involve increasing fatty-acid oxidation in muscle through AMP-activated protein kinase (AMPK) activation, as well as synergizing with insulin in the liver to increase glycogen stores and to inhibit gluconeogenesis (6, 7). In tissue culture and isolated muscle, the trimeric isoform and a trimeric globular C-terminal subdomain activate AMPK (7,8), whereas the hexamer and HMW isoforms activate NF-B (9). Adiponectin also has been implicated in the inflammatory process of the metabolic syndrome, and reduced adiponectin levels have been correlated with impaired forearm blood flow, possibly linking endothelial dysfunction with adiponectin levels (10).Analysis of the transmembrane pathways linking adiponectin to downstream signaling events has yielded conflicting results. Two recently described receptors that bind ad...

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Expression of T‐Cadherin (CDH13, H‐Cadherin) in Human Brain and Its Characteristics as a Negative Growth Regulator of Epidermal Growth Factor in Neuroblastoma Cells

Cited by 163 publications

References 16 publications

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin

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