Abstract:
:High levels of the cell growth inhibitor transforming growth factor-beta1 (TGF-beta1) are often found in a variety of human cancers. However, the physiological significance of this overexpression depends on the availability of the biologically active form of TGF-beta1 within the extracellular matrix of the tumor microenvironment. To determine the expression and activation status of TGF-beta1 in chemically induced tumors, 6-wk-old A/J mice were injected intraperitoneally with either azoxymethane (AOM) (10 mg/kg body weight, once a week for 6 wk) or normal saline solution, and colon tumors were isolated 24 wk following the last injection. An enzyme-linked immunosorbent assay for TGF-beta1 revealed a significant increase (1.7-fold, P < 0.05) in total TGF-beta1 protein in tumors. Interestingly, while 80% of the total TGF-beta1 in the control colon tissues was in the active form, only 50% was found to be active in tumors. Together with our earlier observations that TGF-beta1 mRNA levels are unchanged in A/J tumors, these data further support a mechanism whereby elevated TGF-beta1 levels result from a defective activation and turnover of this protein. Because plasmin is known to be a major activator of TGF-beta1 in vivo, we hypothesized that reduced plasmin activity may be responsible for the observed dysregulation of TGF-beta1 processing in these behaviorally benign tumors. With a fluorogenic peptide substrate for serine proteases, a deficiency in plasmin activity was found in the tumors. Furthermore, semiquantitative reverse transcription (RT)-polymerase chain reaction (PCR) analysis of a panel of genes involved in the plasminogen activation system, including plasminogen activator inhibitor-1 (PAI-1), urokinase-plasminogen activator (u-PA), and urokinase-receptor (u-PAR-1), demonstrated a significant upregulation (approximately fourfold to sixfold, P < 0.05) in the expression of each of these genes in the tumor tissue. In addition, no significant changes were observed in the expression levels of thrombospondin-1 (TSP-1) and insulin-like growth factor type II receptor (IGF-IIR), which also mediate the activation of latent TGF-beta1. To gain further insight into the functionality of the TGF-beta1 pathway, cDNA microarrays were performed and the expression levels of a panel of 21 TGF-beta1-specific target genes were determined in AOM-induced tumors that overexpress the ligand. A significant dysregulation in the expression of each of these targets was observed, providing evidence of aberrant TGF-beta1 signaling in tumors. Overall, the present study demonstrates a very low plasmin activity in A/J colon tumors, possibly as a result of the potent inhibitory effect of PAI-1 on the plasminogen activation cascade. The observed deficiency in plasmin activity may not be sufficiently compensated for by other mechanisms of latent TGF-beta1 activation, including TSP-1 and IGF-IIR, thereby resulting in a decreased fraction of the biologically active form of TGF-beta1 and subsequent aberration in TGF-beta1-specific gene regulation in A/J tumors.
journal_name
Mol Carcinogjournal_title
Molecular carcinogenesisauthors
Guda K,Claffey KP,Dong M,Nambiar PR,Rosenberg DWdoi
10.1002/mc.10120subject
Has Abstractpub_date
2003-05-01 00:00:00pages
51-9issue
1eissn
0899-1987issn
1098-2744journal_volume
37pub_type
杂志文章abstract::Transforming growth factor-beta (TGF-beta) is a growth modulator that inhibits the proliferation of many epithelial cells through interaction with its receptors, the type I and type II receptors (TGF-beta RI and RII) by activating their serine/threonine kinase activities. Loss of growth inhibition by TGF-beta is thoug...
journal_title:Molecular carcinogenesis
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abstract::Krüppel-like factor 4 (KLF4) is a zinc-finger-containing transcription factor with tumor suppressor activity in various cancer types. Cells that sustain double strand breaks (DSBs) in their DNA due to high levels of reactive oxygen species (ROS) can develop genomic instability, which can result in cancer formation. On...
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doi:10.1002/mc.2940050307
更新日期:1992-01-01 00:00:00
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journal_title:Molecular carcinogenesis
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doi:10.1002/mc.2940120102
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journal_title:Molecular carcinogenesis
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abstract::Three okadaic acid class tumor promoters, okadaic acid, dinophysistoxin-1, and calyculin A, have potent tumor-promoting activity in two-stage carcinogenesis experiments on mouse skin. DNA isolated from tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) and each of these tumor promoters revealed the same mutation ...
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doi:10.1002/mc.2940020403
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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更新日期:1996-01-01 00:00:00
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pub_type: 杂志文章,多中心研究,随机对照试验
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abstract::N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis is an important model for squamous cell carcinoma of the human esophagus. In this model, previous studies have shown that the GGA-->GAA Ha-ras codon 12 mutation is present in the majority of papillomas. No other Ha-ras mutation has been identified....
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.2940020404
更新日期:1989-01-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:
更新日期:1998-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2020-08-01 00:00:00
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更新日期:2013-08-01 00:00:00
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pub_type: 杂志文章
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更新日期:1996-06-01 00:00:00
abstract::Mice with conditional gene deletions have been extremely valuable in allowing investigators to study the genes of interest in a tissue-specific manner. The Cre-loxP recombination system provides a powerful tool to produce targeted rearrangements of particular genes. The keratin 5-Cre recombinase (K5Cre) transgenic mou...
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pub_type: 杂志文章
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更新日期:2007-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/(SICI)1098-2744(199605)16:1<12::AID-MC3>3.
更新日期:1996-05-01 00:00:00
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更新日期:1995-09-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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更新日期:2013-04-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
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更新日期:1996-07-01 00:00:00
abstract::Hepatitis B virus (HBV) X protein (HBx) and cyclooxygenase-2 (COX-2) are all playing roles in hepatocellular carcinoma (HCC), but the reversing effects of COX-2 inhibitors on the neoplastic features caused by HBx protein is still unclear. To further evaluate the therapeutic potential of celecoxib on HBx mediated trans...
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更新日期:2009-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2001-04-01 00:00:00
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更新日期:1996-02-01 00:00:00
abstract::Mutations induced by activated benzo[a]pyrene ((+)-anti-B[a]PDE) in Escherichia coli are being investigated, by using both random and adduct-site-specific mutagenesis approaches. A working hypothesis was proposed that the major adduct of (+)-anti-B[a]PDE (formed at N2-Gua) is able to induce different base-substitution...
journal_title:Molecular carcinogenesis
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doi:10.1002/mc.2940130404
更新日期:1995-08-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.20250
更新日期:2008-02-01 00:00:00
abstract::An in vitro model system for xenogenization has been developed in which an immunogenic, nonmalignant phenotype was selected from a highly malignant T-cell line (S49). We showed by single-strand conformation polymorphism and DNA sequence analysis that specific point mutations in the p53 tumor suppressor gene correlated...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.2940080404
更新日期:1993-01-01 00:00:00
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journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/(sici)1098-2744(199707)19:2<137::aid-mc8>3
更新日期:1997-06-01 00:00:00
abstract::In tumor cells that have lost responsiveness to the growth inhibitory effects of transforming growth factor beta (TGFbeta), increased TGFbeta production by the tumor cells often contributes to cancer progression, primarily through paracrine mechanisms. Here we investigated the major components of the activator protein...
journal_title:Molecular carcinogenesis
pub_type: 杂志文章
doi:10.1002/mc.20189
更新日期:2006-08-01 00:00:00
abstract::FAM134B is an autophagy regulator of endoplasmic reticulum and acts as a cancer suppressor in colon cancer. However, the molecular signaling pathways by which FAM134B interacts within colon carcinogenesis is still unknown. Herein, this study aims to determine the interacting partners of FAM134B for the first time in c...
journal_title:Molecular carcinogenesis
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更新日期:2018-11-01 00:00:00