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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor progression and metastasis are the pathologic effects of uncontrolled or deregulated invasive growth, a process in which proteases play a fundamental role. They mediate the degradation of extracellular matrix components and intercellular cohesive structures to allow migration of the cells into the extracellular environment and activate growth and angiogenic factors. In addition to metalloproteases and the plasminogen activation system, another protease, matriptase, contributes substantially to these processes. Matriptase is a type II transmembrane trypsin-like serine protease that is expressed by cells of epithelial origin and is overexpressed in a variety of human cancers. It has been suggested that this protease not only facilitates cellular invasiveness but may also activate oncogenic pathways. This review summarizes current knowledge about matriptase, its putative role in tumor initiation and progression, and its potential as a novel target in anti-cancer therapy.
Cell Mol Life Sci 2006 Dec
PMID:Matriptase and its putative role in cancer. 1713 Oct 55

The role for matrix metalloproteinases (MMPs) in tumor cells invasion and metastasis is well established, and expression of MMPs is recognized as an indication of tumor cell malignancy. Previous studies suggest that the degradation of the basement membrane is a crucial early step in epithelial transformation and ovarian tumorigenesis. Thus, MMPs may also express and exert a role in preneoplastic lesions of ovarian tissues. We investigated the expression of the major metalloproteinases, gelatinase A, 72 kDa type IV collagenase (MMP-2), and gelatinase B, 92 kDa type IV collagenase (MMP-9), and the presence of basement membrane in ovarian tumors and tissues from prophylactic oophorectomies using immunostaining. MMP expression was also characterized in a panel of ovarian cancer cell lines and several nontumorigenic ovarian surface epithelial primary cells by zymography, Northern, and Western blots. We found, surprisingly, that MMP-2 and MMP-9 are expressed more frequently in early lesions than in established carcinomas. No correlation was found between the expression of MMPs and tumor grades or stages. In preneoplastic lesions, MMP-2 or MMP-9 expression often associates with the absence of basement membrane and morphological alterations. MMP-2 is often expressed in nontumorigenic ovarian surface epithelial cells but reduced or absent in cancer cells. Thus, we conclude that MMPs expression does not correlate with the malignancy of ovarian epithelial cells as generally thought. Rather, increased metalloproteinase expression is an early event in ovarian tumorigenesis and associates with the loss of epithelial basement membrane and morphological transformation. We propose that the increased MMP activity is an etiological factor for ovarian cancer risk. We found that MMPs expression does not correlate with the malignancy of ovarian epithelial cells as generally thought. Rather, increased metalloproteinase expression is an early event in ovarian tumorigenesis. The finding suggests roles of MMP in tumor initiation in addition to invasion, and may impact on the strategy for use of MMP inhibitors in cancer prevention.
Mol Carcinog 2007 Feb
PMID:Prominent expression of metalloproteinases in early stages of ovarian tumorigenesis. 1713 4

A majority of breast cancers are hormone-responsive, and require estrogen for growth, and respond to hormonal therapy that blocks estrogen receptor action. Breast tumors with low levels of or completely lacking estrogen receptor fail to respond to antiestrogen therapy yet require estrogen for tumor initiation. To address the importance of local estrogen in oncogene-mediated breast tumorigenesis, we have crossed MMTV-aromatase with MMTV-HER2/neu and examined the incidence of breast cancer in double transgenic mice in comparison with parental strains. Double transgenic mice show normal mammary development and express both transgenes at similar levels to that of parental strains. Tumor incidence in double transgenic mice (<5%) decreased compared to HER2/neu mice (>65%). In addition to a significant decrease in tumorigenesis, these mice expressed ERalpha as well as high levels of ERbeta along with decreased levels of cyclin D1 and phosphorylated pRb among other changes. Furthermore, experiments using THC (ERalpha-agonist and ERbeta-antagonist) clearly demonstrate the critical role of ERbeta in HER2/neu-mediated tumorigenesis. These studies provide the first genetic evidence that estrogen receptor, mainly ERbeta than ERalpha and its dependent changes play an important role in regulating mammary tumorigenesis. These findings provide further evidence for development and testing of novel therapeutic approaches based on selective regulation of estrogen receptors (ERalpha and beta)-dependent actions for the treatment and prevention of breast cancers.
J Steroid Biochem Mol Biol
PMID:HER-2/neu x aromatase double transgenic mice model: the effects of aromatase overexpression on mammary tumorigenesis. 1760 17

Signal transducer and activator of transcription 3 (Stat3) is one of a family of cytoplasmic proteins that participate in normal cellular responses to cytokines and growth factors as transcription factors. Stat3 modulates various physiological functions including cell survival, cell-cycle regulation, and angiogenesis through regulation of gene expression, and its constitutive activation is associated with a number of human epithelial cancers. Recent studies with skin-specific gain and loss of Stat3 function transgenic mice have shown that Stat3 plays critical roles in skin carcinogenesis. Multistage skin carcinogenesis bioassays performed with these transgenic mice clearly demonstrate that Stat3 is required for both tumor initiation and promotion through regulation of genes involved in survival and proliferation, respectively. Stat3 also plays a role in malignant progression of skin tumors by regulating genes that are involved in angiogenesis and invasion. Further studies have revealed that Stat3 plays a critical role in epidermal cell proliferation and survival following exposure to ultraviolet B (UVB) irradiation. In addition, Stat3 is constitutively active in UVB-induced skin tumors from both mice and humans. Collectively, these studies suggest that Stat3 may be a potential target for both the prevention and treatment of human epithelial cancers including skin cancer.
Mol Carcinog 2007 Aug
PMID:Signal transducer and activator of transcription 3 (Stat3) in epithelial carcinogenesis. 1761 Feb 23

Genetic and epigenetic mechanisms contribute to the development of human tumors. However, the conventional analysis of neoplasias has preferentially focused on only one of these processes. This approach has led to a biased, primarily genetic view, of human tumorigenesis. Epigenetic alterations, such as aberrant DNA methylation, are sufficient to induce tumor formation, and can modify the incidence, and determine the type of tumor which will arise in genetic models of cancer. These observations raise important questions about the degree to which genetic and epigenetic mechanisms cooperate in human tumorigenesis, the identity of the specific cooperating genes and how these genes interact functionally to determine the diverse biological and clinical paths to tumor initiation and progression. These gaps in our knowledge are, in part, due to the lack of methods for full-scale integrated genetic and epigenetic analyses. The ultimate goal to fill these gaps would include sequencing relevant regions of the 3-billion nucleotide genome, and determining the methylation status of the 28-million CpG dinucleotide methylome at single nucleotide resolution in different types of neoplasias. Here, we review the emergence and advancement of technologies to map ever larger proportions of the cancer methylome, and the unique discovery potential of integrating these with cancer genomic data. We discuss the knowledge gained from these large-scale analyses in the context of gene discovery, therapeutic application and building a more widely applicable mechanism-based model of human tumorigenesis.
Hum Mol Genet 2007 Apr 15
PMID:Genome-epigenome interactions in cancer. 1761 54

Multiple molecular lesions in human cancers directly collaborate to deregulate proliferation and suppress apoptosis to promote tumorigenesis. The candidate tumor suppressor RASSF1A is commonly inactivated in a broad spectrum of human tumors and has been implicated as a pivotal gatekeeper of cell cycle progression. However, a mechanistic account of the role of RASSF1A gene inactivation in tumor initiation is lacking. Here we have employed loss-of-function analysis in human epithelial cells for a detailed investigation of the contribution of RASSF1 to cell cycle progression. We found that RASSF1A has dual opposing regulatory connections to G(1)/S phase cell cycle transit. RASSF1A associates with the Ewing sarcoma breakpoint protein, EWS, to limit accumulation of cyclin D1 and restrict exit from G(1). Surprisingly, we found that RASSF1A is also required to restrict SCF(betaTrCP) activity to allow G/S phase transition. This restriction is required for accumulation of the anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 and the concomitant block of APC/C-dependent cyclin A turnover. The consequence of this relationship is inhibition of cell cycle progression in normal epithelial cells upon RASSF1A depletion despite elevated cyclin D1 concentrations. Progression to tumorigenicity upon RASSF1A gene inactivation should therefore require collaborating genetic aberrations that bypass the consequences of impaired APC/C regulation at the G(1)/S phase cell cycle transition.
Mol Cell Biol 2008 May
PMID:The RASSF1A tumor suppressor restrains anaphase-promoting complex/cyclosome activity during the G1/S phase transition to promote cell cycle progression in human epithelial cells. 1834 58

Human CD133 (human prominin-1), a five transmembrane domain glycoprotein, was originally identified as a cell surface antigen present on CD34+ hematopoietic stem cells. Although the biological function of CD133 is not well understood, antibodies to CD133 epitopes have been widely used to purify hematopoietic stem and progenitor cells. The cancer stem cell (CSC) hypothesis postulates that a rare population of tumor cells possessing increased capacities for self-renewal and tumor initiation is responsible for maintaining the growth of neoplastic tissue. The expression of the CD133 epitopes, AC133 and AC141, has been shown to define a subpopulation of brain tumor cells with significantly increased capacity for tumor initiation in xenograft models. Following the discovery of the AC133/AC141+ population of brain tumor stem cells, the AC133 and AC141 epitopes have been extensively used as markers for purifying CSCs in other solid tumors. There are, however, several issues associated with the use of the AC133 and AC141 CD133 epitopes as markers for CSCs. The antibodies routinely used for purification of AC133 and AC141-positive cells target poorly characterized glycosylated epitopes of uncertain specificity. Discordant expression of the AC133 and AC141 epitopes has been observed, and the epitopes can be absent despite the presence of CD133 protein. In addition, CD133 expression has recently been shown to be modulated by oxygen levels. These factors, in combination with the uncertain biological role of CD133, suggest that the use of CD133 expression as a marker for CSCs should be critically evaluated in each new experimental system and highlight the need for additional CSC surface markers that are directly involved in maintaining CSC properties.
J Mol Med (Berl) 2008 Sep
PMID:The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. 1853 13

Members of the Sprouty family encode novel proteins that are thought to function primarily as intracellular antagonists of the Ras-signaling pathway. Increased Ras signaling is a critical characteristic of human lung adenocarcinoma, the most common type of non-small cell lung cancer. Sprouty 2 is expressed in the lung epithelium, the tissue layer from which lung cancers arise. We hypothesized that overexpression of Sprouty 2 in the distal lung epithelium would inhibit lung tumorigenesis. To test the hypothesis, the consequences of overexpressing Sprouty 2 in the distal lung epithelium on urethane-induced mouse lung tumorigenesis were determined. Urethane is a chemical carcinogen found in tobacco smoke that causes activating mutations in Kras and induces lung tumors in mice. Sprouty 2-overexpressor mice developed significantly fewer lung tumors compared with their littermate controls (13.2 +/- 1.1 versus 18.1 +/- 1.3, P = 0.006). Tumor diameter was also significantly smaller in Sprouty 2 overexpressors (0.85 mm +/- 0.03 versus 0.95 mm +/- 0.02, P = 0.005). Sprouty 2 overexpression did not alter Kras mutational frequencies in urethane-induced tumors, suggesting that the tumor-suppressing effect of Sprouty 2 overexpression acts at a stage after Kras mutation, perhaps by interfering with receptor tyrosine kinase-induced signaling. These results demonstrate that Sprouty 2 overexpression inhibited both tumor initiation and subsequent tumor growth.
Am J Respir Cell Mol Biol 2009 Jan
PMID:Overexpression of Sprouty 2 in mouse lung epithelium inhibits urethane-induced tumorigenesis. 1863 14

Cancer, second only to heart disease, is the leading cause of death in the US. Although progress has been made in the early detection of cancer and in improvements of cancer therapies, the ability to provide long-term survival has been limited. Increasing evidence suggests that a minute, biologically unique population of cancer stem cells (SCs) exists in most neoplasms and may be responsible for tumor initiation, progression, metastasis, and relapse. Characterization of cancer SCs has led to the identification of key cellular activities that may make cancer SCs vulnerable to therapeutic interventions that target drug-effluxing capabilities, stem cell pathways, anti-apoptotic mechanisms, and induction of differentiation. Phytochemicals, compounds made from fruits, vegetables, and grains, possess anti-cancer properties and represent a promising therapeutic approach for the prevention and treatment of many cancers. This review summarizes the evidence for the cancer SC hypothesis and discusses the potential mechanisms by which phytochemicals might target cancer SCs.
Mol Interv 2008 Aug
PMID:Targeting cancer stem cells with phytochemicals. 1882 43

Resveratrol, a naturally occurring polyphenol, exhibits antioxidant, antiaging, and anticancer activity. Resveratrol has also been shown to inhibit tumor initiation, promotion, and progression in a variety of cell culture systems. Earlier, we showed that paraquat, a bipyridyl herbicide, triggers endoplasmic reticulum stress, cell dysfunction, and dopaminergic cell death. Due to its antioxidant activity, we assessed the ability of resveratrol to rescue cells from the toxic effects of paraquat. While resveratrol did not have any protective effect at low concentrations, it triggered endoplasmic reticulum (ER) stress-induced cell death at higher concentrations (50-250 microM). The present study was carried out to determine the mechanism by which resveratrol triggers ER stress and cell death in dopaminergic N27 cells. Our studies demonstrate that resveratrol triggers ER stress and cell dysfunction, caspase activation, p23 cleavage and inhibition of proteasomal activity in dopaminergic N27 cells. While over expression of uncleavable p23 was associated with decreased cell death, downregulation of p23 protein expression by siRNA resulted in enhancement of ER stress-induced cell death triggered by resveratrol indicating a protective role for the small co-chaperone p23 in dopaminergic cell death.
J Mol Neurosci 2009 Sep
PMID:Endoplasmic reticulum stress-induced cell death in dopaminergic cells: effect of resveratrol. 1914 91


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