UMLS:C0242379 - FACTA Search

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Query: UMLS:C0242379 (lung cancer)
71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN, CD147) is a multifunctional protein that has been implicated in cancer invasion and metastasis by the induction of MMPs. To address its role in primary tumors of human non-small-cell lung cancer we assessed whether EMMPRIN expression is associated with the expression of MMP-2 and MMP-9 and with patient survival. Primary tumors of 150 patients (65 adenocarcinomas, 58 squamous cell carcinomas, and 27 of other subtypes) with completely resected lung cancers were stained by immunohistochemistry. We assessed intensity, extent, and cellular localization of EMMPRIN staining and determined MMP-2 and MMP-9 expression. 145 tumors expressed EMMPRIN (strong expression in 61 tumors), which was predominantly localized at the tumor cell membranes in 102 (68%) patients. We could not determine any correlation between EMMPRIN expression and MMP-2 or MMP-9 expression. The prognostic relevance of EMMPRIN was evaluated by Kaplan-Meier and multivariate Cox regression analysis in patients with adenocarcinoma (n=57) and squamous cell carcinoma of the lung (n=56). The median follow-up period was 36.0 months (range 4-156 months). Staining scores for EMMPRIN and MMP-2 and MMP-9 derived from staining intensities and percentages of positive cells did not predict outcome of patients. In contrast, univariate survival analysis demonstrated that membranous localization of EMMPRIN was associated with shortened survival in patients with adenocarcinoma (P=0.03; log-rank test), but not in squamous cell carcinoma. For the former patients, membranous EMMPRIN expression was also an independent predictor of patient survival (P=0.04; Cox regression analysis). The findings point to a role of EMMPRIN for the progression of adenocarcinoma of the lung that is unrelated to its function as inducer of MMPs.
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PMID:Cellular localization of EMMPRIN predicts prognosis of patients with operable lung adenocarcinoma independent from MMP-2 and MMP-9. 1856 95

It was documented that type IV collagenase with two subtypes of 72 ku/MMP-2 and 92 ku/MMP-9 plays an important role in tumor invasion and metastasis. The endoplasmic reticulum (ER)-retained, single chain Fv antibody fragment (scFv) was used to inhibit the function of type IV collagenase. For expression in mammalian cells, the assembled scFv M97 gene with ER retention signal encoding 6 additional amino acids (SEKDEL) was reamplified by PCR. The amplified fragments were cloned into the pcDNA3.1 vector. The resulting plasmid was sequenced and then introduced into PG cells, a highly metastatic human lung cancer cell line, by lipofectAMINE method. The result of intrabody gene therapy showed that type IV collegenase expression was down regulated significantly as measured by ELISA. The biological behavior of PG cell, such as the ability of in vitro invasion through Matrigel, colony formation on soft agar, was also inhibited by scFv M97 transfection. Animal experiments in a xenograft model of human lung cancer showed that scFv M97 transfection significantly prolonged the survival time of nude mice. The results indicate that intracellular antibody technology represents a novel and efficient way to abrogate selectively the activity of type IV collagenase.
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PMID:Intracellular expression of a single-chain antibody directed against type IV collagenase inhibits the growth of lung cancer xenografts in nude mice. 1872 48

Expression of oncogenic K-Ras is frequently observed in non-small-cell lung cancer. However, oncogenic K-Ras is not sufficient to transform lung epithelial cells and requires collaborating signals that have not been defined. To examine the biological effects of K-Ras in nontransformed lung epithelial cells, stable transfectants were generated in RL-65 cells, a spontaneously immortalized lung epithelial cell line. Expression of K-Ras resulted in extracellular signal-regulated kinase (ERK) activation, which mediated induction of cyclooxygenase (COX)-2 and increased prostaglandin E(2) production. Epithelial cells expressing oncogenic K-Ras showed increased proliferation in two- and three-dimensional tissue culture and delayed formation of hollow acinar structures in three-dimensional matrigel cultures. These affects were mediated through COX-2-dependent activation of beta-catenin signaling and inhibition of apoptosis. ERK activation also led to induction of metalloproteinase (MMP)-9 and cleavage of E-cadherin at two specific sites. This resulted in partial disruption of adherens junctions as determined by decreased transepithelial resistance (TER), and disruption of E-cadherin/beta-catenin interactions. An MMP-9 inhibitor reversed the decrease in TER and inhibited beta-catenin signaling. These data indicate that although expression of oncogenic K-Ras does not transform lung epithelial cells, it alters the phenotype of the cells by increasing proliferation and decreasing cell-cell contacts characteristic of epithelial cells.
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PMID:Oncogenic K-Ras regulates proliferation and cell junctions in lung epithelial cells through induction of cyclooxygenase-2 and activation of metalloproteinase-9. 1903 3

Tissue Factor Pathway Inhibitor-2 (TFPI-2) is a potent inhibitor of plasmin which activates metalloproteinases (MMPs) involved in extracellular matrix (ECM) degradation. Its secretion in ECM makes TFPI-2 a potential inhibitor to regulate tumour invasion and metastasis. Moreover, TFPI-2 is frequently downregulated, particularly in aggressive cancers. In this study, we silenced TFPI-2 in the NCI-H460 non-small cell lung cancer cell line and evaluated the role of TFPI-2 in cell invasion and its impact on MMPs expression. As the effects of siRNA are transient, the consequences of both gene silencing and restoration to normal expression could be studied kinetically in the same cells. We showed that TFPI-2 expression by NCI-H460 cells was effectively downregulated using specific small interfering RNA and this silencing was associated with an increase in the invasive potential of tumour cells while migration was not affected. We also showed that mRNA levels and protein expression of MMP-2, -3, -9, -14 were not influenced by TFPI-2 silencing. Moreover, the gelatinase activity of MMP-2 and MMP-9 was unmodified. In contrast, MMP-1 mRNA levels and protein were significantly and similarly increased in cells transfected with TFPI-2 siRNA. In conclusion, this study confirms that TFPI-2 downregulation can contribute to tumour invasion of lung cancer cells.
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PMID:Transient RNA silencing of tissue factor pathway inhibitor-2 modulates lung cancer cell invasion. 1926 3

Microvesicles (MVs) are shed from cell membranes of several cell types and have an important function in cell-to-cell communication. Exponentially growing lung cancer cells secrete large quantities of MVs and we were interested in their role in tumor progression. We observed that both human and murine lung cancer cell lines secrete more MVs in response to non-apoptotic doses of hypoxia and irradiation. These tumor-derived (t)MVs activate and chemoattract stroma fibroblasts and endothelial cells. Furthermore, they induce expression of several pro-angiopoietic factors in stromal cells such as IL-8, VEGF, LIF, OSM, IL-11 and MMP-9. We also noticed that conditioned media harvested from stroma cells stimulated by tMVs enhanced the metastatic potential of both human and murine lung cancer cells in vivo. Thus, we postulated that tMVs are underappreciated constituents of the tumor microenvironment and play a pivotal role in tumor progression, metastasis and angiogenesis.
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PMID:Lung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumors. 1946 51

Skp2 is one of the components of the E3 ubiquitin ligase which is required for the degradation of tumor suppressor p27. Overexpression of this oncogene is frequently found in human cancers and has been shown to be associated with poor prognosis. In addition to induce p27 degradation and enhance cellular proliferation, Skp2 also plays a role in promoting tumor metastasis. However, the underlying mechanism is unclear. In this study, we established Skp2-overexpressing stable transfectants from A549 human lung cancer cells. We found that these stable transfectants exhibited increased migratory and invasive abilities. In addition, expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 was up-regulated. Enzymatic assay and gelatin zymography confirmed the increase of MMP-2 and MMP-9 activity and neutralization of these two MMPs by antibodies reduced cell invasion. Our results also revealed that Sp1 was involved in the induction of MMP-2 and MMP-9 by Skp2 because treatment of mithramycin or knockdown of Sp1 by small interference RNA attenuated their expressions. Collectively, we provide the first evidence that up-regulation of MMP-2 and MMP-9 is one of the mechanisms by which Skp2 promotes cell invasion.
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PMID:Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. 1962 21

Matrix metalloproteinases (MMPs) secreted by lung cancer (LC) and malignant mesothelioma (MM), especially MMP-2 and MMP-9, play crucial roles in tumor invasion and metastasis. We examined the effect of cytokines, mitogens and inhibitors on MMP-2 and MMP-9 expression in LC and MM cell lines. Human LC (A-549) and MM (MSTO-211H) cell lines were cultured in appropriate media. At near confluence, the cells were washed with PBS and incubated in serum-free medium with various concentrations of several cytokines, mitogens and inhibitors. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by gelatinase zymography and quantitated by densitometry. LC expressed MMP-2 whereas MM expressed MMP-2 and MMP-9. TNF-alpha, IL-1beta, LPS and PMA, stimulated MMP-2 in LC and inhibited MMP-2 in MM, but had no effect on MMP-9. Doxycycline, EGCG and NM inhibited MMP-2 and MMP-9 expression, in both cell lines. Actinomycin-D, cyclohexamide, retinoic acid and dexamethasone inhibited MMP-2 in both cancer cell lines and inhibited MMP-9 in MM. Our results show that cytokines and inhibitors have an up- or down-regulatory effect on MMP-2 and MMP-9 expression in LC and MM, suggesting the clinical value of targeting these proteases for management of LC and MM and their pathogenesis.
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PMID:Modulation of MMP-2 and MMP-9 by cytokines, mitogens and inhibitors in lung cancer and malignant mesothelioma cell lines. 1988 78

Lung cancer is one of the most common malignant diseases in the world, and its prognosis is generally poor. Cancer and metastasis involve numerous biological steps, including angiogenesis in both the primary and metastatic sites. Although various molecules that are involved in both tumor neovascularization (angiogenesis) and invasion have been identified, little is known about how these molecules interact in cancerous microenvironments. We previously reported that the gene expressions of some factors associated with vascularization correlated with the prognosis of non-small cell lung cancer (NSCLC). In this study, we performed multivariate analysis of the mRNA levels of 10 selected genes [VEGF-A, VEGF121, VEGF165, VEGF189, S100A4, E-cadherin, Thrombospondin (TSP)-1, TSP-2, matrix metalloproteinase (MMP)-2, and MMP-9] in 130 NSCLC specimens using the real-time quantitative reverse transcription-polymerase chain reaction. Spearman's rank correlation test was used to determine the co-expression patterns. The analysis demonstrated highly significant co-expressions (P<0.0001) among the VEGF isoforms (VEGF-A, VEGF121, VEGF165, and VEGF189). We also analyzed the correlations among the prognosis, gene expressions, clinical factors (age and gender), and pathological features (histological types, TNM status, stages, lymphatic involvement, and venous involvement) using the Cox proportional hazards model. Multivariate analyses showed that only VEGF189 expression was an independent prognostic indicator (P=0.0252). The alternative splicing variant VEGF189, the cell binding isoform, plays a leading role in the progression of NSCLC.
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PMID:Alternative splicing variant of vascular endothelial growth factor-A is a critical prognostic factor in non-small cell lung cancer. 1988 94

Lung cancer is the leading cause of death among cancers worldwide and non-small cell lung cancer (NSCLC) comprises more than 80% of lung cancer cases. Treatment options for patients with advanced NSCLC have evolved in the last decade with the advent of novel biological agents. Andrographolide, a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to have the potential to be developed as a chemotherapeutic agent. In order to understand the anti-cancer properties of andrographolide, we examined its effect on migration and invasion in human NSCLC A549 cells. The results of wound-healing assay and in vitro transwell assay revealed that andrographolide inhibited dose-dependently the migration and invasion of A549 cells under non-cytotoxic concentrations. Molecular data showed that the effect of andrographolide in A549 cells might be mediated via sustained inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt signal involved in the up-regulation of matrix metalloproteinases (MMPs). Our results showed that andrographolide exerted an inhibitory effect on the activity and the mRNA and protein levels of MMP-7, but not MMP-2 or MMP-9. The andrographolide-inhibited MMP-7 expression or activity appeared to occur via activator protein-1 (AP-1) because of its DNA binding activity was suppressed by andrographolide. Additionally, the transfection of Akt over-expression vector (Akt1 cDNA) to A549 cells could result in an increase expression of MMP-7 concomitantly with a marked induction on cell invasion. These findings suggested that the inhibition on MMP-7 expression by andrographolide may be through suppression on PI3K/Akt/AP-1 signaling pathway, which in turn led to the reduced invasiveness of the cancer cells.
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PMID:Inhibitory effects of andrographolide on migration and invasion in human non-small cell lung cancer A549 cells via down-regulation of PI3K/Akt signaling pathway. 2009 93

Rho and Rho-associated kinase play an important role in focal adhesion, stress fiber formation and cell motility. Fasudil is a kind of Rho kinase inhibitor. The effect and precise molecular mechanism of fasudil on the biology behavior of lung cancer cell A549 remains unclear. The cytotoxic effect of fasudil on A549 cell was measured by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Wound-healing assay was used to evaluate the effect of fasudil on migration activity of A549 cells. The invasion activity of A549 cells was detected by transwell chamber assay. The expression of MMPs was measured by gelatin zymography. RT-PCR and western blot were used to investigate the molecular change of A549 cells after treated with fasudil. Fasudil-inhibited proliferation of A549 cells in a concentration-dependent manner, decreased the migration and invasion activity. After treated with fasudil, the expression of MMP-2 and MMP-9 was significantly inhibited compared with the control group. Furthermore, the expression of RhoA and VEGF of A549 cell treated with fasudil was significantly down-regulated. Our findings indicate that fasudil might have a therapeutic potential for lung cancer though inhibiting cell proliferation, migration, invasion, MMPs activity and down-regulating the expression of RhoA and VEGF.
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PMID:Rho kinase inhibitor fasudil suppresses migration and invasion though down-regulating the expression of VEGF in lung cancer cell line A549. 2030 Sep 76

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