Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epithelial to mesenchymal transition (EMT) has been reported to be related with reduced sensitivity to EGFR tyrosine kinase (EGFR-TK) inhibitors. We performed this study to investigate whether this phenomenon would play a role in acquired resistance to gefitinib. In this study, we established a gefitinib-resistant subline (A549/GR), which was derived from the parental A549 cell line by chronic, repeated exposure to gefitinib. Compared with the A549 cells, the A549/GR cells were approximately 7.7-fold more resistant to gefitinib and they showed the cross-resistance against other EGFR-TK inhibitors, including CL-387,758, erlotinib and ZD6478. Phenotypic changes such as a spindle-cell shape and increased pseudopodia formation suggesting EMT was present in the A549/GR cells. These changes were accompanied by a decrease of E-cadherin and an increase of vimentin, which is a mesenchymal marker. In addition, the ability of invasion and migration was increased in the A549/GR cells. TGF-beta1 treatment for 72 h also induced EMT in the A549 cells and this transition led to resistance to gefitinib. Conversely, this was reversed through the removal of TGF-beta1. In conclusion, induction of EMT may contribute to the decreased efficacy of therapy in primary and acquired resistance to gefitinib.
Lung Cancer 2009 Feb
PMID:Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line. 1859 54

Epilysin (MMP-28) is the newest member of the matrix metalloproteinase (MMP) family of extracellular proteases. Together the MMPs can degrade almost all components of the extracellular matrix (ECM). MMPs also regulate cell behaviour by releasing growth factors and biologically active peptides from the ECM by modulating cell surface receptors and adhesion molecules and by regulating the activity of mediators of the inflammatory pathways. Epilysin differs from most other MMPs as it is expressed in a number of normal tissues, suggestive of functions in tissue homeostasis. The epilysin homologue in Xenopus laevis (XMMP-28) is expressed in neural tissues, where it cleaves the neural cell adhesion molecule. Enhanced expression of epilysin has been observed in basal keratinocytes during wound healing and in different forms of cancer. There are, however, also reports on the downregulation of epilysin in malignant cells. The roles of epilysin in cancer seem to vary based on tumor type and stage of the disease. Importantly, epilysin can induce stable epithelial to mesenchymal transition (EMT) when overexpressed in epithelial lung carcinoma cells. Transforming growth factor beta (TGF-beta) is a crucial mediator of this process, which was characterized by the loss of E-cadherin and increased cell migration and invasion. Current results suggest a plausible interaction between epilysin and TGF-beta also under physiological circumstances, where epilysin activity may not induce EMT but, instead, trigger less permanent changes in TGF-beta signalling and cell motility.
 ...
PMID:Epilysin (MMP-28)--structure, expression and potential functions. 1880 61

Bronchioloalveolar carcinoma (BAC) is a subset of lung adenocarcinoma that has a distinct clinical presentation, tumor biology, response to therapy, and prognosis compared with other subtypes of non-small-cell lung carcinoma. BAC disproportionately affects women, never-smokers, and is characterized by growth along alveolar septae without evidence of stromal, vascular, or pleural invasion. Microscopically, BACs have been divided into mucinous, nonmucinous, and mixed types. We describe a case of young female who received radiation therapy to the mediastinum and chemotherapy for Hodgkin lymphoma and now develops mucinous bronchioalveolar adenocarcinoma of the left lung which to the best of our knowledge has not been previously described after radiotherapy and chemotherapy for Hodgkin lymphoma. The tumor cells express Galectin-3, CD138, p16INK4a, thyroid transcription factor-1, cytokeratin 7, epithelial membrane antigen, carcinoembryonic antigen, E-cadherin, neuron-specific enolase, and S100 whereas no expression of cytokeratin 20, calretinin, and CDX2 is seen.
 ...
PMID:Expression of Galectin-3, CD138, p16INK4a, and TTF-1 in mucinous bronchioloalveolar adenocarcinoma after Hodgkin lymphoma. 1899 17

Studies on a variety of cell lines have shown that p120-catenin can directly regulate the stability of E-cadherin complexes and control the activity of small GTPases to influence cell adhesion. Despite this data, clinical studies of human solid tumors have not been reported to investigate these protein interactions. To explore the correlation between p120-catenin, E-cadherin, and small GTPases in human lung cancer, we examined the expression patterns of p120-catenin, E-cadherin, RhoA, Cdc42, and Rac1, and their prognostic significance in 138 patients with non-small cell lung cancer (NSCLC). While normal bronchial epithelium showed strong membrane expression of p120-catenin and E-cadherin, lung cancer tissues had reduced membrane expression and ectopic cytoplasmic expression of p120-catenin and E-cadherin. Expression of RhoA, Cdc42, and Rac1 was also found to be higher in tumor tissue than in normal lung tissue. A correlation between abnormal p120-catenin, E-cadherin expression, and overexpression of specific small GTPases was also associated with poor differentiation, high TNM stage, and lymph node metastasis in NSCLC patients. We also used an in vitro model to evaluate their expression, and to determine whether protein expression correlated with the invasive capacity of lung cancer cell lines. Consistent with our in vivo data, abnormal expression of p120-catenin and E-cadherin with overexpression of specific small GTPases were significantly associated with the high metastatic capacity of BE1 cells. Based on our results, we conclude that abnormal p120-catenin expression correlates with abnormal E-cadherin expression and specific small GTPase overexpression, which contribute to the malignancy-related to NSCLC.
Lung Cancer 2009 Mar
PMID:Abnormal expression of p120-catenin, E-cadherin, and small GTPases is significantly associated with malignant phenotype of human lung cancer. 1916 67

Hepatocyte growth factor activator inhibitor-1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-associated proteinase inhibitor that potently inhibits a variety of serine proteinases, including those that are membrane bound. Although HAI-1/SPINT1 is widely expressed by epithelial cells and cancer cells, its functional role is still unclear, particularly in cancer. Here, we show that stable knockdown of HAI-1/SPINT1 in the human pancreatic cancer cell line SUIT-2 induces an elongated spindle-like morphology associated with accelerated invasion, thereby mimicking an epithelial to mesenchymal transition (EMT). We found that HAI-1/SPINT1 knockdown significantly reduced the expression of E-cadherin and was accompanied by up-regulation of Smad-interacting protein 1 (SIP1), an E-cadherin transcriptional repressor. In addition, matrix metalloproteinase-9 (MMP-9) was up-regulated. Similar results were obtained in the HLC-1 lung carcinoma cell line. Moreover, a metastatic variant of SUIT-2 (S2-CP8) that showed loss of E-cadherin expression also showed a significantly reduced level of HAI-1/SPINT1. Engineered overexpression of HAI-1/SPINT1 in S2-CP8 resulted in reversion of E-cadherin expression and SIP1 down-regulation, which accompanied reestablishment of epithelial morphology in culture. The EMT caused by HAI-1/SPINT1 knockdown seemed to be mediated, at least partly, by membrane-bound serine proteinases, matriptase/ST14 and TMPRSS4, as knockdown of matriptase/ST14 or TMPRSS4 in HAI-1/SPINT1 knockdown SUIT-2 cells and HLC-1 cells resulted in reversion of SIP1 and/or MMP-9 expression levels. We suggest that interactions between HAI-1/SPINT1 and membrane-bound serine proteinases contribute to transcriptional and functional changes involved in EMT in certain carcinoma cells.
 ...
PMID:Hepatocyte growth factor activator inhibitor type 1 regulates epithelial to mesenchymal transition through membrane-bound serine proteinases. 1922 33

Lung adenocarcinoma with a micropapillary component (MPC) is an aggressive subtype of adenocarcinoma with a papillary component. The aim of this study was to explore the pathobiological properties of a papillary component which generates MPC. We reviewed the 445 cases of resected primary lung adenocarcinoma and confirmed all of the MPC(+) cases (n=150) were found only in the cases of adenocarcinoma with a papillary component (n=228) and no features of the MPC were detected in any of the other histological subtypes without papillary component. Even in the cases of adenocarcinoma with a papillary component, the MPC(+) group (n=150) had significantly poorer outcome than the MPC(-) group (n=78) (P<0.0001). When this MPC(+) cases were divided into grade 0-2 according to the proportion of the tumor occupied by the MPC, the stage I patients with grade 2 MPC had a significantly poorer outcome than the stage I patients with grade 0 or grade 1 MPC. By considering the histological characteristics that MPC has always structural continuity with papillary component, we evaluated the pathobiological profile of (1) MPC, (2) papillary component which generate MPC [PC MPC(+)], and (3) papillary component without MPC [PC MPC(-)]. The mean width of the stalks in the PC MPC(+) was significantly smaller than in the PC MPC(-) (17.64+/-9.53 vs. 26.07+/-10.16mum, P<0.001). Although staining for CD34 and collagen IV showed that MPC lacked both fibrovascular stalks and basement membranes, staining for cleaved caspase 3 showed that apoptotic cells were rare in the MPC (1.0%), and the expression levels of the adhesion molecules E-cadherin, beta-catenin, and CD44 were similar in all three lesions. The immunohistochemical staining scores of hypoxic marker GLUT-1 in the MPC, PC MPC(+), and PC MPC(-) were 69, 26, and 8.6, respectively, and the differences between the MPC and PC MPC(+) and between the PC MPC(+) and PC MPC(-) were significant (P=0.001 and 0.025, respectively). These results indicated that the biological behavior of the papillary component which generates MPC is different from the papillary component without MPC in terms of structural alternation and hypoxic state, and the difference may be related to the aggressive behavior of MPC(+) adenocarcinoma.
Lung Cancer 2010 Mar
PMID:Structural and biological properties of a papillary component generating a micropapillary component in lung adenocarcinoma. 1948 33

The effects of dithiolethione modified valproate, diclofenac and sulindac on non-small cell lung cancer (NSCLC) cells were investigated. Sulfur(S)-valproate and S-diclofenac at 1 microg/ml concentrations significantly reduced prostaglandin (PG)E(2) levels in NSCLC cell lines A549 and NCI-H1299 as did the COX-2 inhibitor DuP-697. In vitro, S-valproate, S-diclofenac and S-sulindac half-maximally inhibited the clonal growth of NCI-H1299 cells at 6, 6 and 15 microg/ml, respectively. Using the MTT assay, 10 microg/ml S-valproate, NO-aspirin and Cay10404, a selective COX-2 inhibitor, but not SC-560, a selective COX-1 inhibitor, inhibited the growth of A549 cells. In vivo, 18mg/kg i.p. of S-valproate and S-diclofenac, but not S-sulindac, significantly inhibited A549 or NCI-H1299 xenograft proliferation in nude mice, but had no effect on the nude mouse body weight. The mechanism by which S-valproate and S-diclofenac inhibited the growth of NSCLC cells was investigated. Nitric oxide-aspirin but not S-valproate caused apoptosis of NSCLC cells. By Western blot, S-valproate and S-diclofenac increased E-cadherin but reduced vimentin and ZEB1 (a transcriptional suppressor of E-cadherin) protein expression in NSCLC cells. Because S-valproate and S-diclofenac inhibit the growth of NSCLC cells and reduce PGE(2) levels, they may prove beneficial in the chemoprevention and/or therapy of NSCLC.
Lung Cancer 2010 May
PMID:Dithiolethione modified valproate and diclofenac increase E-cadherin expression and decrease proliferation of non-small cell lung cancer cells. 1962 93

We investigated the regulatory effect of insulin receptor substrate-1 (IRS-1) on transforming growth factor-beta1 (TGF-beta1)-induced epithelial-mesenchymal transition (EMT). TGF-beta1-induced EMT and cell migration in A549 cells are associated with a decrease in IRS-1 tyrosine phosphorylation and protein levels. Tissue microarray analysis of human lung carcinoma shows a correlation between IRS-1 protein levels and E-cadherin protein levels. High IRS-1 levels coexist with high E-cadherin levels, whereas low IRS-1 levels coexist with low E-cadherin levels, implying a possibility that IRS-1 protein levels may be linked with EMT. Surprisingly, overexpression of IRS-1 in A549 cells completely blocked TGF-beta1-induced EMT and cell migration, inhibited TGF-beta1-mediated expression of snail and slug genes, and abolished TGF-beta1-mediated repression of E-cadherin promoter activity. In contrast, IRS-1 knockdown by RNAi increased the expression of snail and slug genes and induced EMT. Inhibition of protein tyrosine phosphatase with sodium vanadate, which greatly increased the levels of tyrosine-phosphorylated IRS-1, suppressed TGF-beta1-induced actin remodeling and cell morphologic changes. These results show for the first time that TGF-beta1 induces EMT through mechanisms involving the modulation of IRS-1 signaling, and that IRS-1 functions as a critical EMT suppressor that suppresses TGF-beta1-induced EMT via inhibition of snail and slug expression.
 ...
PMID:Insulin receptor substrate-1 suppresses transforming growth factor-beta1-mediated epithelial-mesenchymal transition. 1973 73

Epithelial-mesenchymal transition (EMT) is a critical phenotypic alteration of cancer cells that triggers invasion and metastasis. Lung cancer cells often show mesenchymal phenotypes; however, a causative genetic alteration for the induction of EMT in lung cancer cells remains unknown. Recent studies have shown that the LKB1 gene is mutated in up to one-third of lung adenocarcinomas. Therefore, to pursue the possible involvement of LKB1 inactivation in the induction of EMT in lung carcinogenesis, we generated immortalized lung epithelial cells and lung adenocarcinoma cells with stable or transient LKB1 knockdown. LKB1 knockdown increased cell motility and invasiveness, and induced the expression of several mesenchymal marker proteins accompanied by the expression of ZEB1, a transcriptional repressor for E-cadherin and an EMT inducer. In agreement with the recent findings, expression of miR-200a/c was inversely correlated with that of ZEB1 in LKB1 knockdown clones with mesenchymal phenotype. Furthermore, transient knockdown of LKB1 induced ZEB1 mRNA and increased cell motility, and this motility was suppressed by ZEB1 repression. These results strongly indicate that LKB1 inactivation triggers EMT in lung cancer cells through the induction of ZEB1.
Lung Cancer 2010 Nov
PMID:Involvement of LKB1 in epithelial-mesenchymal transition (EMT) of human lung cancer cells. 2020 41

Dysadherin, a cancer associated cell membrane glycoprotein, has been reported to downregulate E-cadherin. Aberrant expression of E-cadherin has been associated with the development of metastases in patients with cancer. Even though the expression of dysadherin and E-cadherin has been studied in primary non-small cell lung carcinoma, little is known about its expression at the distant metastases sites. We investigate by immunohistochemistry the relationship between E-cadherin and dysadherin in 111 cases of primary lung carcinomas (53 squamous cell carcinomas, 21 adenocarcinomas, 13 large cell carcinomas, and 24 small cell carcinomas), and their distant metastases. The intensity, the expression pattern and the percentage of neoplastic cell staining were recorded and the results were correlated with clinicopathological findings of the subjects. Dysadherin immunostain was expressed in 61 (54.95%) of the cases, and increased dysadherin expression was significantly correlated with tumour size (p=0.003), distant metastases (p=0.0034), and metastasis size (p=0.0008). Reduced E-cadherin expression was noted in 46 (41.45%) of the cases, and was correlated with high-grade tumour (p=0.02), infiltrative growth pattern (p=0.042), and advanced stage (p=0.032). Although the correlation between the expression of dysadherin and E-cadherin was not significant, a group of patients showed reduced E-cadherin expression with dysadherin overexpression. In lung carcinomas dysadherin expression seems to reflect tumour aggressiveness and may be considered a positive marker of poor prognosis when considered alone or/and in combination with down-regulation of E-cadherin.
 ...
PMID:Comparison of the dysadherin and E-cadherin expression in primary lung cancer and metastatic sites. 2071 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>