Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The interaction of connexin 43 and E-cadherin may play an important role in carcinogenesis and malignant behaviour of tumours. In this study, we examined the relationship between connexin 43 and E-cadherin in human non-small cell lung cancers (NSCLC). Expression levels of connexin 43 and E-cadherin were examined in 107 NSCLC specimens by immunohistochemistry. The connexin 43 gene was transfected into lung cancer LH7 cells. The protein localizations and levels of connexin 43 and E-cadherin were detected using immunofluorescence staining and western blot. Cell cycle and proliferation of lung cancer cells were examined using flow cytometry and MTT. We found that reduced expression of both connexin 43 and E-cadherin significantly correlated to poor differentiation, advanced TNM stage, and lymph note metastasis of NSCLCs. Connexin 43 and E-cadherin expression significantly correlated with each other. Over-expression of connexin 43 significantly induced E-cadherin expression. Moreover, connexin 43-transfected LH7 cells showed significantly decreased cell proliferation. The percentage of cells in G1 phase increased, while the number of cells in S and G2 phases significantly decreased. We concluded that concurrent reduction of connexin 43 and E-cadherin may contribute to the development of lung cancer. Connexin 43 may induce E-cadherin expression and inhibit cell proliferation and progression of lung cancer.
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PMID:Connexin 43 recruits E-cadherin expression and inhibits the malignant behaviour of lung cancer cells. 1905 35

Loss of heterozygosity (LOH) and homozygous deletions at chromosome 3p21.3 are common in both small and nonsmall cell lung cancers, indicating the likely presence of tumor suppressor genes (TSGs). Although genetic and epigenetic changes within this region have been identified, the functional significance of these changes has not been explored. Concurrent protein expression and genetic analyses of human lung tumors coupled with functional studies have not been done. Here, we show that expression of the 3p21.3 gene, LIMD1, is frequently down-regulated in human lung tumors. Loss of LIMD1 expression occurs through a combination of gene deletion, LOH, and epigenetic silencing of transcription without evidence for coding region mutations. Experimentally, LIMD1 is a bona fide TSG. Limd1(-/-) mice are predisposed to chemical-induced lung adenocarcinoma and genetic inactivation of Limd1 in mice heterozygous for oncogenic K-Ras(G12D) markedly increased tumor initiation, promotion, and mortality. Thus, we conclude that LIMD1 is a validated chromosome 3p21.3 tumor-suppressor gene involved in human lung cancer development. LIMD1 is a LIM domain containing adapter protein that localizes to E-cadherin cell-cell adhesive junctions, yet also translocates to the nucleus where it has been shown to function as an RB corepressor. As such, LIMD1 has the potential to communicate cell extrinsic or environmental cues with nuclear responses.
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PMID:The chromosome 3p21.3-encoded gene, LIMD1, is a critical tumor suppressor involved in human lung cancer development. 1906 Feb 5

Different isoforms of p120-catenin (p120ctn), a member of the Armadillo gene family, are variably expressed in different tissues as a result of alternative splicing and the use of multiple translation initiation codons. When expressed in cancer cells, these isoforms may confer different properties with respect to cell adhesion and invasion. We have previously reported that the p120ctn isoforms 1 and 3 were the most highly expressed isoforms in normal lung tissues, and their expression level was reduced in lung tumor cells. To precisely define their biological roles, we transfected p120ctn isoforms 1A and 3A into the lung cancer cell lines A549 and NCI-H460. Enhanced expression of p120ctn isoform 1A not only upregulated E-cadherin and beta-catenin, but also downregulated the Rac1 activity, and as a result, inhibited the ability of cells to invade. In contrast, overexpression of p120ctn isoform 3A led to the inactivation of Cdc42 and the activation of RhoA, and had a smaller influence on invasion. However, we found that isoform 3A had a greater ability than isoform 1A in both inhibiting the cell cycle and reducing tumor cell proliferation. The present study revealed that p120ctn isoforms 1A and 3A differently regulated the adhesive, proliferative, and invasive properties of lung cancer cells through distinct mechanisms.
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PMID:P120-catenin isoforms 1A and 3A differently affect invasion and proliferation of lung cancer cells. 1915 Jun 13

p120-catenin, a member of the Armadillo gene family, has emerged as both a master regulator of cadherin stability and an important modulator of small GTPase activities. Therefore, it plays novel roles in tumor malignant phenotype, such as invasion and metastasis. We have reported previously that abnormal expression of p120-catenin is associated with lymph node metastasis in lung squamous cell carcinomas (SCC) and adenocarcinomas. To investigate the role and possible mechanism of p120-catenin in lung cancer, we knocked down p120-catenin using small interfering RNA (siRNA). We found that ablation of p120-catenin reduced the levels of E-cadherin and beta-catenin proteins, as well as the mRNA of beta-catenin. Furthermore, p120-catenin depletion inactivated RhoA, but increased the activity of Cdc42 and Rac1, and promoted proliferation and the invasive ability of lung cancer cells both in vitro and in vivo. Our data reveal that p120-catenin gene knockdown enhances the metastasis of lung cancer cells, probably by either depressing cell-cell adhesion due to lower levels of E-cadherin and beta-catenin, or altering the activity of small GTPase, such as inactivation of RhoA and activation of Cdc42/Rac1.
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PMID:Ablation of p120-catenin enhances invasion and metastasis of human lung cancer cells. 1915 1

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

Epithelial-to-mesenchymal transition is a process in which cells undergo a developmental switch from an epithelial to a mesenchymal phenotype. We investigated the role of this phenomenon in the pathogenesis and progression of adenocarcinoma and squamous cell carcinoma of the lung. Archived tissue from primary tumors (n=325), brain metastases (n=48) and adjacent bronchial epithelial specimens (n=192) were analyzed for immunohistochemical expression by image analysis of E-cadherin, N-cadherin, integrin-alpha v beta 6, vimentin, and matrix metalloproteinase-9. The findings were compared with the patients' clinicopathologic features. High expression of the epithelial-to-mesenchymal transition phenotype (low E-cadherin and high N-cadherin, integrin-alpha v beta 6, vimentin, and matrix metalloproteinase-9) was found in most lung tumors examined, and the expression pattern varied according to the tumor histologic type. Low E-cadherin membrane and high N-cadherin cytoplasmic expression were significantly more common in squamous cell carcinoma than in adenocarcinoma (P=0.002 and 0.005, respectively). Dysplastic lesions had significantly lower expression of the epithelial-to-mesenchymal transition phenotype than the squamous cell carcinomas, and integrin-alpha v beta 6 membrane expression increased stepwise according to the histopathologic severity. Brain metastases had decreased epithelial-to-mesenchymal transition expression compared with primary tumors. Brain metastases had significantly lower integrin-alpha v beta 6 membrane (P=0.04), N-cadherin membrane, and cytoplasm (P<0.0002) expression than the primary tumors. The epithelial-to-mesenchymal transition phenotype is commonly expressed in primary squamous cell carcinoma and adenocarcinoma of the lung; this expression occurs early in the pathogenesis of squamous cell carcinoma. Brain metastases showed characteristics of reversed mesenchymal-to-epithelial transition. Our findings suggest that epithelial-to-mesenchymal transition is a potential target for lung cancer chemoprevention and therapy.
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PMID:Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. 1927 Jun 47

New benzofuranones were synthesized and evaluated toward NCI-H661 non-small cell lung cancer cells. Benzamide derivatives possessed micromolar antiproliferative and histone deacetylase inhibitory activities and modulate histone H4 acetylation. Hydroxamic acids were found to be potent nanomolar antiproliferative agents and HDAC inhibitors. Computational analysis presented a rationale for the activities of the hydroxamate derivatives. Impact of the HDAC inhibition on the expression of E-cadherin and the SEMA3F tumor suppressor genes revealed new promising compounds for lung cancer treatments.
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PMID:Synthesis and modeling of new benzofuranone histone deacetylase inhibitors that stimulate tumor suppressor gene expression. 1938

The tumour suppressor p53 is known to prevent cancer progression by inhibiting proliferation and inducing apoptosis of tumour cells. Slug, an invasion promoter, exerts its effects by repressing E-cadherin transcription. Here we show that wild-type p53 (wtp53) suppresses cancer invasion by inducing Slug degradation, whereas mutant p53 may stabilize Slug protein. In non-small-cell lung cancer (NSCLC), mutation of p53 correlates with low MDM2, high Slug and low E-cadherin expression. This expression profile is associated with poor overall survival and short metastasis-free survival in patients with NSCLC. wtp53 upregulates MDM2 and forms a wtp53-MDM2-Slug complex that facilitates MDM2-mediated Slug degradation. Downregulation of Slug by wtp53 or MDM2 enhances E-cadherin expression and represses cancer cell invasiveness. In contrast, mutant p53 inactivates Slug degradation and leads to Slug accumulation and increased cancer cell invasiveness. Our findings indicate that wtp53 and p53 mutants may differentially control cancer invasion and metastasis through the p53-MDM2-Slug pathway.
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PMID:p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. 1944 27

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


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