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

Gastric adenocarcinoma not located in the cardia still remains second only to lung cancer as the leading cause of cancer-related mortality worldwide, whereas adenocarcinoma of the cardia and gastroesophageal junction has been rapidly rising over the past two decades. Gastric malignancy can be subdivided into diffuse and intestinal pathologic entities that have different epidemiological and prognostic features. Various genetic and environmental factors lead to either abnormal gene overexpression or inappropriate expression of normal genes, whose products confer the malignant phenotype. Advances have been made in genetic changes mostly of the intestinal type; its development is probably a multistep process, as has been well described in colon carcinogenesis. Oncogene overexpression, tumor suppressor loss, and defective DNA mismatch repair is associated with gastric cancer. The most common genetic abnormalities tend to be loss of heterozygosity of particularly tumor suppressor p53 gene or "adenomatous polyposis coli" gene. The latter leads to gastric carcinogenesis through changes related to E-cadherin-catenin complex, which plays a critical role in normal tissue architecture maintenance. Mutation of any of its components results in loss of cell-cell adhesion, thereby contributing to malignancy. Putative trophic factors have also been involved in gastric oncogenesis. E-cadherin/CDH1 gene germline mutations have been recognized in families with an inherited predisposition to diffuse-type malignancy. This review focuses mainly on Helicobacter pylori infection involved in gastric carcinogenesis through various mechanisms, including repopulation of the stomach with bone marrow-derived stem cells that may facilitate gastric cancer progression, thereby necessitating eradication of this bacterium.
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PMID:New aspects of Helicobacter pylori infection involvement in gastric oncogenesis. 1772 Jan 95

MicroRNAs are approximately 22-nucleotide sequences thought to interact with multiple mRNAs resulting in either translational repression or degradation. We previously reported that several microRNAs had variable expression in mammalian cell lines, and we examined one, miR-200c, in more detail. A combination of bioinformatics and quantitative reverse transcription-PCR was used to identify potential targets and revealed that the zinc finger transcription factor transcription factor 8 (TCF8; also termed ZEB1, deltaEF1, Nil-2-alpha) had inversely proportional expression levels to miR-200c. Knockout experiments using anti-microRNA oligonucleotides increased TCF8 levels but with nonspecific effects. Therefore, to investigate target predictions, we overexpressed miR-200c in select cells lines. Ordinarily, the expression level of miR-200c in non-small-cell lung cancer A549 cells is low in contrast to normal human bronchial epithelial cells. Stable overexpression of miR-200c in A549 cells results in a loss of TCF8, an increase in expression of its regulatory target, E-cadherin, and altered cell morphology. In MCF7 (estrogen receptor-positive breast cancer) cells, there is endogenous expression of miR-200c and E-cadherin but TCF8 is absent. Conversely, MDA-MB-231 (estrogen receptor-negative) cells lack detectable miR-200c and E-cadherin (the latter reportedly due to promoter region methylation) but express TCF8. The ectopic expression of miR-200c in this cell line also reduced levels of TCF8, restored E-cadherin expression, and altered cell morphology. Because the down-regulation of E-cadherin is a crucial event in epithelial-to-mesenchymal transition, loss of miR-200c expression could play a significant role in the initiation of an invasive phenotype, and, equally, miR-200c overexpression holds potential for its reversal.
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PMID:Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. 1780 4

TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon and gastric cancer tissues. However, the biological functions of TMPRSS4 in cancer are unknown. Here we show, using reverse transcription-PCR, that TMPRSS4 is highly elevated in lung cancer tissues compared with normal tissues and is also broadly expressed in a variety of human cancer cell lines. Knockdown of TMPRSS4 by small interfering RNA treatment in lung and colon cancer cell lines was associated with reduction of cell invasion and cell-matrix adhesion as well as modulation of cell proliferation. Conversely, the invasiveness, motility and adhesiveness of SW480 colon carcinoma cells were significantly enhanced by TMPRSS4 overexpression. Furthermore, overexpression of TMPRSS4 induced loss of E-cadherin-mediated cell-cell adhesion, concomitant with the induction of SIP1/ZEB2, an E-cadherin transcriptional repressor, and led to epithelial-mesenchymal transition events, including morphological changes, actin reorganization and upregulation of mesenchymal markers. TMPRSS4-overexpressing cells also displayed markedly increased metastasis to the liver in nude mice upon intrasplenic injection. Taken together, these studies suggest that TMPRSS4 controls the invasive and metastatic potential of human cancer cells by facilitating an epithelial-mesenchymal transition; TMPRSS4 may be a potential therapeutic target for cancer treatment.
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PMID:TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition. 1796 9

The proneural basic-helix-loop-helix protein achaete-scute homologue 1 (ASH1) is expressed in a very limited spectrum of normal and cancerous cells in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features, which prompted us to investigate the molecular function of ASH1 in relation to its involvement in carcinogenic processes. Herein, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/beta-catenin signaling, E-cadherin, and integrin beta1 through ASH1-mediated deacetylation and repressive trimethylation of lysine 27 (H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. In addition, ASH1-transduced A549 adenocarcinoma cells exhibited markedly altered morphology characteristics compared with lung cancer cells with neuroendocrine features both in vitro and in vivo and also grew faster in vivo. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions.
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PMID:Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer. 1833 43

Lung cancer is the leading cause of cancer death in both men and women. Tumor metastasis is an essential aspect of lung cancer progression. nm23-H1 is a metastasis suppressor gene. The molecular mechanism by which nm23-H1 suppresses the metastasis is still unclear. Here, we compared the gene expression profile of human large cell lung cancer cell line NL9980 by nm23-H1 gene silencing with that of negative control cells to comprehensively investigate nm23-H1-mediated changes in gene expression of NL9980 cells. Microarray assay revealed that expression of 733-known genes (1.9%, 733/38,500) were altered in response to nm23-H1 gene silencing, including 466 upregulated genes and 267 downregulated. real-time PCR assay of the expression changes indicated that 81.82% (45/55) of verified genes were consistent with that observed in microarray assay. The upregulated genes included MMP-1, -2, SNAI2, CXCL1, 2, 3, PAI-2, while the downregulated genes included cystatin B, TIMP-2, E-cadherin, centrin-2, all of which have been associated with tumor metastasis. Furthermore, we confirmed by Western blot that the expression of MMP-1 and -2 were significantly increased while that of cystatin B was dramatically decreased in NL9980-nm23-H1 silencing cells. The NL9980-nm23-H1 silencing cells exhibited significantly more S phase growth and invasive ability. Thus, silencing of nm23-H1 gene caused metastasis-related gene expression changes in lung cancer cells. The knockdown of nm23-H1 expression may change the lung cancer cells to a more invasive phenotype through alteration in the expression of a set of genes.
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PMID:Alteration in gene expression profile and biological behavior in human lung cancer cell line NL9980 by nm23-H1 gene silencing. 1844 Mar 2

Hypermethylation of CpG islands is well known as a major inactivation mechanism of tumor suppressor genes. E-cadherin (E-cad) as a tumor invasion suppressor has been reported in several invasive and metastatic carcinomas. However, its significance in carcinogenesis of primary non-small cell lung cancer (NSCLC) is not well documented. This study was designed to assess the significance with 95 pairs of carefully collected NSCLC tumors and corresponding nonmalignant tissue samples. We carried out PCR-SSCP (single-strand conformation polymorphism) and PCR-RFLP (restriction fragment length polymorphism) screening for DNA variants, bisulfite conversion-specific MSP for methylation analysis, reverse transcription (RT)-PCR for mRNA and immunohistochemistry (IHC) for protein expression assays. To investigate effect of promoter-hypermethylation on E-cad expression, we also did demethylation experiment in six cell lines. First, we found that the -160A carriers (a single nucleotide polymorphism (SNP) in the promoter region of E-cad) had an increased risk for lung cancer development when compared to DNA from healthy volunteers (OR (odds ratio)=2.81; 95% CI (confidence interval), 1.36-5.86). Methylation of E-cad occurred with a significantly higher frequency in tumors than corresponding normal peritumoral tissues (P<10(-5)). Reduced expression of E-cad was detected as a distinct molecular feature of tumors in comparison to corresponding counterparts. Moreover, the methylation alteration was detected more frequently in low-differentiated tumors than in well-differentiated ones. Defective expression of E-cad in methylated cell lines was markedly recovered after treated with 5-Aza-dC (5-aza-2'-deoxycytidine). Thus, promoter-hypermethylation of E-cad is significantly associated with its defective expression and tumor differentiation, and the demethylating observation proposes a therapeutic strategy to reverse the tumor's malignancy by restoring normal expression of E-cad.
Lung Cancer 2008 Nov
PMID:Promoter-hypermethylation associated defective expression of E-cadherin in primary non-small cell lung cancer. 1846 19

E-cadherin expressed highly in 95C and lowly in 95D lung cancer cells which were from the same patient, but core-fucosylated E-cadherin highly expressed in 95D cells. Therefore, Fut8 and Fut8-RNAi constructs were transfected into 95C and 95D cells, respectively. In Fut8-transfectants, reduction of nuclear beta-catenin was noted when E-cadherin was core-fucosylated, while accumulation of nuclear beta-catenin was observed in Fut8-RNAi transfectants. In E-cadherin-negative MDA-MB-231 cells either Fut8 or Fut8-RNAi transfection couldn't affect nuclear beta-catenin. However, cotransfection of E-cadherin with Fut8 caused nuclear beta-catenin reduction. Furthermore, enhanced binding of E-cadheirn with beta-catenin as well as alpha-catenin were observed in Fut8-transfectants, and reduction of tyrosine 654 phosphorylation on beta-catenin and its transcriptional activity were also noted at the same time. Overall, the current results suggested that core-fucosylated E-cadherin regulated nuclear beta-catenin accumulation in lung cancer cells.
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PMID:E-cadherin core fucosylation regulates nuclear beta-catenin accumulation in lung cancer cells. 1855 67

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

Curcumin (diferuloylmethane) is an active component of the spice turmeric and has a diversity of antitumor activities. In this study, we found that curcumin can inhibit cancer cell invasion and metastasis through activation of the tumor suppressor DnaJ-like heat shock protein 40 (HLJ1). Human lung adenocarcinoma cells (CL1-5) treated with curcumin (1-20 mumol/L) showed a concentration-dependent reduction in cell migration, invasion, and metastatic ability, and this was associated with increased HLJ1 expression. Knockdown of HLJ1 expression by siRNA was able to reverse the curcumin-induced anti-invasive and antimetastasis effects in vitro and in vivo. The HLJ1 promoter and enhancer in a luciferase reporter assay revealed that curcumin transcriptionally up-regulates HLJ1 expression through an activator protein (AP-1) site within the HLJ1 enhancer. JunD, one of the AP-1 components, was significantly up-regulated by curcumin (1-20 mumol/L) in a concentration- and time-dependent manner. Knockdown of JunD expression could partially reduce the curcumin-induced HLJ1 activation and diminish the anti-invasive effect of curcumin, indicating that JunD would seem to be involved in curcumin-induced HLJ1 expression. Curcumin was able to induce c-Jun NH(2)-kinase (JNK) phosphorylation, whereas the JNK inhibitor (SP-600125) could attenuate curcumin-induced JunD and HLJ1 expression. Activation of HLJ1 by curcumin further leads to up-regulation of E-cadherin and a suppression of cancer cell invasion. Our results show that curcumin induces HLJ1, through activation of the JNK/JunD pathway, and inhibits lung cancer cell invasion and metastasis by modulating E-cadherin expression. This is a novel mechanism and supports the application of curcumin in anti-cancer metastasis therapy.
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PMID:Curcumin inhibits lung cancer cell invasion and metastasis through the tumor suppressor HLJ1. 1879 31

Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer (NSCLC). Nicotine, an active component of cigarettes, has been found to induce proliferation of lung cancer cell lines. In addition, nicotine can induce angiogenesis and confer resistance to apoptosis. All these events are mediated through the nicotinic acetylcholine receptors (nAChRs) on lung cancer cells. In this study, we demonstrate that nicotine can promote anchorage-independent growth in NSCLCs. In addition, nicotine also induces morphological changes characteristic of a migratory, invasive phenotype in NSCLCs on collagen gel. These morphological changes were similar to those induced by the promigratory growth factor VEGF. The proinvasive effects of nicotine were mediated by alpha7-nAChRs on NSCLCs. RT-PCR analysis showed that the alpha7-nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines. Nicotine was found to promote proliferation and invasion in human breast cancer. The proinvasive effects of nicotine were mediated via a nAChR, Src and calcium-dependent signaling pathway in breast cancer cells. In a similar fashion, nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells. Most importantly, nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition (EMT), characterized by reduction of epithelial markers like E-cadherin expression, ZO-1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells. Therefore, it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers.
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PMID:Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines. 1884 24


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