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

Human MnSOD localizes to the mitochondria and plays a key protective role by detoxifying oxygen free radicals. The MnSOD mRNA 3' UTR contains a 280-bp region (Alu-like element or Alu-E) that shows high homology to human Alu and 7SL sequences. MnSOD 3' UTR probes hybridize to a specific cytoplasmic RNA species of approximately 300 nucleotides. This antisense RNA is most likely 7SL RNA based on its size, ubiquitousness, high levels, and lack of inducibility. Hybridization of this small RNA to the MnSOD 3' UTR may modulate posttranscriptional MnSOD gene expression. This regulation could occur by several means including inhibition of translation and mRNA destabilization. Regulation at the level of translational initiation does not seem to occur as MnSOD mRNA containing the Alu-E is efficiently bound by ribosomes. To test the role of the MnSOD 3' UTR, and in particular the Alu-E in gene expression, luciferase reporter gene constructs were made containing various regions of the MnSOD 3' UTR including the Alu-E. These constructs were transfected into human A549 lung carcinoma cells and luciferase activity was measured. Reporter constructs containing the MnSOD 3' UTR and the Alu-E repress luciferase activity. Taken together, these results suggest that naturally occurring antisense RNA may bind MnSOD mRNA and repress its expression. These results also suggest that other mRNAs containing Alu elements may be similarly repressed.
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PMID:The 3' UTR of human MnSOD mRNA hybridizes to a small cytoplasmic RNA and inhibits gene expression. 1092 31

Inhibitory regulators of apoptosis play a critical role in the responsiveness of tumour cells to cytotoxic agents. The X-linked inhibitor of apoptosis protein (XIAP) is a member of a novel family of Inhibitor of Apoptosis (IAP) proteins. Here we show that acute low dose ionizing irradiation results in the translational upregulation of XIAP that correlates with an increased resistance to radiation in non-small cell lung carcinoma. This upregulation is mediated by an internal ribosome binding mechanism via an IRES element located within a XIAP 5' UTR. Transient overexpression of XIAP rendered human carcinoma cells resistant to low dose gamma-irradiation. By contrast, the antisense targeting of XIAP resulted in increased cell death following irradiation advocating a distinct role for XIAP in radiation resistant phenotype of human cancers. Oncogene (2000) 19, 4174 - 4177
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PMID:Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death. 1096 79

DAP-kinase is a pro-apoptotic Ca(2+) calmodulin-regulated serine/threonine kinase that participates in a wide array of apoptotic systems initiated by interferon-gamma, TNF-alpha, activated Fas, and detachment from extracellular matrix. It was isolated by an unbiased functional approach to gene cloning aimed at hitting central mediators of the apoptotic process. This 160 Kd protein kinase is localized to actin microfilaments and carries interesting modules such as ankyrin repeats and the death domain. The death promoting effects of DAP-kinase depend on its intact catalytic activity, the correct intracellular localization, and on the presence of the death domain. A few mechanisms restrain the killing effects of the protein in healthy cells. The enzyme's active site is negatively controlled by an adjacent CaM regulatory domain whose effect is relieved by binding to Ca(2+)-activated calmodulin. A second mode of autoinhibition engages the serine-rich C-terminal tail, spanning the last 17 amino acids of the protein. A link between DAP-kinase and cancer has been established. It was found that the mRNA and protein expression is frequently lost in various human cancer cell lines. Analysis of the methylation status of DAP-kinase's 5' UTR in DNA extracted from fresh tumor samples, showed high incidence of hypermethylation in several human carcinomas and B cell malignancies. The anti-tumorigenic effect of DAP-kinase was also studied experimentally in mouse model systems where the re-introduction of DAP-kinase into highly metastatic mouse lung carcinoma cells who had lost the protein, strongly reduced their metastatic capacity. Thus, it appears that loss of DAP-kinase confers a selective advantage to cancer cells and may play a causative role in tumor progression. A few novel kinases sharing high homology in their catalytic domains with DAP-kinase have been recently identified constituting altogether a novel family of death promoting serine/threonine kinases.
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PMID:DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer. 1131 98

Cyclooxygenases (COXs) are key enzymes that convert arachidonic acid to prostaglandins. Overexpression of COX-2, one of the COX isozymes, has been shown to be an early event in lung carcinogenesis and may play an important role in lung cancer development. A common single nucleotide polymorphism, T8473C, located within a potential functional region in the 3'UTR of COX-2 gene was identified and we hypothesized that this COX-2 variant is associated with lung cancer risk. To test this hypothesis, we genotyped this variant in a case-control study of 322 histologically-confirmed lung cancer patients and 323 age and sex frequency-matched cancer-free controls in a Chinese population. The results showed that the frequencies of variant genotypes 8473CT/CC were significantly less common in the cases (27.3%) than in the controls (35.3%) (P=0.034), suggesting that the 8473C allele was protective against lung cancer. Multivariate logistic regression analyses revealed that the COX-2 variant genotypes (8473CT/CC) were associated with a significantly decreased risk of lung cancer compared with the 8473TT wild-type homozygotes (OR=0.64, 95% CI=0.45-0.92). When we defined the reference group as non-smokers having the 8473CT/CC variant genotypes, the smokers with the 8473TT wild-type genotype had the greatest risk (adjusted OR=5.28, 95% CI=3.10-9.00). These findings indicate that the COX-2 T8473C polymorphism may contribute to lung cancer susceptibility in the Chinese population. Further larger molecular epidemiological studies are warranted to confirm these findings.
Lung Cancer 2005 Apr
PMID:A common polymorphism in the 3'UTR of cyclooxygenase 2/prostaglandin synthase 2 gene and risk of lung cancer in a Chinese population. 1577 67

Fifty single-nucleotide polymorphisms (SNPs) associated with amino acid changes in 36 genes involved in diverse DNA repair pathways were assessed for associations with risk for small cell lung carcinoma (SCLC) by a case-control study consisting of 211 SCLC cases and 685 controls. An SNP, Val83Met, in the MTH1 (microtT homolog 1) gene encoding a triphosphatase that hydrolyzes pro-mutagenic oxidized nucleoside triphosphates, such as 8-hydroxy-dGTP and 2-hydroxy-dATP, showed the strongest and a significant association with SCLC risk [odds ratio (OR)=1.6, 95% confidence interval (CI): 1.2-2.2, P=0.004], while three other SNPs in the TP53, BLM and SNM1 genes, respectively, also showed marginal associations (0.05<P<0.1). Another SNP, which causes a nucleotide change in the 5'-UTR of MTH1 transcripts leading to alternative translation initiation, was additionally examined and the SNP also showed a significant association (OR=1.7, 95% CI: 1.2-2.3, P=0.002). The two SNPs in the MTH1 gene were in linkage disequilibrium, and the OR for carrying a copy of the haplotype consisting of both the risky SNP alleles was 2.0 (95% CI: 1.2-3.2, P=0.002). The present results indicate that inter-individual differences in MTH1 activities due to SNPs are involved in susceptibility to SCLC.
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PMID:Association of polymorphisms in the MTH1 gene with small cell lung carcinoma risk. 1677 34

ABT-737 is a subnanomolar inhibitor of the antiapoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w. Although ABT-737 triggers extensive cell death in many small-cell lung carcinoma (SCLC) cell lines, some of the SCLC cell lines and the majority of the cancer cell lines derived from other solid tumors were found to be resistant to ABT-737. To better understand the mechanism of resistance to ABT-737, we screened a short interfering RNA library consisting of short interfering RNA against 4000 'druggable' targets in an SCLC-derived cell line, NCI-H196. By comparing the knockdowns with phenotypes, all of the three top 'hits' from the screen were found to result from off-target gene silencing. Interestingly, the three off-target siRNAs were found to knock down an antiapoptotic Bcl-2 family protein Mcl-1 owing to the complementation between their seed regions with the 3' untranslated region (3' UTR) of Mcl-1. Furthermore, reducing the level of Mcl-1 using siRNAs or the small-molecule compounds Bay43-9006 and Seliciclib was sufficient to overcome the resistance to ABT-737 in the resistant SCLC cell line and cancer cell lines derived from other solid tumors. These results provide further evidence that Mcl-1 is the major factor that causes resistance to ABT-737 in cancer cells derived from diverse solid tumors, and the combination of Mcl-1 downregulating agents with ABT-737 could be potent therapeutic regimens for patient with ABT-737-resistant SCLC and many other types of solid tumors.
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PMID:'Seed' analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. 1717 63

The reported association between D12S1034 and lung adenocarcinoma (ADCA) risk [Yanagitani N, Kohno T, Sunaga N, et al. Localization of a human lung adenocarcinoma susceptibility locus, possibly syntenic to the mouse Pas1 locus, in the vicinity of the D12S1034 locus on chromosome 12p11.2-p12.1. Carcinogenesis. 2002;23:1177-83] prompted us to carry out a case-control study in lung ADCA and healthy control subjects to test possible involvement of single-nucleotide polymorphisms (SNPs) in D12S1034 flanking genes RASSF8 and BHLHB3, whose minimal distances from D12S1034 are approximately 16-24 kb. RASSF8 contains a RAS-associated domain and is a candidate tumor suppressor, whereas BHLHB3 is a basic helix-loop-helix domain-containing protein that functions as a transcriptional repressor. We observed no significant association between common SNPs in RASSF8 (rs1546550 in the 3'-UTR and 3 intronic SNPs) and BHLHB3 (Ala298Val and rs1048155 in the 3'-UTR) with lung ADCA risk. However, patient groups carrying one or two copies of the BHLHB3 Val298 variation (i.e., Ala/Val or Val/Val genotypes) had a higher proportion of short-term survivors (hazard ratio, 1.8; 95% confidence interval, 1.2-2.7) compared with those carrying the Ala/Ala genotype. A replication study in an independent Norwegian lung cancer population of multiple cancer histotypes failed to replicate the significant association of BHLHB3 Ala298Val with survival; such association, however, was confirmed by analysis of ADCA only from both populations. Our results suggest that BHLHB3 variants may affect lung ADCA prognosis.
Lung Cancer 2007 Apr
PMID:Common polymorphisms in D12S1034 flanking genes RASSF8 and BHLHB3 are not associated with lung adenocarcinoma risk. 1719 98

We found that p53-deficient (p53(-/-)) lung carcinoma (H1299) cells express robust levels of cell surface uPAR and uPAR mRNA. Expression of p53 protein in p53(-/-) cells suppressed basal and urokinase (uPA)-induced cell surface uPAR protein and increased uPAR mRNA degradation. Inhibition of p53 by RNA silencing in Beas2B human airway epithelial cells conversely increased basal as well as uPA-mediated uPAR expression and stabilized uPAR mRNA. Purified p53 protein specifically binds to the uPAR mRNA 3' untranslated region (3'UTR), and endogenous uPAR mRNA associates with p53. The p53 binding region involves a 37-nucleotide uPAR 3'UTR sequence, and insertion of the p53 binding sequence into beta-globin mRNA destabilized beta-globin mRNA. Inhibition of p53 expression in these cells reverses decay of chimeric beta-globin-uPAR mRNA. These observations demonstrate a novel regulatory role for p53 as a uPAR mRNA binding protein that down-regulates uPAR expression, destabilizes uPAR mRNA, and thereby contributes to the viability of human airway epithelial or lung carcinoma cells.
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PMID:Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA. 1754 71

Normal function of insulin-like growth factor II receptor (IGF2R) gene has been associated with negative control of tumor growth in vivo and in vitro. Rare alleles at a 3' UTR short tandem repeat polymorphism of IGF2R are known to decrease transcript stability. One such allele (A2/B2) increases significantly the risk of oral squamous cell carcinoma and non-small cell lung carcinoma (NSCLC) in Caucasians. To determine potential association(s) between A2/B2 presence and development and/or progression of disease, we examined in 103 NSCLC patients, free of IGF2R allelic imbalance aberrations, the 3' UTR allelic status in relation to tumor kinetic parameters (proliferation index-PI and apoptotic index-AI) and clinicopathological data. PCR and automated sequence analyses were employed to genotype the IGF2R 3' UTR polymorphism. Given that, oncogenic mitogens, which escape degradation by IGF2R, can also activate p53 through a DNA damage response, the patterns between p53 status and IGF2R genetic constitution were also evaluated in relation to the above parameters. The A2/B2 variant was significantly more common (p=0.005, chi2-test) in lung cancer patients (25% vs 15%). Its presence was accompanied by high cellular proliferation (p=0.028, t-test) along with increased tumor cell growth (GI=PI/AI) (p=0.022, t-test) and it was significantly found in advanced stages. Also, patients carrying the A2/B2 in their genetic constitution that exhibit aberrant p53 expression have faster growing tumors and progress more rapidly to advanced stages. In conclusion, the IGF2R-A2/B2 variant probably provides a selective advantage for NSCLC progression through increased tumor growth.
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PMID:The 3' UTR IGF2R-A2/B2 variant is associated with increased tumor growth and advanced stages in non-small cell lung cancer. 1803 32

X-ray repair cross-complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the base excision repair (BER) and single-strand break repair (SSBR) pathway. Single nucleotide polymorphisms (SNPs) in XRCC1 may alter protein function and repair capacity, thus lead to genetic instability and carcinogenesis. To establish our understanding of possible relationships between XRCC1 polymorphisms (5'UTR -77T>C, Arg194Trp, Arg280His and Arg399Gln) and the susceptibility to lung cancer among women nonsmokers, we performed a hospital-based case-control study of 350 patients with newly diagnosed lung cancer and 350 cancer-free controls, frequency matched by age. Our results showed that exposure to cooking oil fume was associated with increased risk of lung cancer in Chinese women nonsmokers [odds ratio (OR)=2.51, 95% confidence interval (CI) [1.80-3.51], P<0.001]. Individuals with homozygous XRCC1 399Gln/Gln genotype (OR=1.75, 95% CI [1.02-3.01]) and XRCC1 -77 combined TC and CC genotype (OR=1.66, 95% CI [1.13-2.42]) showed a slightly higher risk for lung cancer overall. In the subgroup of adenocarcinoma cases, adjusted ORs were increased for individuals with homozygous XRCC1 399Gln/Gln genotype (OR=2.62, 95% CI [1.44-4.79]) and XRCC1 -77 combined TC and CC genotype (OR=1.85, 95% CI [1.19-2.86]). Haplotype analysis showed that T-Trp-Arg-Gln haplotypes were associated with an increased risk of lung cancer among women nonsmokers (OR=2.26, 95% CI [1.38-3.68]), however, we did not observe a statistically significant joint effect of cooking oil fume and 399Gln or -77C variant allele on lung cancer among women nonsmokers. In conclusion, XRCC1 Arg399Gln and T-77C polymorphisms may alter the risk of lung cancer in women nonsmokers in China.
Lung Cancer 2008 Nov
PMID:XRCC1 polymorphisms, cooking oil fume and lung cancer in Chinese women nonsmokers. 1840 70


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