Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrant expression of DNA polymerase beta, a key enzyme involved in base excision repair, leads to genetic instability and carcinogenesis. Pol beta expression has been previously shown to be regulated at the level of transcription, but there is also evidence of post-transcriptional regulation, since rat transcripts undergo alternative polyadenylation, and the resulting 3'UTR contain at least one regulatory element. Data presented here indicate that RNA of the short 3'UTR folds to form a strong secondary structure (hairpin). Its regulatory role was established utilizing a luciferase-based reporter system. Further studies led to the identification of a protein factor, which binds to this element-the anti-apoptotic, cytoskeleton-related protein Hax-1. The results of in vitro binding analysis indicate that the formation of the RNA-protein complex is significantly impaired by disruption of the hairpin motif. We demonstrate that Hax-1 binds to Pol beta mRNA exclusively in the form of a dimer. Biochemical analysis revealed the presence of Hax-1 in mitochondria, but also in the nuclear matrix, which, along with its transcript-binding properties, suggests that Hax-1 plays a role in post-transcriptional regulation of expression of Pol beta.
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PMID:Hairpin structure within the 3'UTR of DNA polymerase beta mRNA acts as a post-transcriptional regulatory element and interacts with Hax-1. 1770 38

FAS and FAS ligand (FASL) play key roles in apoptotic signaling and down-regulation of this pathway may facilitate tumorigenesis. Alterations in apoptosis genes may affect cancer risk by influencing individual susceptibility to environmental carcinogens. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in FAS and FASL modified the association between breast cancer risk and a marker of environmental exposures, polycyclic aromatic hydrocarbon (PAH)-DNA adducts. We examined polymorphisms in FAS (5' UTR -1377G/A and 5' UTR -670G/A) and FASL (5' UTR -844C/T) in 1053 breast cancer cases and 1102 population-based controls. There was no significant association between these genetic polymorphisms and breast cancer risk. The presence of at least one variant allele (GA or AA) in FAS1377 was associated with a 36% increase in breast cancer risk among those with detectable PAH-DNA adduct levels [odds ratio (OR) = 1.36, 95% confidence interval (CI) = 1.01-1.83]. In addition, lactation history significantly modified the association between FAS1377 and FAS670 genetic variants and breast cancer risk (OR = 1.46, 95% CI = 1.04-2.06 and OR = 1.71, 95% CI = 1.13-1.58, respectively, in those who ever lactated compared with those who did not with the wild-type alleles). Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in the FAS gene and detectable PAH-DNA adducts.
Carcinogenesis 2007 Dec
PMID:Genetic polymorphisms in the apoptosis-associated genes FAS and FASL and breast cancer risk. 1796 19

MicroRNAs are an abundant class of noncoding RNAs, typically 20-23 nucleotides in length that are often evolutionarily conserved in metazoans and expressed in a cell and tissue specific manner. MicroRNAs exert their gene regulatory activity primarily by imperfectly base pairing to the 3' UTR of their target mRNAs, leading to mRNA degradation or translational inhibition. In cancer, microRNAs are often dysregulated with their expression patterns being correlated with clinically relevant tumor characteristics. Recently, microRNAs were shown to be directly involved in cancer initiation and progression. This review focuses primarily on emerging developments in the microRNA field that impact our understanding of how these molecules contribute to carcinogenesis.
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PMID:MicroRNAs in carcinogenesis. 1800 Mar 78

The aldo-keto reductase 1C3 (AKR1C3) gene located on chromosome 10p15-p14, a regulator of myeloid cell proliferation and differentiation, represents an important candidate gene for studying human carcinogenesis. In a prospectively enrolled population-based case-control study of Han Chinese conducted in Kaohsiung in southern Taiwan, a total of 114 leukemia cases and 221 controls <20 years old were recruited between November 1997 and December 2005. The present study set out to evaluate the association between childhood leukemia and both maternal and offspring's genotypes. To do so, we conducted a systematic assessment of common single-nucleotide polymorphisms (SNPs) at the 5' flanking 10 kb to 3' UTR of AKR1C3 gene. Gln5His and three tagSNPs (rs2245191, rs10508293 and rs3209896) and one multimarker (rs2245191, rs10508293 and rs3209896) were selected with average 90% coverage of untagged SNPs by using the HapMap II data set. Odds ratios and 95% confidence intervals were adjusted for age and gender. After correcting for multiple comparisons, we observed that risk of developing childhood leukemia is significantly associated with rs10508293 polymorphism on intron 4 of the AKR1C3 gene in both offspring alone and in the combined maternal and offspring genotypes (nominal P < 0.0001, permutation P < 0.005). The maternal methylenetetrahydrofolate reductase A1298C polymorphism was found to be an effect modifier of the maternal intron 4 polymorphism of the AKR1C3 gene (rs10508293) and the childhood leukemia risk. In conclusion, this study suggests that AKR1C3 polymorphisms may be important predictive markers for childhood leukemia susceptibility.
Carcinogenesis 2008 May
PMID:Maternal and offspring genetic variants of AKR1C3 and the risk of childhood leukemia. 1833 82

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.
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PMID:XRCC1 polymorphisms, cooking oil fume and lung cancer in Chinese women nonsmokers. 1840 70

MicroRNAs (miRNAs) are small (20-22 nt), non-coding RNAs involved in post-transcriptional gene silencing. Their binding to the 3' UTR of target mRNAs influences the translation or stability of the transcripts. miRNAs have been shown to regulate several developmental and physiological processes, including stem cell differentiation and the immune response. Recent findings report their involvement in hair follicle morphogenesis (ablation of miRNAs from keratinocytes causes several defects, such as evagination instead of invagination), in psoriasis (skin-specific expression of miR-203 and psoriasisspecific expression of miR-146a, miR-21 and miR-125b in the skin), in autoimmune diseases affecting the skin, such as SLE and ITP, in wound healing (changes in the expression of specific miRNA at specific phases of the regeneration process), and in skin carcinogenesis (a novel miRNA signature that includes induction of miR-21, a candidate oncogenic miRNA). Researchers worldwide are interested in miRNAs as potential therapeutic targets (such as in the case of psoriasis) and potential diagnostic biomarkers (such as in case of SLE).
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PMID:Importance of microRNAs in skin morphogenesis and diseases. 1885 72

Cyclooxygenase-2 (COX-2) influences carcinogenesis through regulation of angiogenesis, apoptosis and cytokine expression. We aimed to evaluate association of COX-2 polymorphisms with predisposition to esophageal squamous cell carcinoma (ESCC), its phenotype variability and modulation of environmental risk in northern Indian population. We genotyped 174 patients with ESCC and 216 controls for COX-2 gene polymorphisms (-765G>C; -1195G>A; -1290A>G; 3'UTR 8473T>C) using PCR-RFLP. Data were statistically analyzed using chi-square test and logistic regression model. COX-2 -765C allele carriers were at increased risk for ESCC (OR=1.66; 95% CI=1.08-2.54; P=0.004). However, -1195G>A; -1290A>G; 3'UTR 8473T>C polymorphisms of COX-2 gene were not significantly associated with ESCC. We observed significantly enhanced risk for ESCC due to interaction between COX-2 -1195GAx-765GC+CC genotypes (OR=4.60; 95% CI=1.63-13.01; P=0.004). High risk to ESCC was also observed with respect to COX-2 haplotypes, A(-1290)G(-1195)C(-765)T(8473) and A(-1290)A(-1195)C(-765)T(8473) [OR=3.35; 95% CI=0.83-13.44; P=0.089; OR=4.28; 95% CI=0.43-42.40; P=0.246] however, it was not statistically significant. Stratification of subjects based on gender showed that females were at higher risk for ESCC due to COX-2 -765C carrier genotypes (OR=2.97; 95% CI=1.23-7.18; P=0.016). In association of genotypes with clinical characteristics, -765C carrier genotype conferred risk of ESCC in middle third of esophagus (OR=1.78; 95% CI=1.08-2.93; P=0.023). In case-only analysis, interaction of environmental risk factors and COX-2 genotypes did not further modulate the risk for ESCC. In summary, COX-2 -765G>C polymorphism confers ESCC susceptibility particularly in females and patients with middle third anatomical location of the tumor. Interaction of COX-2 -1195GA and -765C carrier genotypes also modulates ESCC risk.
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PMID:Functional polymorphisms of cyclooxygenase-2 (COX-2) gene and risk for esophageal squmaous cell carcinoma. 1942 70

A complex interaction of host genetic and environmental factors may be relevant in the development of Helicocobacter pylori-related gastric carcinogenesis. We investigated the effect of vascular endothelial growth factor (VEGF) gene polymorphisms on the risk of gastric cancer (GC) and peptic ulcer diseases in a Japanese population. The G1612A(rs10434) and C936T(rs3025039) polymorphisms in the 3' untranslated region (3'-UTR) of VEGF gene were genotyped in a total of 844 subjects including 385 GC, 143 ulcer including 98 gastric ulcer (GU), 45 duodenal ulcer (DU), and 316 nonulcer subjects. The 1612A carrier held a significantly higher risk of GC when compared to both noncancer and nonulcer (overall noncancer vs. GC; OR = 1.61, 95% CI = 1.17-2.21, P = 0.0038, nonulcer vs. GC; OR = 1.54, 95% CI = 1.07-2.22, P = 0.0197). The 1612A carrier was more closely associated with an increased risk of noncardiac cancer (OR = 1.64, 95% CI = 0.17-2.21, P = 0.0038), lower third cancer (OR = 1.97, 95% CI = 1.30-3.00, P = 0.002), and Lauren's diffuse-type cancer (OR = 1.75, 95% CI = 1.24-2.46, P = 0.001), while the same genotype was not associated with the progression of GC. The C936T genotype was not associated with a risk of GC and its progression. Both the G1612A and C936T genotypes were not associated with the risk of peptic ulcer diseases. Our data suggest that the G1612A, but not C936T polymorphisms in the 3'-UTR of VEGF gene is associated with the susceptibility to GC in the Japanese population.
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PMID:Effect of polymorphisms in the 3' untranslated region (3'-UTR) of vascular endothelial growth factor gene on gastric cancer and peptic ulcer diseases in Japan. 1949 79

Lung cancer is the leading cause of death from cancer in the world. Although the molecular network of lung carcinogenesis has been partly known at the levels of genes and proteins, and personalized therapy based on the genetic changes has made considerable progress in the last decade, the high mortality rate is not markedly changed. MicroRNAs (miRNAs), a class of short endogenous RNAs, acting as post-transcriptional regulators of gene expression, are similar with siRNAs in both the biosynthesis and the function steps. While, miRNAs mostly silence gene expression by binding imperfectly matched sequences in the 3' UTR of target mRNA, which is different with siRNAs by targeting ORF of mRNA with a perfectly complementary manner. miRNAs have multiple functions in lung development, and abnormal expression of miRNAs could lead to lung tumorigenesis. The different expression profiles of miRNAs in lung cancer, and the stability of miRNAs in serum, all together make them as new potentially clinical biomarkers for diagnosis and prognosis. Moreover, miRNAs may serve as either novel potential targets acting directly as oncogenes (e.g. miR-17-92 cluster) or directly therapeutic molecules working as tumor suppressor genes (e.g. let-7 family). RNAi technology based on miRNAs has many advantages over siRNAs, such as in vivo stability, highly RNA promoter-compatibility and no overt toxicity. Eventually, it might overcome the present disadvantages and become a good candidate for lung cancer therapy.
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PMID:Potential uses of microRNA in lung cancer diagnosis, prognosis, and therapy. 1951 23

The somatostatin receptor subtype 2 (sst2) behaves as a tumor suppressor when expressed and stimulated by its ligand somatostatin in pancreatic cancer. We reveal a mechanism underlying oncosuppressive action of sst2, whereby this inhibitory receptor upregulates the expression of the secreted angioinhibitory factor thrombospondin-1 (TSP-1), as demonstrated in exocrine BxPC-3 and endocrine BON pancreatic cancer cells. The sst2-dependent upregulation of TSP-1 occurs through the inhibition of the PI3K pathway. It depends on transcriptional and translational events, involving a previously undescribed IRES in the 5'-UTR of TSP-1 mRNA. Chick chorioallantoic membrane was used as an in vivo model to demonstrate that TSP-1 is a critical effector of the inhibitory role of sst2 on the neoangiogenesis and oncogenesis induced by pancreatic cancer cells. TSP-1 reduced in vitro tubulogenesis of endothelial cells when grown in conditioned medium from pancreatic cancer cells expressing sst2, as compared to those expressing the control vector. TSP-1 inhibited tumor cell-induced neoangiogenesis by directly sequestering the proangiogenic factor VEGF, and inactivating the angiogenesis initiated by VEGFR2 phosphorylation in endothelial cells. Using human pancreatic tissue-microarrays, the expression of both sst2 and TSP-1 was shown to be correlated during the pancreatic neoplastic program. Both proteins are nearly undetectable in normal exocrine pancreas and in most invasive cancer lesions, but their expression is strikingly upregulated in most preinvasive cancer-adjacent lesions. The upregulation of both sst2 and TSP-1 tumor suppressors may function as an early negative feedback to restrain pancreatic carcinogenesis.
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PMID:Thrombospondin-1 is a critical effector of oncosuppressive activity of sst2 somatostatin receptor on pancreatic cancer. 1980


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