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

Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3'UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60-0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62-0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47-0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53-0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62-0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3'UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood.
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PMID:A DRD1 polymorphism predisposes to lung cancer among those exposed to secondhand smoke during childhood. 2528 86

To obtain microRNA (miRNA) profile and clarify their biological function in tumorigenic Sca-1(+) CD34(+) cells during carcinogenesis of lung adenocarcinoma. After intranasal infection with recombinant Adeno-Cre viruses (AdV-Cre), lung adenocarcinoma was identified pathologically in Lox-stop-lox Kras (LSL-Kras) G12D mice. Sca-1(+) CD34(+) cells were sorted by flow cytometry and tested for tumor-initiating ability, self-renewal and tumorigenicity. MiRNA profiles were obtained using microarray and further confirmed by real-time RT-PCR (qRT-PCR). MiRNA functions were predicted bioinformatically, and miR-294 function was verified to explore its role in tumor migration and invasion. Lung adenocarcinoma was induced in LSL-Kras G12D mice within 30 days. In vivo, the tumorigenicity of Sca-1(+) CD34(+) cells was 25 times stronger than Sca-1(-) CD34(-) cells. During tumorigenesis of lung adenocarcinoma, the expression of 145 miRNAs in Sca-1(+) CD34(+) cells increased and 72 miRNAs decreased (P < 0.01). Four successively up-regulated miRNAs (miR-15a*, miR-203, miR-294 and miR-295*) and three successively down-regulated ones (miR-19b, miR-483 and miR-615-5p) were identified. Among them, miR-294 could constitutively bind to 3'-UTR of matrix metalloproteinase 3 (MMP3), and down-regulate MMP3 protein expression. MiR-294 also significantly inhibited migration and invasion of Lewis lung cancer cells. MiRNAs are characteristically expressed in tumor-initiating Sca-1(+) CD34(+) cells of lung adenocarcinoma, and may play important roles during the carcinogenesis of lung adenocarcinoma.
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PMID:MicroRNA profile of tumorigenic cells during carcinogenesis of lung adenocarcinoma. 2620 83

ERBB4, one of four ErbB receptor tyrosine kinase family members, plays an important role in the etiology and progression of lung cancer. In this study, we found that the ERBB4 protein levels were consistently up-regulated in lung cancer tissues, whereas the mRNA levels varied randomly, suggesting that a post-transcriptional mechanism was involved in regulating ERBB4 expression. Because microRNAs are powerful post-transcriptional regulators of gene expression, we used bioinformatic analyses to search for microRNAs that can potentially target ERBB4. We identified specific targeting sites for miR-193a-3p in the 3'-UTR of ERBB4. We further identified an inverse correlation between miR-193a-3p levels and ERBB4 protein levels, but not mRNA levels, in lung cancer tissue samples. By overexpressing or knocking down miR-193a-3p in lung cancer cells, we experimentally confirmed that miR-193a-3p directly recognizes the 3'-UTR of the ERBB4 transcript and regulates ERBB4 expression. Furthermore, the biological consequences of the targeting of ERBB4 by miR-193a-3p were examined in vitro via cell proliferation, invasion, and apoptosis assays and in vivo using a mouse xenograft tumor model. We demonstrated that the repression of ERBB4 by miR-193a-3p suppressed proliferation and invasion and promoted apoptosis in lung cancer cells and that miR-193a-3p exerted an anti-tumor effect by negatively regulating ERBB4 in xenograft mice. Taken together, our findings provide the first clues regarding the role of miR-193a-3p as a tumor suppressor in lung cancer through the inhibition of ERBB4 translation.
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PMID:miR-193a-3p functions as a tumor suppressor in lung cancer by down-regulating ERBB4. 2539 51

MiR-153 was reported to be dysregulated in some human cancers. However, the function and mechanism of miR-153 in lung cancer cells remains unknown. In this study, we investigated the role of miR-153 in human non-small-cell lung cancer (NSCLC). Using qRT-PCR, we demonstrated that miR-153 was significantly decreased in clinical NSCLC tissues and cell lines, and downregulation of miR-153 was significantly correlated with lymph node status. We further found that ectopic expression of miR-153 significantly inhibited the proliferation and migration and invasion of NSCLC cells in vitro, suggesting that miR-153 may be a novel tumor suppressor in NSCLC. Further integrated analysis revealed that ADAM19 is as a direct and functional target of miR-153. Luciferase reporter assay demonstrated that miR-153 directly targeted 3'UTR of ADAM19, and correlation analysis revealed an inverse correlation between miR-153 and ADAM19 mRNA levels in clinical NSCLC tissues. Knockdown of ADAM19 inhibited migration and invasion of NSCLC cells which was similar with effects of overexpression of miR-153, while overexpression of ADAM19 attenuated the function of miR-153 in NSCLC cells. Taken together, our results highlight the significance of miR-153 and ADAM19 in the development and progression of NSCLC.
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PMID:MiR-153 inhibits migration and invasion of human non-small-cell lung cancer by targeting ADAM19. 2547 31

Global changes in gene expression accompany the development of cancer. Thus, inherited variants in miRNA-binding sites are likely candidates for conferring inherited susceptibility. Using an in silico approach, we compiled a comprehensive list of SNPs predicted to modulate miRNA binding in genes from several key lung cancer pathways. We then investigated whether these SNPs were associated with lung cancer risk in two independent populations. In general, SNPs in miRNA-binding sites are rare. However, some allelic variation was observed. We found that rs1126579 in CXCR2 was associated with a reduced risk of lung cancer in both European American [ORTT vs. CC 0.56 (0.37-0.88); P = 0.008] and Japanese [ORTT vs. CC 0.62 (0.38-1.00); P = 0.049] populations. Furthermore, we found that the SNP disrupted a novel binding site for miR-516a-3p, led to a moderate increase in CXCR2 mRNA and protein expression, and increased MAPK signaling. Moreover, analysis of rs1126579 with serum levels of IL8, its endogenous ligand, supported an interaction whereby rs1126579-T and high serum IL8 conferred synergistic protection from lung cancer. Our findings demonstrate a function for a 3'UTR SNP in modulating CXCR2 expression, signaling, and susceptibility to lung cancer.
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PMID:Identification of a functional SNP in the 3'UTR of CXCR2 that is associated with reduced risk of lung cancer. 2548 Sep 45

The aim of the present study was to investigate the role of miR-124 in lung cancer and identify the potential predictive value of miR-124 in postoperative non-small cell lung cancer (NSCLC) patients. We detected miR-124 expression in A549, NCL-H460 and normal lung epithelial BEAS-2E cells and showed a significantly lower expression level of miR-124 in NSCLC cells than in BEAS-2E cells. Upregulation of miR-124 expression levels in both A549 and NCL-H460 cells by transfection with miR-124 mimics suppressed cell proliferation and induced apoptosis. Further investigation revealed that miR-124 bound directly to the 3' UTR region of STAT3, thereby inhibiting STAT3 expression. In addition, miR-124 levels detected in NSCLC tissues were lower than those in adjacent normal lung tissues, while the opposite was observed for STAT3. In NSCLC, the expression levels of miR-124 and STAT3 correlated significantly with the tumor node metastases (TNM) stage, differentiation grade and lymph node metastasis, while the levels of these molecules did not differ significantly by gender, age, location, smoking index, pleural invasion or pathological type. The expression level of miR-124 was significantly associated with disease-free survival (DFS) in both positive and negative lymph node groups. Furthermore, patients with low miR-124 or high STAT3 expression generally received a worse prognosis in terms of both overall survival (OS) and DFS. In conclusion, our findings suggest that miR-124 functions as a tumor suppressor by targeting STAT3, and that miR-124 may potentially serve as a useful biomarker for the prognosis of NSCLC patients.
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PMID:The tumor suppressor miR-124 inhibits cell proliferation by targeting STAT3 and functions as a prognostic marker for postoperative NSCLC patients. 2553 8

Ku80 is involved in DNA double-strand breaks (DSBs) repair. Ku80 is overexpressed in lung cancer tissues, yet, molecular mechanisms have not been examined. We identified that miRNA, hsa-miR-526b, is bound to the 3'-UTR of Ku80 mRNA, thus decreasing Ku80 expression in NSCLC cells. Hsa-miR-526b was downregulated in NSCLC tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation. Overexpression of Ku80 and downregulation of hsa-miR-526b were associated with poor clinical outcomes of NSCLC patients. Hsa-miR-526b suppressed NSCLC cell proliferation, clonogenicity, and induced cell cycle arrest and apoptosis. Hsa-miR-526b inhibited xenografts and orthotopic lung tumor growth. Further, Ku80 knockdown in NSCLC cells suppressed tumor properties in vitro and in vivo similar to hsa-miR-526b overexpression. In agreement, Ku80 restoration partially reversed cell cycle arrest and apoptosis induced by hsa-miR-526b in NSCLC cells in vitro and in vivo. In addition, hsa-miR-526b overexpression or Ku80 knockdown increased p53 and p21CIP1/WAF1 expression. These findings reveal that hsa-miR-526b is a potential target in cancer therapy.
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PMID:By downregulating Ku80, hsa-miR-526b suppresses non-small cell lung cancer. 2559 43

Our previous study demonstrated that microRNA 5100 (miR-5100) is overexpressed in lung cancer tissues; however, the function of miR-5100 remained elusive. In this study, we demonstrate that miR-5100 is highly expressed in a wide variety of lung cancer tissues and lung cancer cell lines. Exogenous expression of miR-5100 in A549 and H1299 lung cancer cells enhanced proliferation and colony formation, and conversely, suppression of miR-5100 exhibited inhibitory effects. Furthermore, we demonstrate that miR-5100 promotes tumor growth in nude mice. These effects may result from the ability of miR-5100 to promote G1/S transition and downregulate cyclin D1 and cyclin-dependent kinases 2 (CDK2) expressions in lung cancer stable cells. Using a bioinformatics target prediction tool, we identified Rab6 as a potential target of miR-5100. Consistently, overexpression of miR-5100 specifically reduced the expression of a luciferase reporter containing the predicted binding site from the 3'untranslated region (3'UTR) of Rab6 and decreased the accumulation of endogenous Rab6 in A549 and H1299 cells. Moreover, exogenous expression of Rab6 compromised the effects of miR-5100 on cell proliferation and colony formation. Our data suggest that miR-5100 promotes tumor growth by facilitating the G1/S transition and targeting Rab6.
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PMID:miR-5100 promotes tumor growth in lung cancer by targeting Rab6. 2575 17

Resistance to radiation is a major problem in cancer treatment. The mechanisms of radioresistance remain poorly understood; however, mounting evidence supports a role for microRNAs (miRNAs) in the modulation of key cellular pathways mediating the response to radiation. The present study aimed to identify specific miRNAs and their effect on radioresistant cells. The global miRNA profile of an established radioresistant lung cancer cell line and the corresponding control cells was determined. Differential expression of the miRNAs was confirmed by quantitative real-time PCR (qRT-PCR). The binding effect of identical novel miRNAs and target mRNAs was determined by luciferase assay. Lung cancer cells were transfected with miRNA-specific mimics or inhibitors. The DNA-dependent protein kinase (DNA-PKcs) protein level was tested by western blot analysis. Radiosensitivity of cancer cells was determined using colony formation assay. Among the differentially expressed miRNAs, 25 miRNAs were overexpressed while 18 were suppressed in the radioresistant cells, both basally and in response to radiation compared to their control. An miRNA signature miR-1323 exhibited a >5-fold increase in the radioresistant cells. miR-1323 was demonstrated to bind to PRKDC 3'UTR, which is involved in DNA repair. Ectopic expression of miR-1323 significantly increased the survival fraction of irradiated cancer cells. Inhibition of miR-1323 reversed the radioresistance of cancer cells and subsequently suppressed the expression of miR-1323-regulated DNA-PKcs protein. The present study indicated that miRNAs are involved in the radioresistance of human lung cancer cells. A possible mechanism for resistance to radiation was via enhanced DNA repair. The present study demonstrated a role for miR-1323 in modulating radioresistance and highlights the need for further study investigating the potential role of miR-1323 as both a predictive marker of response and a novel therapeutic agent with which to enhance the efficacy of radiotherapy.
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PMID:Knockdown of microRNA-1323 restores sensitivity to radiation by suppression of PRKDC activity in radiation-resistant lung cancer cells. 2582 95

Cyclin E1, encoded by the CCNE1 gene, promotes G1/S transition, chromosome instability, and oncogenesis. Here, we show that miR-497 and miR-34a target the 3'-UTR of CCNE1. miR-497 and miR-34a are downregulated in cancer cells and their ectopic expression inhibited cell proliferation and colony formation in vitro, and inhibited tumor growth in a xenograft model. The effect of simultaneous overexpression of miR-497 and miR-34a on the inhibition of cell proliferation, colony formation, and tumor growth, and the downregulation of cyclin E1 was stronger than the effect of each miRNA alone. The synergistic actions of miR-497 and miR-34a partly correlated with cyclin E1 levels. When cells stably expressing CCNE1 were transfected with the Hi-miR-497/34a plasmid, there was no effect on colony formation, compared with that of cells transfected with either Hi-miR497 or Hi-miR34a. These results indicate cyclin E1 is downregulated by both miR-497 and miR-34a, which synergistically retard the growth of human lung cancer cells.
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PMID:miR-497 and miR-34a retard lung cancer growth by co-inhibiting cyclin E1 (CCNE1). 2590 21


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