Deletions at chromosome 2q and 12p are early and frequent molecular alterations in bronchial epithelium and NSCLC of long-term smokers

Grepmeier, Ulrike; Dietmaier, Wolfgang; Merk, Johannes; Wild, Peter J.; Obermann, Ellen C.; Pfeifer, Michael; Hofstaedter, Ferdinand; Hartmann, Arndt; Woenckhaus, Matthias

doi:10.3892/ijo.27.2.481

Cited by 34 publications

(39 citation statements)

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“…However, the data in the present study, together with those recently reported in normal and cancer cells (29), indicate that promoter methylation is an additional mechanism regulating the expression of miR-200c, a critical miRNA that controls epithelial differentiation and invasion. It is noteworthy that the presence of the mir-200c gene in a chromosomal region (12p12) frequently altered in lung cancer (30) could represent an additional mechanism of inactivation.…”

Section: Discussionmentioning

confidence: 99%

Loss of miR-200c Expression Induces an Aggressive, Invasive, and Chemoresistant Phenotype in Non–Small Cell Lung Cancer

Ceppi

Mudduluru

Kumarswamy

et al. 2010

Molecular Cancer Research

284

228

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The development of metastases is the main reason for cancer-related death in non-small cell lung cancer (NSCLC). The initiation of metastasis involves an increase in cell motility mediated by the loss of cell-cell adhesion caused by E-cadherin repression, in a process commonly known as epithelial-to-mesenchymal transition. A role for microRNA-200 family members in regulating epithelial-to-mesenchymal transition has recently been indicated but data about their expression in lung tumors is still unavailable. The present study investigated the expression of miR-200c in a panel of NSCLC cell lines (n = 9), and a strong inverse correlation with invasion was detected. Reintroduction of miR-200c into highly invasive/aggressive NSCLC cells induced a loss of the mesenchymal phenotype by restoring E-cadherin and reducing N-cadherin expression, and inhibited in vitro cell invasion as well as in vivo metastasis formation. Moreover, miR-200c overexpression restored the sensitivity of NCI-H1299 cells to cisplatin and cetuximab. Hypermethylation of the promoter region was found to be responsible for the loss of miR-200c in invasive cells, as evaluated by 5-aza-2′-deoxycytidine treatment, methylation-specific PCR, and bisulfite sequencing. In primary tumor specimens obtained from 69 patients with consecutively resected NSCLC, lower miR-200c expression levels were found to be associated with a poor grade of differentiation (P = 0.04), a higher propensity to lymph node metastases (P < 0.01), and with a lower E-cadherin expression (P = 0.01). These data indicate that the loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype, and that assessment of its expression could contribute to a better clinicopathologic definition of patients with NSCLC. Mol Cancer Res; 8(9); 1207-16. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Loss of miR-200c Expression Induces an Aggressive, Invasive, and Chemoresistant Phenotype in Non–Small Cell Lung Cancer

Ceppi

Mudduluru

Kumarswamy

et al. 2010

Molecular Cancer Research

284

228

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“…[20][21] RhoE resides in 2q23.3 region, and numerous studies have demonstrated frequent alterations of 2q in lung cancer. Two prior studies using microsatellite markers showed loss of heterozygosity (LOH) in 2q in non-small cell lung cancer patients, even in bronchial epithelium of long-term smokers, [22][23] whereas another recent study applied comparative genomic hybridization (CGH) to evaluate 2q gains in lung metastases of colorectal carcinomas. 24 However, there are no published studies involving application of the real-time PCR technique to determine the DNA copy numbers.…”

Section: Discussionmentioning

confidence: 99%

“…Our study reports a percentage of copy number changes in tumors that is much higher than the average reported data (about 40%), which could be the result of the higher sensitivity and precision of real-time PCR methods, but is consistent with the view that 2q alteration is an early and frequent molecular event in Non-small cell lung caner of long-term smokers. [22][23] RhoE, as an important component of the signaling pathways, its expression is highly regulated transcriptionally and a variety of studies using microarray analyses have suggested that RhoE mRNA can be altered under various physiological and pathological conditions. [25][26][27][28][29] Here we found that expression of RhoE mRNA was significantly associated with RhoE gene copy number changes (p < 0.05).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of RhoE in non-small cell lung cancer (NSCLC) is associated with smoking and correlates with DNA copy number changes

Zhang¹,

Hu²,

Zhou³

et al. 2007

Cancer Biology & Therapy

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RhoE, a small G protein, is constitutively GTP bound within the cell and can regulate actin cytoskeleton reorganization, leading to the appearance of aggregates of actin filaments. Although emerging evidence suggests that RhoE is causally involved in cancer formation and progression, little is known about its significance in solid cancer, including lung cancer. In the present study, the expression of RhoE was analyzed using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR), real-time RT-PCR, immunohistochemistry and western blot in 30 patients with Non-small Cell Lung Cancer (NSCLC). Then the correlation of RhoE overexpression with clinical parameters was evaluated. Furthermore, the possible reasons contributing to the RhoE expression were examined by real-time genomic PCR and mutation analysis on DNA sequence and cDNA sequence. Our results revealed that RhoE expression was dramatically increased in lung cancer tissues compared with adjacent nontumoral lung tissues (p < 0.01). Immunohistochemistry showed a strong cytoplasmic staining in cancer cells compared with positive membrane staining in adjacent nontumoral proliferative alveolar epitheliums. Moreover, the overexpression of RhoE was significantly associated with the patients' smoking history (p < 0.05). 72% tumor tissues displayed DNA copy number changes based on the DNA levels in the matched adjacent nontumoral lung tissues and this copy number changes correlated significantly with RhoE expression and smoking history (p < 0.05). Three polymorphisms were identified but no correlation was found with the clinicopathological features. To our knowledge, this is the first report demonstrating that overexpression of RhoE correlated with smoking and DNA copy number changes, suggesting that RhoE may serve as a molecular marker to identify high-risk individuals and assist in the identification of additional pathways of carcinogenesis.

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“…By analysis of 371 lung adenocarcinomas using dense SNP arrays, Weir et al 5 found that 26 of 39 autosomal chromosome arms showed consistent large-scale copy-number gain or loss and 31 focal alterations, including 24 amplifications and 7 homozygous deletions. Previous studies suggested that fractional allelic losses located primarily on chromosomes 1p, 2p, 2q, 3p, 6q, 7p, 9p, 12p, 16p, 17p, 17q, 19p, and 21q occur more frequently in lung carcinomas than in adjacent normal tissues, [6][7][8][9][10][11][12][13][14][15][16][17] indicating the existence of tumor-suppressor genes or potential candidates, such as HLJ1 at 1p31, FHIT at 3p14, RASSF1A, FUS1, LIMD1, SEMA3B, and SEMA3F at 3p21, p16 at 9p21, and p53 at 17p13.…”

Section: Genetic Changesmentioning

confidence: 99%

Genetic and epigenetic changes in lung carcinoma and their clinical implications

Wen

Zhang

et al. 2011

Modern Pathology

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Lung cancer is the leading cause of cancer deaths worldwide. Recent advance in targeted therapy for lung cancer patients with epidermal growth factor receptor (EGFR) mutations has demonstrated a promising development toward personalized therapy for lung cancer patients. The development of lung cancer is a complex process, involving a series of genetic and epigenetic changes. Tobacco smoke is the predominant etiologic risk factor for lung cancer. However, some lung cancers, especially adenocarcinomas, arise in patients who have never smoked, suggesting the importance of host genetic/epigenetic susceptibility in the occurrence and development of lung cancer. Understanding of these genetic and epigenetic changes will further aid in the biomarker-driven personalized therapy for lung cancer patients. In this review, we summarize the genetic and epigenetic alterations observed in lung cancers, including chromosomal loss of heterozygosity, tumor-suppressor gene mutation, gene methylation, histone modification, and microRNA expression changes. Clinical and preclinical studies have implied specific genetic/epigenetic changes for clinical application in lung cancer patients. However, more efforts are required in validation of the identified molecular markers in lung cancer patients for early detections, assessment for treatment response, and survival predictions.

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Deletions at chromosome 2q and 12p are early and frequent molecular alterations in bronchial epithelium and NSCLC of long-term smokers

Cited by 34 publications

References 0 publications

Loss of miR-200c Expression Induces an Aggressive, Invasive, and Chemoresistant Phenotype in Non–Small Cell Lung Cancer

Loss of miR-200c Expression Induces an Aggressive, Invasive, and Chemoresistant Phenotype in Non–Small Cell Lung Cancer

Overexpression of RhoE in non-small cell lung cancer (NSCLC) is associated with smoking and correlates with DNA copy number changes

Genetic and epigenetic changes in lung carcinoma and their clinical implications

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