Current smoking-specific gene expression signature in normal bronchial epithelium is enhanced in squamous cell lung cancer
Department of Pathology, University Medical Centre Groningen, Groningen, The Netherlands. The Journal of Pathology
(Impact Factor: 7.43).
06/2009; 218(2):182-91. DOI: 10.1002/path.2520
Cigarette smoking is the main risk factor for the development of squamous cell lung carcinoma (SCC). However, the smoking-related molecular changes in SCC have not been studied. Gene expression studies in both histologically normal bronchial epithelium and SCC epithelial samples identified genes differentially expressed between current and ex-smokers. Subsequently, expression levels of the smoking-related genes in normal bronchial epithelium were compared with those in SCC cells, since we hypothesized that the smoking-induced changes would be also deregulated in SCC. Gene expression profiles were generated using Agilent whole human genome microarrays on laser-microdissected normal bronchial epithelium and SCC samples. Expression levels of 246 genes, mainly related to oxidative stress response, were significantly different between normal bronchial epithelium of current and ex-smokers. Such a differential gene expression profile did not exist in SCC cells of smokers and ex-smokers. Interestingly, when comparing SCC and normal bronchial epithelium from ex-smokers, the vast majority of these 246 genes were also deregulated in SCC. When comparing SCC with normal epithelium from smokers, 22% of the up-regulated genes showed a similar high expression in SCC whereas 79% of the down-regulated genes were even further reduced in SCC as compared to current smokers. The down-regulated genes included several tumour suppressor genes, such as C9orf9, INHBB, LRIG1, SCGB3A1, SERPINI2, STEAP3 and ZMYND10. Thus, our study shows that the majority of genes up-regulated in normal bronchial epithelium of current smokers show similar high expression levels in SCC, while down-regulated genes are even further repressed in SCC. Our data indicate that smoking-related changes in normal bronchial epithelial cells persist in malignant transformed squamous cells.
Available from: Håkan Hedman
- "LRig1 is down-regulated in non-small cell lung cancer and lung carcinoma in situ    (Kvarnbrink et al., unpublished observation). Both the mRNa and protein levels of LRig1 are associated with the survival of nonsmall cell lung cancer patients. "
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Optimal treatment decisions for cancer patients require reliable prognostic and predictive information. However, this information is inadequate in many cases. Several recent studies suggest that the leucine-rich repeats and immunoglobulin-like domains (LRIG) genes, transcripts, and proteins have prognostic implications in various cancer types.
Material and methods:
Relevant literature was identified on PubMed using the key words lrig1, lrig2, and lrig3. LRIG mRNA expression in cancer versus normal tissues was investigated using the Oncomine database.
The three human LRIG genes, LRIG1, LRIG2, and LRIG3, encode single-pass transmembrane proteins. LRIG1 is a negative regulator of growth factor signaling that has been shown to function as a tumor suppressor in vitro and in vivo in mice. The functions of LRIG2 and LRIG3 are less well defined. LRIG gene and protein expression are commonly dysregulated in human cancer. In early stage breast cancer, LRIG1 copy number was recently shown to predict early and late relapse in addition to overall survival; in nasopharyngeal carcinoma, loss of LRIG1 is also associated with poor survival. LRIG gene and protein expression have prognostic value in breast cancer, uterine cervical cancer, head-and-neck cancer, glioma, non-small cell lung cancer, prostate cancer, and cutaneous squamous cell carcinoma. In general, expression of LRIG1 and LRIG3 is associated with good survival, whereas expression of LRIG2 is associated with poor survival. Additionally, LRIG1 regulates cellular sensitivity to anti-cancer drugs, which indicates a possible role as a predictive marker.
LRIG gene statuses and mRNA and protein expression are clinically relevant prognostic indicators in several types of human cancer. We propose that LRIG analyses could become important when making informed and individualized clinical decisions regarding the management of cancer patients.
Available from: Hwanseok Rhee
- "The development of cancer is a multistep process that involves the accumulation of a wide range of genetic and phenotypic alterations , leading to the aberrant expression of genes that regulate cell proliferation. Microarrays have been used extensively to identify differential gene expression profiles in many cancers, which has aided in the screening, prognosis, and classification of tumors, and microarray expression profiling has provided important information about lung carcinogenesis     . However, microarrays have limitations, including low sensitivity  , low dynamic range , and hybridization artifacts . "
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The development of reliable gene expression profiling technology increasingly impacts our understanding of lung cancer biology. Here, we used RNA sequencing (RNA-Seq) to compare the transcriptomes of non-small cell lung cancer (NSCLC) and normal lung tissues and to investigate expression in lung cancer tissues.
We enrolled 88 male patients (mean age, 61.2 years) with NSCLC. RNA-Seq was performed on 88 pairs of NSCLC tumor tissue and non-tumor tissue from 54 patients with adenocarcinoma and 34 patients with squamous cell carcinoma. Immunohistochemistry was performed to validate differential candidate gene expression in a different NSCLC group.
RNA-Seq produced 25.41 × 106 (± 8.90 × 106) reads in NSCLC tissues and 24.70 × 106 (± 4.70 × 106) reads in normal lung tissues [mean (± standard deviation)]. Among the genes expressed in both tissues, 335 were upregulated and 728 were downregulated ≥ 2-fold (P < 0.001). Four upregulated genes–CBX3, GJB2, CRABP2, and DSP–not previously reported in lung cancer were studied further. Their altered expression was verified by immunohistochemistry in a different set of NSCLC tissues (n = 154). CBX3 was positive in 90.3% (139 cases) of the samples; GJB2, in 22.7% (35 cases); CRABP2, in 72.1% (111 cases); and DSP, in 17.5% (27 cases). The positive rate of CRABP2 was higher in adenocarcinoma than squamous cell carcinoma (p < 0.01).
CBX3 and CRABP2 expression was markedly increased in lung cancer tissues and especially CRABP2 may be promising candidate genes in lung adenocarcinoma.
Available from: John F Brothers
- "The first study analyzed both lung SCC compared to the normal epithelium of the bronchi and adenocarcinoma as compared to the normal alveolar lung tissue . The second study focused on SCC and normal bronchial epithelium . Abnormalities in the normal bronchial tissue that were similar to those identified in the tumor were seen in tumor suppressor genes and oncogenes, as well as different functions such as xenobiotic metabolism and redox stress, matrix degradation, and cell differentiation. "
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ABSTRACT: Lung cancer is the leading cause of cancer death worldwide in part due to our inability to identify which smokers are at highest risk and the lack of effective tools to detect the disease at its earliest and potentially curable stage. Recent results from the National Lung Screening Trial have shown that annual screening of high-risk smokers with low-dose helical computed tomography of the chest can reduce lung cancer mortality. However, molecular biomarkers are needed to identify which current and former smokers would benefit most from annual computed tomography scan screening in order to reduce the costs and morbidity associated with this procedure. Additionally, there is an urgent clinical need to develop biomarkers that can distinguish benign from malignant lesions found on computed tomography of the chest given its very high false positive rate. This review highlights recent genetic, transcriptomic and epigenomic biomarkers that are emerging as tools for the early detection of lung cancer both in the diagnostic and screening setting.
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