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
Source: PubMed

ABSTRACT 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.

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    • "LRig1 is down-regulated in non-small cell lung cancer and lung carcinoma in situ [14] [31] [50] (Kvarnbrink et al., unpublished observation).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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    ABSTRACT: Background. 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. Results. 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. Conclusions. 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.
    Acta oncologica (Stockholm, Sweden) 09/2014; 53(9):1-8. DOI:10.3109/0284186X.2014.953258
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    • "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 [5] [6] [7] [8] [9]. However, microarrays have limitations, including low sensitivity [10] [11], low dynamic range [11], and hybridization artifacts [12]. "
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    ABSTRACT: Introduction 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. Methods 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. Results 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). Conclusions CBX3 and CRABP2 expression was markedly increased in lung cancer tissues and especially CRABP2 may be promising candidate genes in lung adenocarcinoma.
    Lung cancer (Amsterdam, Netherlands) 06/2014; 84(3). DOI:10.1016/j.lungcan.2014.03.018
    • "As mentioned above, STEAP1 was cloned from highly STEAP1 expressing prostate cancer cells (Hubert et al., 1999). In subsequent studies many STEAPs have been found to be over-expressed in different human and murine cancers (including prostate, bladder, breast, colon and lung carcinoma, ES, anaplastic thyroid carcinoma and malignant melanoma) compared to normal tissues rendering them as attractive therapeutic targets and biomarkers (Hubert et al., 1999; Gomes et al., 2012; Yang et al., 2001; Porkka et al., 2002; Li et al., 2004; Maia et al., 2008; Lazarevic et al., 2008; Boelens et al., 2009; Khan et al., 2010; Antico Arciuch et al., 2011; Giulianelli et al., 2011; Grunewald et al., 2012a, b; Hayashi et al., 2011b; Valenti et al., 2010). STEAP1, in particular, appears to be greatly over-expressed in many cancers (Figure 3). "
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    ABSTRACT: The human six-transmembrane epithelial antigen of the prostate (STEAP) protein family contains at least five homologous members. The necessity of multiple homologous STEAP proteins is still unclear, but their peculiar and tissue-specific expression suggests that they are assigned to distinct functional tasks. This concept is supported by the fact that especially STEAP1, and to a lesser extent STEAP2 and -4, are highly over-expressed in many different cancer entities, while being only minimally expressed in a few normal tissues. Despite their very similar domain organisation, STEAP3 seems to act as a potent metalloreductase essential for physiological iron uptake and turnover, while in particular STEAP4 appears to be rather involved in responses to nutrients and inflammatory stress, fatty acid and glucose metabolism. Moreover, individual STEAP proteins possess overlapping functions important for growth and survival of cancer cells. Due to their membrane-bound localisation and their high expression in many different cancers such as prostate, breast and bladder carcinoma as well as Ewing's sarcoma, STEAP proteins have been recognised and utilised as promising targets for cell- and antibody-based immunotherapy. This review summarises our present knowledge of the individual members of the human STEAP family and highlights the functional differences between them.
    Biology of the Cell 07/2012; 104(11):641-57. DOI:10.1111/boc.201200027
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