Diversity of gene expression in adenocarcinoma of the lung

Garber, Mitchell E.; Troyanskaya, Olga G.; Schluens, Karsten; Petersen, Simone; Thaesler, Zsuzsanna; Pacyna-Gengelbach, Manuela; Rijn, Matt van de; Rosen, Glenn D.; Perou, Charles M.; Whyte, Richard I.; Altman, Russ B.; Brown, Patrick O.; Botstein, David; Petersen, Iver

doi:10.1073/pnas.241500798

Cited by 1,131 publications

(890 citation statements)

References 27 publications

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“…The modulation of its expression has been revealed in numerous developmental, physiological and pathological processes. Recently, STC1 has also been reported to be induced in a variety of tumors including the breast (McCudden et al, 2004), colon (Gerritsen et al, 2002), ovary (Ismail et al, 2000), lung cancer (Garber et al, 2001), thyroid medullary carcinoma (Watanabe et al, 2002), hepatocarcinoma (Okabe et al, 2001), pheochromocytoma (Eisenhofer et al, 2004), neuroblastoma (Wong et al, 2002), osteosarcoma and fibrosarcoma (Jellinek et al, 2000). The possible use of STC1 expression levels for the diagnosis of human breast, hepatocellular and colorectal cancer has also been proposed (Fujiwara et al, 2000;Wascher et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Regulation of microRNA expression by HMGA1 proteins

et al. 2009

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The High Mobility Group proteins HMGA1 are nuclear architectural factors that play a critical role in a wide range of biological processes. Since recent studies have identified the microRNAs (miRNAs) as important regulators of gene expression, modulating critical cellular functions such as proliferation, apoptosis and differentiation, the aim of our work was to identify the miRNAs that are physiologically regulated by HMGA1 proteins. To this purpose, we have analysed the miRNA expression profile of mouse embryonic fibroblasts (MEFs) carrying two, one or no Hmga1 functional alleles using a microarray (miRNA microarray). By this approach, we found a miRNA expression profile that differentiates Hmga1-null MEFs from the wild-type ones. In particular, a significant decrease in miR-196a-2, miR-101b, miR-331 and miR-29a was detected in homozygous Hmga1-knockout MEFs in comparison with wild-type cells. Consistently, these miRNAs are downregulated in most of the analysed tissues of Hmga1-null mice in comparison with the wild-type mice. ChIP assay shows that HMGA1 is able to bind regions upstream of these miRNAs. Moreover, we identified the HMGA2 gene product as a putative target of miR-196a-2, suggesting that HMGA1 proteins are able to downregulate the expression of the other member of the HMGA family through the regulation of the miR-196a-2 expression. Finally, ATXN1 and STC1 gene products have been identified as targets of miR-101b. Therefore, it is reasonable to hypothesize that HMGA1 proteins are involved in several functions by regulating miRNA expression.

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Section: Discussionmentioning

confidence: 99%

Regulation of microRNA expression by HMGA1 proteins

et al. 2009

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“…This would suggest that such cells may be compensating for high levels of RAS oncoprotein signaling by increasing MTH1 levels to enhance detoxification of an oxidative lesion that contributes to the DDR and senescence induction (Moiseeva et al, 2009;Rai et al, 2009). Indeed, analysis of the ONCOMINE data sets indicates that MTH1 levels are significantly elevated in pancreatic adenocarcinomas and in nonsmall cell lung carcinomas, two human cancer types characterized by endogenous RAS mutations (Garber et al, 2001;Buchholz et al, 2005). Taken together, these various observations indicate that the oxidative stress and senescence response elicited by the RAS oncoprotein acts in large part through oxidation of substrates within the guanine deoxynucleotide pool, and that the resulting incorporation of oxidized dNTPs explains the DDR evoked as part of the resulting oncogenic RAS-induced senescence.…”

Section: Resultsmentioning

confidence: 99%

Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

et al. 2010

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Approximately 20% of tumors contain activating mutations in the RAS family of oncogenes. As tumors progress to higher grades of malignancy, the expression of oncogenic RAS has been reported to increase, leading to an oncogene-induced senescence (OIS) response. Evasion of this senescence barrier is a hallmark of advanced tumors indicating that OIS serves a critical tumorsuppressive function. Induction of OIS has been attributed to either RAS-mediated production of reactive oxygen species (ROS) or to induction of a DNA damage response (DDR). However, functional links between these two processes in triggering the senescent phenotype have not been explicitly described. Our previous work has shown that, in cultured untransformed cells, preventing elimination of oxidized guanine deoxyribonucleotides, which was achieved by suppressing expression of the cellular 8-oxodGTPase, human MutT homolog 1 (MTH1), sufficed to induce a DDR as well as premature senescence. Here, we demonstrate that overexpression of MTH1 can prevent the oncogenic H-RAS-induced DDR and attendant premature senescence, although it does not affect the observed elevation in ROS levels produced by RAS oncoprotein expression. Conversely, we find that loss of MTH1 preferentially induces an in vitro proliferation defect in tumorigenic cells overexpressing oncogenic RAS. These results indicate that the guanine nucleotide pool is a critical target for intracellular ROS produced by oncogenic RAS and that RAS-transformed cells require robust MTH1 expression to proliferate.

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“…Lung adenocarcinomas can form centrally but they tend to be associated with the epithelia of the peripheral airways. Recently, it has been suggested that adenocarcinoma can be classified into two distinct subtypes on the basis of gene expression patterns (Bhattacharjee et al, 2001;Garber et al, 2001). These two subtypes may be delineated by TTF (thyroid transcription factor)-1 expression, which is a lineage marker for peripheral airway cells, including type I and II pneumocytes (Yatabe et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas

et al. 2004

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S100A2 gene products were shown to be frequently and dramatically over-represented in non-small cell lung cancer (NSCLC) lesions over normal tissue by microarray analysis. We have now analysed an independent series of NSCLC tumours and multiple matched normal bronchial epithelial sites by RT -PCR and immunohistochemistry to investigate: whether this expression pattern can be confirmed and whether elevated expression is associated with tumour histology, clinical outcome or preneoplasia. In this second series, S100A2 was strongly expressed in 76% (35 out of 46) of tumours, more frequently in squamous cell than adenocarcinomas (Po0.002). This strong expression was not related to high-level gene amplification, but was associated in one of five informative cases with an allele-specific imbalance in transcript levels. Most tumours strongly expressed the DNp63 transcript, the product of which is a putative regulator of S100A2 transcription and while all but one of the tumours positive for DNp63 expressed S100A2, others negative for this regulator also expressed the gene. Contrary to the hypothesis that S100A2 is a tumour suppressor, no somatic mutations were identified in the coding sequence in 44 tumours. Furthermore, an examination of multiple tumour-free epithelial sites from 20 patients showed that strong expression was often associated with increasing levels of disorder in preinvasive bronchial lesions (Po0.0001).

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Diversity of gene expression in adenocarcinoma of the lung

Cited by 1,131 publications

References 27 publications

Regulation of microRNA expression by HMGA1 proteins

Regulation of microRNA expression by HMGA1 proteins

Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas

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