Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma

Kopantzev, E. P.; Monastyrskaya, G.S.; Виноградова, Т В; Zinovyeva, M. V.; Костина, М. Б.; Filyukova, O. B.; Tonevitsky, Alexander G.; Сухих, Г. Т.; Свердлов, Е. Д.

doi:10.1016/j.lungcan.2008.02.011

Cited by 85 publications

(65 citation statements)

References 69 publications

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“…Striking overlaps exist between genes involved in development and cancer (Kho et al 2004;Liu et al 2006;Ben-Porath et al 2008;Kopantzev et al 2008). All three transcription factors in this study are well-established developmental regulators.…”

Section: Discussionmentioning

confidence: 68%

Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis

Gocheva

Oudin

et al. 2015

Genes Dev.

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Despite the fact that the majority of lung cancer deaths are due to metastasis, the molecular mechanisms driving metastatic progression are poorly understood. Here, we present evidence that loss of Foxa2 and Cdx2 synergizes with loss of Nkx2-1 to fully activate the metastatic program. These three lineage-specific transcription factors are consistently down-regulated in metastatic cells compared with nonmetastatic cells. Knockdown of these three factors acts synergistically and is sufficient to promote the metastatic potential of nonmetastatic cells to that of naturally arising metastatic cells in vivo. Furthermore, silencing of these three transcription factors is sufficient to account for a significant fraction of the gene expression differences between the nonmetastatic and metastatic states in lung adenocarcinoma, including up-regulated expression of the invadopodia component Tks5 long , the embryonal protooncogene Hmga2, and the epithelial-to-mesenchymal mediator Snail. Finally, analyses of tumors from a genetically engineered mouse model and patients show that low expression of Nkx2-1, Foxa2, and Cdx2 strongly correlates with more advanced tumors and worse survival. Our findings reveal that a large part of the complex transcriptional network in metastasis can be controlled by a small number of regulatory nodes that function redundantly, and loss of multiple nodes is required to fully activate the metastatic program.[Keywords: lung adenocarcinoma; metastasis; Nkx2-1; Foxa2; Cdx2; genetically engineered mouse model of cancer] Supplemental material is available for this article.

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Section: Discussionmentioning

confidence: 68%

Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis

Gocheva

Oudin

et al. 2015

Genes Dev.

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“…INMT is widely distributed in mammalian tissues (52), especially in the lung and testis. INMT gene expression has been linked to cancer: gene expression was downregulated in non-small cell lung cancer (53) and in more aggressive forms of metastatic prostate cancer (54), whereas it was upregulated in the uterus of mice with loss of phosphatase and tensin homolog (PTEN; the earliest detectable genetic lesion in the endometrioid subtype of endometrial cancer) together with the activation of several ER-a-dependent pathways (55). Whether or not the role of INMT in cancer is dependent on its function in selenium metabolism needs to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Selenium metabolism to the trimethylselenonium ion (TMSe) varies markedly because of polymorphisms in the indolethylamine N-methyltransferase gene

Kuehnelt

Engström

Skröder

et al. 2015

The American Journal of Clinical Nutrition

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Background: Selenium is an essential element, but its metabolism in humans is not well characterized. A few small studies indicate that the trimethylselenonium ion (TMSe) is a common selenium metabolite in humans.Objective: This study aimed to elucidate the human metabolism of selenium to TMSe. Design: Study individuals constituted subsamples of 2 cohorts: 1) pregnant women (n = 228) and their 5-y-old children (n = 205) in rural Bangladesh with poor selenium status [median urinary selenium (U-Se): 6.4 mg/L in mothers, 14 mg/L in children] and 2) women in the Argentinian Andes (n = 83) with adequate selenium status (median U-Se: 24 mg/L). Total U-Se and blood selenium were measured by inductively coupled plasma mass spectrometry (ICPMS), and urinary concentrations of TMSe were measured by high-performance liquid chromatography/vapor generation/ICPMS. A genomewide association study (GWAS) was performed for 1,629,299 (after filtration) single nucleotide polymorphisms (SNPs) in the Bangladeshi women (n = 72) by using Illumina Omni5M, and results were validated by using real-time polymerase chain reaction. Results: TMSe "producers" were prevalent (approximately onethird) among the Bangladeshi women and their children, in whom TMSe constituted w10-70% of U-Se, whereas "nonproducers" had, on average, 0.59% TMSe. The TMSe-producing women had, on average, 2-mg U-Se/L higher concentrations than did the nonproducers. In contrast, only 3 of the 83 Andean women were TMSe producers (6-15% TMSe in the urine); the average percentage among the nonproducers was 0.35%. Comparison of the percentage of urinary TMSe in mothers and children indicated a strong genetic influence. The GWAS identified 3 SNPs in the indolethylamine Nmethyltransferase gene (INMT) that were strongly associated with percentage of TMSe (P , 0.001, false-discovery rate corrected) in both cohorts. Conclusions: There are remarkable population and individual variations in the formation of TMSe, which could largely be explained by SNPs in INMT. The TMSe-producing women had higher U-Se concentrations than did nonproducers, but further elucidation of the metabolic pathways of selenium is essential for the understanding of its role in human health. The MINIMat trial was registered at isrctn.org as ISRCTN16581394.Am J Clin Nutr 2015;102:1406-15.

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“…NaPi2b is a multitransmembrane, sodium-dependent phosphate transporter (7), which is expressed in human lung, ovarian, and thyroid cancers (8,9). As a member of the SLC34 solute carrier protein family (10), it is responsible for transcellular inorganic phosphate absorption and maintenance of phosphate homeostasis (7,11,12) and has been associated with cell differentiation (13) and tumorigenesis (14). The differential expression in tumor relative to most normal tissues, cell-surface localization, and endocytosis makes it a promising target for ADC therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Development of an Anti-NaPi2b (SLC34A2) Antibody–Drug Conjugate as a Therapeutic for Non–Small Cell Lung and Ovarian Cancers

Lin¹,

Rubinfeld²,

Zhang³

et al. 2015

Clinical Cancer Research

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Purpose: Antibody-drug conjugates (ADC) selectively deliver a cytotoxic drug to cells expressing an accessible antigenic target. Here, we have appended monomethyl auristatin E (MMAE) to an antibody recognizing the SLC34A2 gene product NaPi2b, the type II sodium-phosphate cotransporter, which is highly expressed on tumor surfaces of the lung, ovary, and thyroid as well as on normal lung pneumocytes. This study evaluated its efficacy and safety in preclinical studies.Experimental Design: The efficacy of anti-NaPi2b ADC was evaluated in mouse ovarian and non-small cell lung cancer (NSCLC) tumor xenograft models, and its toxicity was assessed in rats and cynomolgus monkeys.Results: We show here that an anti-NaPi2b ADC is effective in mouse ovarian and NSCLC tumor xenograft models and well-tolerated in rats and cynomolgus monkeys at levels in excess of therapeutic doses. Despite high levels of expression in normal lung of non-human primate, the crossreactive ADC exhibited an acceptable safety profile with a dose-limiting toxicity unrelated to normal tissue target expression. The nonproliferative nature of normal pneumocytes, together with the antiproliferative mechanism of MMAE, likely mitigates the potential liability of this normal tissue expression.Conclusions: Overall, our preclinical results suggest that the ADC targeting NaPi2b provides an effective new therapy for the treatment of NSCLC and ovarian cancer and is currently undergoing clinical developments.

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Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma

Cited by 85 publications

References 69 publications

Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis

Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis

Selenium metabolism to the trimethylselenonium ion (TMSe) varies markedly because of polymorphisms in the indolethylamine N-methyltransferase gene

Preclinical Development of an Anti-NaPi2b (SLC34A2) Antibody–Drug Conjugate as a Therapeutic for Non–Small Cell Lung and Ovarian Cancers

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