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Gene expression changes induced by LKB1 expression in human lung adenocarcinoma cell lines

ABSTRACT: LKB1 is a tumor suppressor lost in approximately 30% of lung adenocarcinomas. It is a serine-threonine kinase involved in regulating metabolism, proliferation, and cell polarity. We have characterized its association with mRNA expression profiles in resected tumors and in cell lines, but little is known about the direct effects of LKB1 on the regulation of these genes. This study investigates the effects of LKB1 activity on mRNA expression in two LKB1-mutant lung adenocarcinoma cell lines, H2122 and A549. Wild-type LKB1 has been stably expressed in these cell lines using a pBABE retrovirus as well as an empty pBABE control and a kinase-dead mutant of LKB1 (K78I) control (Addgene). Samples submitted are two cell lines, three experimental conditions, and three replicates, for a total of 17 samples (one sample was excluded for poor RNA quality). Gene expression of these samples are analyzed to determine transcriptional regulatory effects of LKB1 expression. Results of this analysis are compared to our analysis of resected human tumors to determine gene patterns that are differentially expressed between LKB1-deficient and LKB1-wild-type tumors whose expression is also affected by restoration of LKB1 in vitro. RMA gene expression was taken from two cell lines stably expressing LKB1 or controls of K78I mutant LKB1 or empty pBABE vector. Log2 average expression differences are calculated and compared to results from analysis of gene expression associated with LKB1 loss in resected human tumors.

ORGANISM(S): Homo sapiens

SUBMITTER: David Carbone

PROVIDER: E-GEOD-51266 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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LKB1 modulates lung cancer differentiation and metastasis

Project description:Inherited mutation in LKB1 results in the Peutz-Jeghers syndrome (PJS), characterized by intestinal hamartomas and a modestly increased frequency of gastrointestinal and breast cancer1. Somatic inactivation of LKB1 occurs in human lung adenocarcinoma2-4, but its tumor suppressor role in this tissue is unknown. Here we show that somatic Lkb1 deficiency strongly cooperates with somatic K-rasG12D activating mutation to accelerate the development of mouse lung tumorigenesis. Lkb1 deficiency in the setting of K-rasG12D mutation (K-ras Lkb1L/L) was associated with decreased tumor latency and increased tumor aggressiveness including metastasis. Furthermore, tumors from K-ras Lkb1L/L mice demonstrated histologies--squamous, adenosquamous and large cell--not seen with K-rasG12D mutation, Ink4a/Arf inactivation, or p53 inactivation alone or in combination. Experiments in vitro suggest that LKB1 suppresses lung tumorigenesis and progression through both p16INK4a-ARF-p53 dependent and independent mechanisms. These data indicate that LKB1 regulates lung tumor progression and differentiation. Keywords: cancer research To analyze the role of LKB1 in lung cancer progression and differentiation, we have dissected the lung tumors from mice with/without lkb1 loss and performed the microarray analyses to compare their gene expression pattern. In addition, we have also performed microarray analysis in both A549 and H2126 cell lines after reconsistitution of either wt-lkb1 or the kinase dead form of lkb1 (lkb1-KD) to confirm what we observed from in vivo studies.

2007-08-28 | E-GEOD-6135 | biostudies-arrayexpress

Gene expression changes induced by LKB1 expression in human lung adenocarcinoma cell lines

Project description:LKB1 is a tumor suppressor lost in approximately 30% of lung adenocarcinomas. It is a serine-threonine kinase involved in regulating metabolism, proliferation, and cell polarity. We have characterized its association with mRNA expression profiles in resected tumors and in cell lines, but little is known about the direct effects of LKB1 on the regulation of these genes. This study investigates the effects of LKB1 activity on mRNA expression in two LKB1-mutant lung adenocarcinoma cell lines, H2122 and A549. Wild-type LKB1 has been stably expressed in these cell lines using a pBABE retrovirus as well as an empty pBABE control and a kinase-dead mutant of LKB1 (K78I) control (Addgene). Samples submitted are two cell lines, three experimental conditions, and three replicates, for a total of 17 samples (one sample was excluded for poor RNA quality). Gene expression of these samples are analyzed to determine transcriptional regulatory effects of LKB1 expression. Results of this analysis are compared to our analysis of resected human tumors to determine gene patterns that are differentially expressed between LKB1-deficient and LKB1-wild-type tumors whose expression is also affected by restoration of LKB1 in vitro.

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Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

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Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

Project description:Excessive glucose production in the liver is a key factor in the hyperglycemia observed in diabetes mellitus type 2. It is generally agreed to result from an increase in hepatic gluconeogenesis. Considerable attention has been devoted to the transcriptional regulation of key gluconeogenic enzymes, but much less is known about the regulation of amino-acid catabolism, which generates gluconeogenic substrates. Here, we highlight a novel role of LKB1 in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect was observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion was associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic and pharmacological approaches, we identified the aminotransferases and specifically, Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis. The present dataset is from the phosphoproteomic analysis of fasting mice in a study where a global quantitative analysis ( PXD013478 ) is also described in the same publication.

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