Profiling the Downstream Genes of Tumor Suppressor <i>PTEN</i> in Lung  Cancer Cells by Complementary DNA Microarray

Hong, Tse-Ming; Yang, Pan‐Chyr; Peck, Konan; Chen, Jeremy J.W.; Yang, Shuenn-Chen; Chen, Yen-Chu; Wu, Cheng‐Wen

doi:10.1165/ajrcmb.23.3.4002

Cited by 67 publications

(49 citation statements)

References 25 publications

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“…Of 709 genes identified to be suppressed by Pten overexpression or up-regulated due to Pten deficiency in the above mentioned papers, only Cyclin B1 (27,30) and MYBL2 (25,27) showed consistent results by more than one laboratory; whereas totally opposing results about Drg-1 were reported (25,27,31). Several possibilities could explain these discrepancies.…”

Section: Discussionmentioning

confidence: 96%

PTEN Deletion Leads to Up-regulation of a Secreted Growth Factor Pleiotrophin

Huo

et al. 2006

Journal of Biological Chemistry

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PTEN 4 (phosphatase and tensin homologue deleted on chromosome ten) is the first phosphatase identified as a tumor suppressor (1-3). Loss of function mutations or reduced expression of the PTEN gene are found at high frequencies in a wide variety of human tumors, including glioblastoma, as well as endometrial, prostate, colorectal, lung, and breast cancers. Experimental and clinical evidence demonstrate that PTEN is a critical tumor suppressor (4).PTEN acts primarily as a negative regulator of the phosphoinositide 3-kinase (PI3K) pathway by virtue of its lipid phosphatase activity (5-7). Loss of PTEN leads to an increase in the phosphatidylinositol 3-phosphate level, mimicking the effect of constitutive PI3K activation. Phosphatidylinositol 3-phosphate accumulation results in the activation of various protein kinases, including the PDK1 and PKB/AKT serine/threonine kinases. AKT is the central node in the PTEN-regulated pathway and activated AKT has been shown to promote cell cycle progression, cell growth, cell survival, cell migration, angiogenesis, protein synthesis, and glucose metabolism through phosphorylation of its substrates (8, 9).Aside from acting as a negative regulator of the PI3K pathway, which depends on its lipid phosphatase activity, PTEN also functions independently of its lipid phosphatase activity. Raftopoulou et al. (10) showed that PTEN inhibits cell migration through its C2 domain and dephosphorylates itself depending on its protein phosphatase activity. Freeman et al. (11) demonstrated that PTEN physically associates with p53 in the nucleus, which in turn stabilizes p53 and affects p53 protein levels and transcription activity. Recently, Okumura (12) reports that the PTEN C-terminal domain physically interacts with the oncogenic MSP58 protein and suppresses cell transformation induced by MSP58 expression, independent of its catalytically activity.To further understand the biological functions of PTEN, we undertook an unbiased approach by comparing gene expression profiles of a Pten Ϫ/Ϫ mouse embryonic fibroblast (MEF) cell line with that of its isogenic counterpart (11, 13) using microarray technology. Among genes that are differentially expressed in these cell lines, we found that pleiotrophin (Ptn) was up-regulated in the Pten Ϫ/Ϫ MEFs as well as mammary tumor tissues of Pten conditional knock-out mice (14). Further experiments indicated that the expression of Ptn was regulated by the PI3K pathway, and Ptn overexpression contributes to tumorigenesis caused by PTEN loss. Microarray Analysis-Mouse cDNA microarrays containing 8,928 elements were printed by the UCLA Microarray Core Facility. Total RNA was isolated using TRIzol reagent (Invitrogen) according to the manufacturer's instructions. MATERIALS AND METHODS Cell Culture and Generation of Immortalized Fibroblasts-Fibro-For probe labeling and microarray hybridization, a protocol published by Xiang et al. (15) was adopted with minor modifications. Briefly, cDNA probes that incorporate aminoallyl-dUTP (aa-dUTP; Sigma) were synthesized...

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Section: Discussionmentioning

confidence: 96%

PTEN Deletion Leads to Up-regulation of a Secreted Growth Factor Pleiotrophin

Huo

et al. 2006

Journal of Biological Chemistry

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“…It is reported that both IL4 and IL13 share signalling events in human colon carcinoma cell lines (HT29 and WiDr), and that both IL13 and IL4 induce phosphorylation of IL4 STAT (STAT6) (Murata et al, 1996;Terabe et al, 2000). The leukocyte elastase inhibitor is one of the possible target genes of PTEN (Hong et al, 2000). Up-regulation of leukocyte elastase inhibitor is thought to protect cancer cells from damage by immune cells, so that weakness of the IL13 -IL4 Stat signalling pathway would allow cancer cells to escape from the immune response of the host.…”

Section: Genes Related To Immunitymentioning

confidence: 99%

Differential gene expression profiles of gastric cancer cells established from primary tumour and malignant ascites

et al. 2002

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Advanced gastric cancer is often accompanied by metastasis to the peritoneum, resulting in a high mortality rate. Mechanisms involved in gastric cancer metastasis have not been fully clarified because metastasis involves multiple steps and requires a combination of altered expressions of many different genes. Thus, independent analysis of any single gene would be insufficient to understand all of the aspects of gastric cancer peritoneal dissemination. In this study, we performed a global analysis of the differential gene expression of a gastric cancer cell line established from a primary main tumour (SNU-1) and of other cell lines established from the metastasis to the peritoneal cavity (SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB). The application of a high-density cDNA microarray method made it possible to analyse the expression of approximately 21 168 genes. Our examinations of SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB showed that 24 genes were upregulated and 17 genes down-regulated besides expression sequence tags. The analysis revealed the following altered expression such as: (a) up-regulation of CD44 (cell adhesion), keratins 7, 8, and 14 (epitherial marker), aldehyde dehydrogenase (drug metabolism), CD9 and IP3 receptor type3 (signal transduction); (b) down-regulation of IL2 receptor g, IL4-Stat (immune response), p27 (cell cycle) and integrin b4 (adhesion) in gastric cancer cells from malignant ascites. We then analysed eight gastric cancer cell lines with Northern blot and observed preferential up-regulation and down-regulation of these selected genes in cells prone to peritoneal dissemination. Reverse transcriptase -polymerase chain reaction confirmed that several genes selected by DNA microarray were also overexpressed in clinical samples of malignant ascites. It is therefore considered that these genes may be related to the peritoneal dissemination of gastric cancers. The results of this global gene expression analysis of gastric cancer cells with peritoneal dissemination, promise to provide a new insight into the study of human gastric cancer peritoneal dissemination.

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“…Established cell lines, tumor derived primary cell cultures, and immunopurified cells procured through tissue dissociation and cell sorting have been studied as surrogates. [10][11][12][13][14][15][16] However, such studies are limited by flaws related to artificial in vitro conditions, prolonged propagation, and/or stressful purification procedures, all of which are expected to induce marked changes in the transcriptome, as cells are deprived from their natural metabolic, paracrine, endocrine and immune milieu, and lose critical adhesive interactions affecting their function in the tumor microenvironment.…”

mentioning

confidence: 99%