Gene expression analysis of terminal differentiation of human melanoma cells highlights global reductions in cell cycle-associated genes

Huynh, Kim; Kim, Gyoungmi; Kim, Dong Joon; Yang, Suk–Jin; Park, Seong-min; Yeom, Young‐Il; Fisher, Paul B.; Kang, Dong‐Chul

doi:10.1016/j.gene.2008.11.013

Cited by 19 publications

(18 citation statements)

References 33 publications

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“…Many genes playing important roles in apoptosis were down-regulated during tumor progress (11)(12)(13). In this study, we show for the first time that NAIF1 is down-regulated or the expression was lost in gastric cancer tissue.…”

Section: Discussionmentioning

confidence: 63%

NAIF1 is down-regulated in gastric cancer and promotes apoptosis through the caspase-9 pathway in human MKN45 cells

Luo

Zhao²,

Zhong³

et al. 2011

Oncol Rep

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Abstract. Many key proteins are down-regulated or lose their function during cancer genesis and accelerate the progress of cancer. We found that nuclear apoptosis-inducing factor 1 (nAIF1) was highly expressed in normal gastric tissues but was down-regulated or lost in gastric cancer tissues (p<0.001). nAIF1 expression was higher in well-differentiated (p=0.004) than in moderately-or poorly-differentiated gastric cancer. nAIF1 expression was associated with different t stages (p=0.024). In vitro, nAIF1 can inhibit tumor cell proliferation and induce g0/g1 phase cell cycle arrest in the MKn45 cell line. nAIF1 can induce apoptosis through activation of procaspase-9 rather than procaspase-8 followed by activation of the caspase-3 pathway. We designed and constructed two truncation mutants, pegFpn1-nls and pegFp-n1-grr, and identified the n-terminal 1-90 amino acid domain of nAIF1, which is a helix-turn-helix motif and which was sufficient for inducing apoptosis. Therefore, these findings suggest that NAIF1 plays an inhibitory role in the initial steps of gastric cancer genesis and may provide new strategies for developing anti-cancer drugs using small molecular polypeptides. Introductiongastric cancer is a highly frequent malignancy worldwide with an estimated incidence of 934000 new cases per year in 2002 (1,2). More than 42% of gc patients are found in china alone (3). currently, targeted therapies designed to induce apoptosis in cancer cells selectively are the most promising anti-cancer strategies. Many efforts have been made to cure gastric cancer, most of which based on developing effective apoptotic therapeutic approaches such as activation of cell surface death receptors, inhibition of cell survival signaling and others (4-6).nAIF1 (nuclear apoptosis-inducing factor 1) was found to induce apoptosis when overexpressed in Hela and HeK293 cells (7). Another study showed nAIF1 was related to transposition because of its trihelix motif (8). However, little information exists on the relationship between nAIF1 and cancer genesis and progress, thus this study investigated the expression and function of nAIF1 in cancer.We found nAIF1 was highly expressed in normal stomach tissue, but was down-regulated or lost in gastric cancer tissue (P<0.001). This event significantly correlated with the tumor differential t stage. Functional studies indicated nAIF1 can reduce cell viability in human gastric cell line MKn45 by g0/g1 phase cell cycle arrest and induce apoptosis 48 h posttransfection. Western blot analysis indicated nAIF1 triggered procaspase-3 and procaspase-9 activation and pArp cleavage in MKN45. Furthermore, we identified that the 1-90 amino acids domain was the core functional domain of nAIF1 for inducing apoptosis. Thus, our findings provide a potential target for gc apoptotic therapeutic approach. Materials and methodsReagents. Mtt, pI and DApI were purchased from sigma (UsA). Monoclonal antibody against β-actin was purchased from sigma-Aldrich (UsA). the antibody against pArp and procaspase-8 were purchased ...

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Section: Discussionmentioning

confidence: 63%

NAIF1 is down-regulated in gastric cancer and promotes apoptosis through the caspase-9 pathway in human MKN45 cells

Luo

Zhao²,

Zhong³

et al. 2011

Oncol Rep

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“…AURKA overexpression may play a role in tumor development and progression via promoting cancer cell survival, stimulating the PI3K pathway and activating Akt [38]. Additionally, AU-RKA has been down-regulated in differentiation of metastatic HO-1 human melanoma cells, and therefore contributes to HO-1 cell proliferation [39]. Notably, TOP2A is considered as an oncogene in tumor and significantly involved in cell cycle, thus associated with tumor cell growth, proliferation and migration [40].…”

Section: Discussionmentioning

confidence: 99%

Identification of potential therapeutic targets for melanoma using gene expression analysis

Quan¹,

Shi²,

Tian³

et al. 2015

neo

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Metastatic melanoma represents a significant cause of death in patients with melanoma and the frequency is increasing. The aim of this study was to identify potential therapeutic targets for metastatic melanoma.Gene expression profile GSE44660 was downloaded from Gene Expression Omnibus database. A total of 22 samples were analyzed in our study, including 3 specimens of normal melanocytes, 12 specimens of melanoma LNM (lymph node metastasis) and 7 specimens of MBM (melanoma brain metastasis). DEGs (differentially expressed genes) in LNM and MBM were identified respectively using Limma package. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways analyses of common DEGs between two comparison groups were performed using DAVID, followed by cancer-related genes and transcription factor analysis. PPI (protein-protein interaction) network was constructed by STRING, and significant key genes were selected.Totally, 401 common DEGs were identified. Disease analysis showed that ICAM1 (intercellular adhesion molecule 1) and NBN (nibrin) were related to melanoma. In the PPI network, BIRC5 (baculoviral IAP repeat containing 5), BUB1 (BUB1 mitotic checkpoint serine/threonine kinase), GMNN (geminin, DNA replication inhibitor), AURKA (aurora kinase A), TOP2A (topoisomerase (DNA) II alpha) and BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B) were with higher degree more than 50.ICAM1, NBN, BIRC5, BUB1, BUB1B, GMNN, AURKA and TOP2A may play key roles in the progression and development of melanoma. They may be used as specific therapeutic targets in the treatment of metastatic melanoma. However, further experiments are still needed to confirm our results.

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“…Functional characterization of the mda genes including mda-5/IFIH1, mda-6/p21 syntenin, and hPNPase confirms their important contribution to terminal differentiation and other key physiological processes (Jiang et al, 1995(Jiang et al, , 1996Kang et al, 2002;Leszczyniecka et al, 2002). Recently, microarray analysis of gene expression during terminal differentiation identified 44 down-regulated and 166 up-regulated genes (Huynh et al, 2009). Among the downregulated genes, approximately 34%, including FOXM1, are directly involved in cell cycle progression, suggesting that suppression of defined genes potentially contribute to growth inhibition during induction of differentiation.…”

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confidence: 88%

“…Suppression of FOXM1 expression during terminal differentiation of HO-1 cells (Huynh et al, 2009) could result in decreased expression of cell cycle-associated genes, which, in turn, should interfere with cell cycle progression. Although the mechanism of FOXM1 activation and its role in cell cycle progression have been intensively studied, the precise mechanism of FOXM1 regulation is not fully clarified.…”

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confidence: 99%

FOXM1 expression mediates growth suppression during terminal differentiation of HO‐1 human metastatic melanoma cells

Huynh

Soh

Dash

et al. 2010

Journal Cellular Physiology

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Induction of terminal differentiation represents a potentially less toxic cancer therapy. Treatment of HO-1 human metastatic melanoma cells with IFN-β plus mezerein (MEZ) promotes terminal differentiation with an irreversible loss of growth potential. During this process, the transcription factor FOXM1 is down-regulated potentially inhibiting transactivation of target genes including those involved in G(2)/M progression and cell proliferation. We investigated the mechanism of FOXM1 down-regulation and its physiological role in terminal differentiation. Genetic and pharmacological studies revealed that FOXM1 down-regulation was primarily caused by MEZ activation of PKCα and co-treatment with IFN-β plus MEZ augmented the effect of PKCα. Promoter analysis with a mutated E-box on the FOXM1 promoter, and in vitro and in vivo binding assays confirm a direct role of c-Myc on FOXM1 expression. Reduction of c-Myc and overexpression of Mad1 by IFN-β plus MEZ treatment should cause potent and persistent reduction of FOXM1 expression during terminal differentiation. Overexpression of FOXM1 restored expression of cell cycle-associated genes and increased the proportion of cells in the S phase. Our experiments support a model for terminal differentiation in which FOXM1 down-regulation via activation of PKCα followed by suppression of c-Myc expression, are causal events in promoting growth inhibition during terminal differentiation.

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Gene expression analysis of terminal differentiation of human melanoma cells highlights global reductions in cell cycle-associated genes

Cited by 19 publications

References 33 publications

NAIF1 is down-regulated in gastric cancer and promotes apoptosis through the caspase-9 pathway in human MKN45 cells

NAIF1 is down-regulated in gastric cancer and promotes apoptosis through the caspase-9 pathway in human MKN45 cells

Identification of potential therapeutic targets for melanoma using gene expression analysis

FOXM1 expression mediates growth suppression during terminal differentiation of HO‐1 human metastatic melanoma cells

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