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Construction of IRX4-inducible system in pancreatic cancer cell lines, PK-1 and PK-9

ABSTRACT: Epigenetic gene silencing by aberrant DNA methylation is one of the important mechanisms leading to the loss of key cellular pathways in tumorigenesis. We have previously reported that IRX4 (Iroquois homeobox 4) was highly downregulated by promoter hypermethylation in pancreatic cancer cell lines as well as in resected primary pancreatic cancers. Based on these data, we have constructed a tetracycline-inducible IRX4 expressing system using pancreatic cancer cell lines PK-1 and PK-9. IRX4 induction significantly suppressed cell growth and caused apoptosis in both PK-1 and PK-9. Because IRX4 is a sequence-specific transcription factor, we tried to analyze IRX4 downstream events by performing microarray analyses using IRX4 inducible PK-1 cells with or without tetracycline. We found that IRX4 induction upregulated several genes that had tumor suppressive functions such as PRDM1, CRYAB, and IL32, and downregulated several genes that had oncogenic functions such as PTCH1, CD36, TFAP2C, and MUC4. These results suggest that DNA methylation-mediated silencing of IRX4 may contribute to pancreatic tumorigenesis through aberrant transcriptional regulation of cancer-related genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141246 | GEO | 2020/10/11

REPOSITORIES: GEO

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Project description:We hypothesized that the potential ability of the 18 kDa mitochondrial translocator protein (TSPO) to regulate gene expression may underlie its numerous reported functions, ranging from mitochondrial activity till mental disorders. Therefore, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 1 hr the TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. After 24 hrs primarily gene expression for enzymes and other proteins is changed. The associated gene products are known to affect various cellular functions: programmed cell death, cell cycle, viability, proliferation, migration, differentiation, development, tumorigenesis, and inflammatory / immune responses. Our microscopic studies showed intense TSPO mitochondrial labeling but no TSPO signal in the cell nuclei. Thus, it appears that the TSPO is part of the retrograde mitochondrial-nuclear signaling pathway for modulation of gene expression and thereby may exert its numerous effects on cell function, phenotype, and disease. U118MG cells (1.255 Ã 106) were seeded in Petri dishes (i.e. 28.5 Ã 103 cells / cm2) and allowed to proliferate for 3 days in full medium. Experiments for gene expression assayed with microarray typically consisted of three experimental groups and a vehicle control group (n = 3 for each group). Serum deprived medium was applied for 24 hrs, in the experimental groups ending with the inclusion a choice of various PK 11195 exposures i.e. either 1 hr, 3 hrs, or 24 hrs. Exposure to PK 11195 implies serum deprived medium with 1% alcohol (vehicle) and PK 11195 (25 ÂµM final concentration) for the required time period. 25 ÂµM of PK 11195 is the optimal concentration for these types of experiments with U118MG cells (Kugler et al., 2008). The cells were collected by trypsinization, washed by centrifugation in phosphate buffered saline (PBS) (400 Ã g, 5 min), and lysed [RLT lysis buffer provided with the RNeasy Mini Kit diluted with Î²-mercaptoethanol (1 : 100)], according to the manufacturer's instructions. Lysates were stored at -70oC.

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Construction of IRX4-inducible system in pancreatic cancer cell lines, PK-1 and PK-9

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