PLD1 promotes tumor invasion by regulation of MMP-13 expression via phosphorylation of NF-kB in bladder cancer
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ABSTRACT:
PROVIDER: PRJNA698962 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13612400_1.fastq.gz | Fastqsanger.gz | |||
| SRR13612400_2.fastq.gz | Fastqsanger.gz | |||
| SRR13612401_1.fastq.gz | Fastqsanger.gz | |||
| SRR13612401_2.fastq.gz | Fastqsanger.gz | |||
| SRR13612402_1.fastq.gz | Fastqsanger.gz |
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Project description:Invasion of bladder cancer (BC) cells from the mucosa into the muscle layer is canonical for BC progression while phospholipase D isoform 1 (PLD1) is known to mediate development of cancer through phosphatidic acid (PA) production. We therefore used in silico, in vitro and in vivo approaches to detail the effect of PLD1 on BC invasion. In BC patients, higher levels of PLD1 expression were associated with poor prognosis. PLD1 knockdown significantly suppressed cellular invasion by human BC cells and matrix metalloproteinase-13 (MMP-13) was observed to be an invasion mediator gene. In our mouse bladder carcinogenesis model, the development of invasive BCs was suppressed by PLD1 knockout and a global transcriptomic analysis in this model indicated MMP-13 as a potential tumor invasion gene with NF-kB (nuclear factor-kB) as its transcription regulator. Furthermore, PA administration increased both MMP-13 expression and NF-kB p65 phosphorylation levels. Collectively, we demonstrate that PLD1 promotes tumor invasion of BC by regulation of MMP-13 expression via phosphorylation of NF-kB p65. Our results suggest that PLD1 is a potential therapeutic target to prevent progression in BC patients.
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Project description:Aberrant regulation of NF-kB pathway is believed to be a major event contributing to malignant transformation and progression of prostate cancer (PCa). P65 consists of a DNA-binding and dimerization domain (RHD), nuclear localization signal (NLS) and transactivation domains (TA1 and TA2). The c-terminal 30 amino acids (TA1 domain) comprise the most important transactivation domain and NF-kB transactivation may be regulated by multiple phosphorylation in this domain. This p536 is located in TA1 domain and is conserved in human, mouse, chicken. We previously discovered that p536 is present in majority of PCa and associated with ERG expression indicating that ERG can significantly enhance phosphorylation of p65 at Ser536 in vivo. We have successfully generated a dominant negative (DN) p65 which has been mutated (S536A) such that it cannot be phosphorylated at Ser 536 and cannot carry out Ser536 phosphorylation dependent functions. We also generated two mutants S536D and S536E which are the phosphomimetic mutant that resembles phospho-p65 and can be detected by anti-phospho-p65 antibody. We carried out microarray studies and discovered a set of p536 regulated genes compared with wild type p65 regulated gene set.
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Project description:To address the role of NF-kB in aging in vivo, we utilized a well-characterized system that allows inducible and site-specific inhibition of NF-kB activity in murine skin. The hormone binding domain of the mutant estrogen receptor that is responsive to 4-hydroxytamoxifen (4-OHT) was fused to a mutant of p50 (IDNkB, inducible dominant negative NF-kB) that dimerizes with other NF-kB subunits but is unable to bind DNA, thus dominantly inhibiting NF-kB activity. Expression was driven within the basal layer of murine epidermis by the keratin 14 promoter in transgenic mice. To test whether NF-kB activity is required to maintain age-associated gene expression, we applied topical 4-OHT and ethanol vehicle (EtOH) for two weeks to the right (R) and left (L) dorsal flanks, respectively, of chronologically aged transgenic mice (O, 18-23 months). Young transgenic mice (Y, 1 month) were treated in parallel as control. Skin samples were harvested and analyzed for gene expression using mouse cDNA microarrays containing 35,217 elements, representing 18,880 unique genes. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
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