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| Home > Publications database > Plakophilin 1 deficiency in prostatic tumors is correlated with immune cell recruitment and controls the up-regulation of cytokine expression post-transcriptionally. |
| Home > Publications database > Plakophilin 1 deficiency in prostatic tumors is correlated with immune cell recruitment and controls the up-regulation of cytokine expression post-transcriptionally. |
| Journal Article | DKFZ-2022-02870 |
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2023
Wiley-Blackwell
Oxford [u.a.]
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Please use a persistent id in citations: doi:10.1111/febs.16680
Abstract: Plakophilin (PKP1) 1 is a member of the arm-repeat family of catenins and acts as structural component of desmosomes, which are important stabilizers of cell-cell adhesion. Besides this, PKP1 also occurs in a non-junctional, cytoplasmic form contributing to post-transcriptional regulation of gene expression. Moreover, PKP1 is expressed in prostate epithelium but its expression is frequently downregulated in prostate cancers with a more aggressive phenotype. This observation may imply a tumor-suppressive role of PKP1. We found that, in prostatic adenocarcinomas with PKP1 deficiency, the occurrence of T-cells, B-cells, macrophages and neutrophils was significantly increased. In a PKP1-deficient prostatic cancer cell line expressing IL8, these levels were statistically meaningfully reduced upon PKP1 re-expression. When analyzing prostatic PKP1-knockdown cell lines, the mRNA and protein levels of additional cytokines, namely CXCL1 and IL6, were upregulated. The effect was rescued upon re-expression of a PKP1 RNAi-resistant form. The corresponding mRNAs were co-precipitated with cytoplasmic PKP1, indicating that they are components of PKP1-containing mRNA ribonucleoprotein particles. Moreover, the mRNA half-lives of CXCL1, IL8 and IL6 were significantly increased in PKP1-deficient cells, showing that these mRNAs were stabilized by PKP1. In an in vitro migration assay, the higher cytokine concentrations led to higher migration rates of THP1 and PBMC cells. This finding implies that PKP1 loss of expression in vivo correlates with recruitment of immune cells into the tumor area to set up a tumor-specific environment. One may speculate that this newly established tumor environment has tumor-suppressive characteristics and thereby accelerates tumor progression and metastasis.
Keyword(s): Prostate cancer ; cytokine mRNA stability ; immune cell recruitment ; plakophilin 1 ; tumor environment
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