DKK3 protective role in prostate cancer is partly due to the modulation of immune-related pathways

      While it is considered one of the most common cancers and the leading cause of death in men worldwide, prognostic stratification and treatment modalities are still limited for patients with prostate cancer (PCa). Recently, the introduction of genomic profiling, as well as, the use of new techniques like next-generation sequencing (NGS) in many cancers provides novel tools for the discovery of new molecular targets that might improve our understanding of the genomic aberrations in PCa and the discovery of novel prognostic and therapeutic targets. In this study, we investigated the possible mechanisms through which Dickkopf-3 (DKK3) produces its possible protective role in prostate cancer using NGS in both the DKK3 overexpression PCa cell line (PC3) model, as well as, our patients’ cohort consisting of 9 prostate cancer and 5 benign prostatic hyperplasia. Interestingly, our results have shown that DKK3 transfection-modulated genes are involved in the regulation of cell motility, senescence-associated secretory phenotype (SASP), and cytokine signaling in the immune system, as well as, in the regulation of adaptive immune response. Further analysis of our NGS using our in vitro model revealed the presence of 36 differentially expressed genes between DKK3 transfected cells and PC3 empty vector. In addition, both CP and ACE2 genes were differentially expressed not only between the transfected and empty group but also between the transfected and mock cells. The top common differentially expressed genes (DEGs) between the DKK3 overexpression cell line and in our patients’ cohort showed the list of the following; IL32, IRAK1, RIOK1, HIST1H2BB, SNORA31, AKR1B1, ACE2 and CP. The upregulated genes including IL32, HIST1H2BB and SNORA31 showed tumor suppressor functions in various cancers including PCa. On the other hand, both IRAK1 and RIOK1 were downregulated and involved in tumor initiation, tumor progression, poor outcome and radiotherapy resistance.  Together, our results highlighted the possible role of the DKK3 related genes in protecting against PCa initiation and progression.</p

DataSheet_1_Genetic analysis of CFH and MCP in Egyptian patients with immune-complex proliferative glomerulonephritis.docx

Glomerulonephritis (GN) is a complex disease with intricate underlying pathogenic mechanisms. The possible role of underlying complement dysregulation is not fully elucidated in some GN subsets, especially in the setting of autoimmunity or infection. In the current study, diagnosed cases of lupus nephritis (LN) and post-infectious GN (PIGN) were recruited for molecular genetic analysis and targeted next-generation DNA sequencing was performed for two main complement regulating genes: in the fluid phase; CFH, and on tissue surfaces; MCP. Three heterozygous pathogenic variants in CFH (Q172*, W701*, and W1096*) and one likely pathogenic heterozygous variant in MCP (C223R) have been identified in four of the studied LN cases. Additionally, among the several detected variants of uncertain significance, one novel variant (CFH:F614S) was identified in 74% of the studied LN cases and in 65% of the studied PIGN cases. This variant was detected for the first time in the Egyptian population. These findings suggest that subtle mutations may be present in complement regulating genes in patients with immune-complex mediated category of GN that may add to the disease pathogenesis. These findings also call for further studies to delineate the impact of these gene variants on the protein function, the disease course, and outcome.</p