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Molecular Mediator of Prostate Cancer Progression and Its Implication in Therapy
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam, Kaustubh Datta
Mutations in spop (Speckle-type POZ protein) gene (6-15% of PCa) represents a subclass of fusion-negative PCa patients with poor prognosis [219–221]. SPOP is a POZ domain adaptor protein that modulates the transcriptional repression activities of genes and thus involve an error-prone method to repair broken DNA strands. SPOP forms a complex with CULLIN3 E3 ubiquitin ligase, and ubiquitinates for degradation of SRC-3/ AIB1, a cofactor of AR [222]. SPOP mutation therefore can activate AR in castration-resistant prostate cancer [223, 224]. SPOP mutation also activates Hedgehog pathway, polycomb group protein BMI1, which then promotes the progression of prostate cancer [225–227]. SPOP mutations are strongly associated with copy loss of CHD, FOXO3 and PRDM1 and rarely have accompanying mutations in PTEN or PIK3CA or TP53 in localized cancers [228]. SPINK1 overexpression is another molecular event found in 5-10% of PCa, which usually does not show gene rearrangement [229]. Although SPINK expression and ERG-negative status are not always mutually exclusive [230–232], SPINK1 encodes a secreted serine peptidase inhibitor, which may involve EGFR in its tumorigenic effects, and thus promotes an aggressive subtype of PCa [232]. It is strongly associated with copy loss of PTEN [230]. Other genetic events that are detected in fusion-negative prostate cancer are methylation of miR-26a, high expression of EZH2, and deletion of tumor suppressor MAP3K7/TAK1 [233–235].
Intestinal Immune Adaptation and Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Responsible for much of the ontogenetic change in epithelial gene expression is the transcriptional repressor B lymphocyte–induced maturation protein (BLIMP1, also called PRDM1) (11, 12). BLIMP1 is highly expressed in the intestinal epithelium during the suckling period. It represses expression of a number of metabolic genes found in the adult intestine, such as sucrase isomaltase, trehalase, adenosine deaminase, and arginase 2, and drives expression of argininosuccinate synthetase 1, lactase, and β-galactosidase required during neonatal life. Additionally, BLIMP1 represses the formation of crypts, epithelial cell proliferation, and renewal and promotes immune tolerance by reduction of epithelial expression of MHC class I (13). Mice deficient in intestinal epithelial BLIMP1 expression are born with an adult-like epithelium with crypts and Paneth cells but also an inappropriate set of metabolic enzymes. Not unexpectedly, the majority of these animals die during the first week of life. Comparative stem cell organoid analyses revealed that the suckling-to-weaning transition of the intestinal epithelium is independent of microbial factors and intrinsically programmed (14).
Including Genetic Variables in NTCP Models Where Are We? Where Are We Going?
Published in Tiziana Rancati, Claudio Fiorino, Modelling Radiotherapy Side Effects, 2019
Sarah L. Kerns, Suhong Yu, Catharine M. L. West
Though genome-wide studies of GxE in late radiotherapy toxicity are only in recent years becoming feasible, initial research findings are encouraging. For example, another study investigating second malignancy after radiotherapy, but using a genome-wide approach, found one common SNP and two rare variants that modified the effect of radiation exposure on breast cancer risk after childhood cancer (Morton et al. 2017). Similarly, another GWAS identified genetic variants near PRDM1 that were associated with increased risk of developing a second malignancy in survivors of pediatric Hodgkin’s lymphoma who were treated with radiotherapy as children, and this effect was not seen in those treated with radiotherapy as adults, suggesting interaction between PRDM1 and exposure to ionizing radiation that could also depend on the developmental stage (Best et al. 2011). In the GWAS of prostate cancer patients treated with pelvic radiotherapy described above (Fachal et al. 2014), a statistical interaction was detected for SNPs in the TANC1 locus and total radiation dose.
PD-1 checkpoint blockade enhances adoptive immunotherapy by human Vγ2Vδ2 T cells against human prostate cancer
Published in OncoImmunology, 2021
Mohanad H. Nada, Hong Wang, Auter J. Hussein, Yoshimasa Tanaka, Craig T. Morita
IL-27 links inhibitory receptor expression on normal T cells due to activation by TCR and CD28 with inhibitory receptor expression on “exhausted” T cells found in chronic viral infections and cancer where inhibitory receptors are constitutively expressed on non-blastic T cells. “Exhausted” murine TIL cells isolated from melanoma tumors, express a module of co-inhibitory receptors (PD-1, LAG-3, TIM-3, and TIGIT).38 These receptors are part of a larger co-inhibitory gene program that is shared in several physiological contexts and driven by IL-27. The transcription factors, PRDM1 and c-MAF, function as cooperative regulators of the module.38 We propose that strong TCR stimulation of Vγ2Vδ2 T cells, such as is afforded by exposure to bisphosphonate-treated tumor cells, partially activates the co-inhibitory module due to induction of PRDM1 and/or c-MAF perhaps through IL-27- or TCR-signaling. A similar array of inhibitory receptors is expressed by Vγ2Vδ2 T cells as is expressed by activated CD8 αβ T cells and exhausted TIL cells including PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT. Unlike the situation with exhausted T cells, co-inhibitory module expression is transient and not chronic. This may serve to limit Vγ2Vδ2 T cells activity to prevent tissue damage.
How to conduct research of rare autoimmune diseases
Published in Modern Rheumatology, 2018
Systemic sclerosis is one of autoimmune disease characterized by fibrosis of connective tissues resulting in organ damage. We collected more than 1000 DNA from patients with SSc in Japanese in collaboration with many researchers. We collaborated with French group with comparative number of GWAS data and conducted meta-analysis and follow-up study to identify novel susceptibility genes. As a result, our data set included 4436 cases and 14,751 controls. We successfully identified PRDM1 and GSDM1 as novel susceptibility genes to SSc [24]. Especially, PRDM1 is adjacent to ATG5, a known susceptibility gene to SSc and was not identified as a susceptibility gene in previous studies. We found that a variant showing strongest association with ATG5 was absent in Asian population and PRDM1 showed an independent association from ATG5. This example well described the impact of trans-ethnic meta-analysis which used different LD architectures to identify unknown susceptibility markers.
Differential Activation of Immune Effector Processes in Mature Compared to Immature Sacrococcygeal Teratomas
Published in Fetal and Pediatric Pathology, 2022
Mette Hambraeus, Jenny Karlsson, Ioanna Kasselaki, Catharina Hagerling, Lars Hagander, David Gisselsson
It has been suggested that SCTs derive from primordial germ cells (PGCs), which are thought to arise in the fetal epiblast during the second week of gestation [7,20]. From week 3-4 of gestation, PGCs have been observed in the yolk sac wall, and from here they migrate through the hindgut to the genital ridges, which marks the end of the PGC stage [20]. In line with previous studies [9], our results show a high expression of certain genes involved in early germ cell differentiation and pluripotency. The transcription profile was found across all histological subtypes. Compared to the reference group of tumors, SCTs showed a high expression of SOX2, which encodes a protein required for stem-cell maintenance in central nervous tissue. This protein combines with OCT4 to form a transcription factor that controls a number of genes required for embryological development [21]. We also found increased expression of genes normally active in early germ cell development, i.e. PRMD1, TFAP2C, and KIT [19]. SOX2 regulates KIT-expression in PGCs and is essential for survival and continued proliferation [22]. The transcriptional regulator PRMD1 (BLIMP1) is a signature gene for germ cell-commitment in active migratory and gonadal PGCs [20]. It induces TFAP2C, which further regulates germ cell specific genes and inhibits somatic differentiation [23]. PRDM1, TFAP2C and KIT are regulators of hematopoietic stem cells, antibody secreting plasma cells and formation of the placenta, and may therefore be expressed throughout fetal development [24–26]. However, the combined expression is generally considered to reflect a germ cell profile and the expression decreases during the initial primordial germ cell stage [19,27].