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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
One of the most common recurrent genomic rearrangement in prostate cancer is the fusion of androgen regulated gene TMPRSS2 to ETS family of transcription factors, the most common one being ERG [61, 63, 64]. Gene fusion is detected in ~50% of prostate cancer patients and occurs due to improper repair of double stranded breaks. Because of TMPRSS2-ERG fusion, the expression of this family of transcription factors is regulated by androgen axis in prostate cancer cells. It has been suggested that AR itself increases the probability of this specific fusion event to occur in cancer cells [51, 65, 66]. Interestingly, ~90 % patients with early onset of prostate cancer have been detected with the fusion and the prostate cancer in these patients is also dependent on AR axis suggesting an AR-dependent fusion mechanism [67–69]. Fusion of other ETS factors such as ETV1, ETV4, and ETV5 with binding factors such as TMPRSS2, HERV-K, KLK2, SLC45A3, CANT1, HERV-K17, DDX5 and FOXP1 have also been reported [51, 61, 63–69]. These ETS transcription factors promote the expression of genes such as MYC, EZH2 and SOX9 involved in proliferation, dedifferentiation, migration, invasion and oncogenesis [70–72]. TMPRSS2-ERG fusion has been detected in both low and high-grade intraepithelial neoplasia (PIN) and is therefore thought to be an early event in prostate cancer [51, 63, 66]. PIN is also detected in mouse prostate when overexpressing prostate-specific ETV1 in transgenic mice. Interestingly, no tumor is developed in this mouse model, suggesting the requirement of other genetic alterations for oncogenic transformation [73–75]. Some studies also reported increased expression of ETS factors in hormone-naïve and castration-resistant metastatic prostate cancer indicating potential roles of fusion genes in advanced cancer [54, 75, 76]. Studies have indicated co-operation between TMPRSS2-ERG fusion and other oncogenic events such as PTEN loss, AKT activation and AR overexpression, which promotes the emergence of advanced prostate cancer [77, 78]. The TMPRSS2-ERG fusion can activate RAS-MAPK and is associated with downregulation of WNT and TGFβ signaling pathways [79–83]. Moreover, removal of these fusion proteins reduces tumor growth in nude mice highlighting the potential of ETS transcription factors as target for prostate cancer [84–86]. Inhibiting upstream signaling kinases and downstream targets of ETS transcription factors are also considered as effective therapeutic target as an alternative of directly targeting the ETS factors [73, 87, 88]. Because of its cancer-specific expression and potential impact on tumor initiation and growth, many studies investigated the prognostic importance of ETS gene rearrangement. The results are conflicting as they reported association of ETS fusions with both aggressive and indolent disease [64, 89–91]. There could be several reasons for this anomaly, including heterogeneity of the prostate tumors, study cohorts and the impact of sampling.
The commensal bacterium Lactiplantibacillus plantarum imprints innate memory-like responses in mononuclear phagocytes
Published in Gut Microbes, 2021
Aize Pellon, Diego Barriales, Ainize Peña-Cearra, Janire Castelo-Careaga, Ainhoa Palacios, Nerea Lopez, Estibaliz Atondo, Miguel Angel Pascual-Itoiz, Itziar Martín-Ruiz, Leticia Sampedro, Monika Gonzalez-Lopez, Laura Bárcena, Teresa Martín-Mateos, Jose María Landete, Rafael Prados-Rosales, Laura Plaza-Vinuesa, Rosario Muñoz, Blanca de las Rivas, Juan Miguel Rodríguez, Edurne Berra, Ana M. Aransay, Leticia Abecia, Jose Luis Lavín, Hector Rodríguez, Juan Anguita
Analysis of monocyte transcriptomic profiles also allowed us to identify the impact of priming in several metabolic pathways of monocytes in comparison with cells acutely exposed to L. plantarum, especially in those monocytes pre-stimulated with live bacteria (Figure 4a). Although we did not find great changes in the expression levels within members of central metabolic pathways, we observed that some adjacent metabolic pathways were enriched in our functional study. Indeed, our data showed the upregulation of folic acid metabolism, amino acid and carboxylic acid biosynthesis, and monocarboxylic acid catabolism, and the downregulation of hyaluronan biosynthesis, negative regulation of lipid storage, and glycerol transport (Table S1). Specifically, we observed the upregulation of three pyruvate dehydrogenase kinases genes (PDK2, PDK3, PDK4) in cells primed with live bacteria, as well as a decreased expression of ACO1 and ACOD1, coding for aconitase and aconitate decarboxylase, suggesting a reduction in the integrity of the tricarboxylic acid (TCA) cycle and the itaconate pathway. We also found the differential regulation of several genes coding for metabolite transporters (Figure 3e), including those for glucose (SLC2A1), other hexoses and monocarboxylic compounds (SLC2A6, SLC45A3, SLC16A5), and amino acids (SLC1A2, SLC16A10), which possibly contribute to changes in cellular metabolism.