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Breast cancer epigenetic targets for precision medicine
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Recently, carnitine palmitoyl transferase-1A (CPT1A) was identified as a new tumor specific target in human breast cancer (Pucci et al., 2016). It has been suggested before that CPT1A variant 2 product is involved in the epigenetic regulation of cancer survival, cell death escaping, and metastasis pathways. Indeed, the inactivation of CPT1A variant 2 by using small interfering RNAs (siRNAs) led to apoptosis in several breast cancer cell lines. CPT1A silencing was associated with reduction of HDAC activity and histone hyperacetylation, leading to upregulated transcription of proapoptotic genes (BAD, CASP9, COL18A1) and downmodulation of invasion and metastasis genes (TIMP-1, PDGF-A, SERPINB2). Thus, CPT1A has been proposed as a new tumor-specific target, more effective than the well-known aforementioned HDAC inhibitors (Pucci et al., 2016).
Endotypes and Asthma
Published in Jonathan A. Bernstein, Mark L. Levy, Clinical Asthma, 2014
Pranabashis Haldar, Rachid Berair
Eosinophilic inflammation represents one terminal pathway of a broader network of cellular activity that occurs as part of the Th2 immune response. In this context, it may itself be viewed as a biomarker of a broader phenotype of “Th2-driven” asthma. At a molecular level, IL-5-driven eosinophilic inflammation is accompanied by the upregulation of other Th2 cytokines, classically IL-4 (B-cell isotype switching to IgE) and IL-13 (airway hyperresponsiveness and mucus cell hypersecretion). Indeed, the expression of three genes inducible with IL-13 (POSTN, CLCA1, and SERPINB2) has been utilized to provide molecular validation of the Th2 phenotype.17 However, the significant heterogeneity in the coexpression of Th2 cytokines is increasingly recognized, suggesting that eosinophilic asthma itself is not an endotype. This is supported by the differences in clinical expression: eosinophilic bronchitis, a disease characterized by eosinophilic airway inflammation without airway hyperresponsiveness typically expresses IL-5 but not IL-1318; among patients with airway hyperresponsiveness, subgroups with high and low IgE titers are well recognized, contributing to the characterization of other important asthma phenotypes described here.
Small molecule inhibitor of nicotinamide N-methyltransferase shows anti-proliferative activity in HeLa cells
Published in Journal of Obstetrics and Gynaecology, 2021
Serra Akar, Tuğçe Duran, Ali Ahmed Azzawri, Nadir Koçak, Çetin Çelik, Halil İbrahim Yıldırım
Treatment with 5MQ produced varying effects on the EMT-associated transcription factors ZEB1 and TWIST mRNAs. TWIST expression was shown to be induced by NNMT (Kanska et al. 2017). Consistently, treatment with 5MQ led to a 54% downregulation of TWIST mRNA. ZEB1 is an upstream regulator of NNMT (Kanska et al. 2017). Since ZEB1 was reported to be a strong inducer of NNMT expression (Kanska et al. 2017), the inhibition of NNMT and thereby decrease in the end products of the NNMT-catalyzed reaction may lead to ZEB1 upregulation by inducing a negative feedback loop. In HEK-293 cells, ZEB1 mRNA levels following treatment with 5MQ were relatively unaffected. However, further studies are necessary to elucidate the exact relationships between the activities of NNMT and ZEB1. SERPIN1 (serine peptidase inhibitor or plasminogen activator inhibitor 1) mRNA, which showed a significant correlation with ZEB1 mRNA levels in breast cancer cells (Lehmann et al. 2016) were also reduced following NNMT inhibition. The transcription of SERPIN1 may be through NNMT and not ZEB1 directly. SerpinB2, which is a urokinase plasminogen activator, which was elevated about 120 fold in HEK-293 cells following 5MQ treatment, was recently associated with prolonged survival and inhibition in cell proliferation and metastasis in pancreatic cancer (Croucher et al. 2008).
SerpinB2 deficiency in mice reduces bleeding times via dysregulated platelet activation
Published in Platelets, 2019
Wayne A Schroder, Thuy T Le, Joy Gardner, Robert K. Andrews, Elizabeth E. Gardiner, Leonie Callaway, Andreas Suhrbier
SerpinB2 (also known as plasminogen activator inhibitor type 2 or PAI-2) is a member of the clade B or ovalbumin-like serine protease inhibitor (ov-serpin) subgroup of the serpin superfamily. SerpinB2 can be expressed by variety of cells including monocytes and macrophages, syncytiotrophoblasts, keratinocytes, fibroblasts, endothelial cells, dendritic cells and cancer cells [1–6]. SerpinB2 lacks a classical secretory signal peptide and is usually localized to the cytoplasm. However, SerpinB2 can reach the extracellular milieu via loss of plasma membrane integrity [5] or microparticle formation, with SerpinB2 expressed on microparticles, potentially via an association with phosphatidylserine and annexins [4,7].
Leukemia cell-derived microvesicles induce T cell exhaustion via miRNA delivery
Published in OncoImmunology, 2018
Jieke Cui, Qing Li, Mei Luo, Zhaodong Zhong, Shu Zhou, Lin Jiang, Na Shen, Zhe Geng, Hui Cheng, Li Meng, Shujuan Yi, Hui Sun, Feifei Wu, Zunmin Zhu, Ping Zou, Yong You, An-Yuan Guo, Xiaojian Zhu
One aspect that merits further consideration is the change of regulatory networks in T cells after the delivery of exogenous miRNAs. We explored the potential molecules and associated mechanisms in the transformation of T cells by sequencing and bioinformatics analyses, especially regarding the miRNAs mentioned above, which can result in T cell activation and exhaustion.19,35 According to our bioinformatics analyses, the NF-κB pathway, which is a key regulator involved in T cell activation and exhaustion,19,35 was the most significantly regulated pathway during the process of exhaustion. Activation of the transcription factor NF-κB is critical for cytokine production and T cell survival after T cell receptor engagement. However, persistent NF-κB signaling is sufficient to impair both T cell function and survival.17 As mentioned above, epigenetic modification of the NF-κB pathway is the major change observed after PD-1 blockage.9 Our results further indicated that SerpinB2, IL-1β and CXCL5 are downstream targets of the MV-associated miRNAs and they are pivotal in NF-κB pathway. IL-1β is known as a classical activator of the NF-κB pathway, which suggests that the downregulation IL-1β by miR-21 might participate in the inactivation and consequent exhaustion of T cells.21 SerpinB2 is widely known as an inhibitor of extracellular urokinase plasminogen activator. Recent studies have implicated SerpinB2 in the regulation of Th1 and Th2 immune responses.36 In addition, SerpinB2 deficiency is known to impair its ability to protect T cells from NF-κB-induced cell death and dysfunction.22 CXCL5 is a downstream product of NF-κB and the most prominently expressed CXCR2 ligand, and its downstream pathway helps to establish an immunosuppressive microenvironment in cancers.18 During the process of T cell exhaustion, the level of CXCL5 increased at first and then decreased, consistent with the trend of NF-ĸB levels. In addition to the above factors, CD62 L, another NF-κB activator, was also downregulated during the T cell exhaustion.37 Nevertheless, the exact role of all these factors in the exhaustion of T cells remains to be elucidated.