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Genetics of gastric cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
MSI predisposes the genome to the mutational inactivation of tumor suppressor genes that have microsatellite repeats in their exons, such as transforming growth factor β receptor type II (TGFBR2), BAX, insulin-like growth factor II receptor (IGF2R), and E2F4. Duval et al. studied a series of 22 gastric cancers and found the following results: TCF4 mutations 9% (2/22), TGFBR2 mutations 86% (n = 19/22), BAX mutations 14% (n = 3/22), IGFR2 mutations 32% (n = 7/22), MSH3 mutations 9% (n = 2/21), and MSH6 mutations 54% (n = 5/23) (Duval et al., 1999). The inactivation of these genes appears to be part of a unique pathway of gastric carcinogenesis that can be distinguished from tumors that display chromosomal instability (CIN). For example, TP53 mutations occur uncommonly in MSI gastric cancers but are observed in the majority of microsatellite stable (MSS) cancers consistent with there being two distinct pathways that lead to gastric cancer formation (Luinetti et al., 1998; Renault et al., 1996; Strickler et al., 1994; Yamamoto et al., 1999). In addition, low level MSI (1 microsatellite locus shifted) has been detected in a subset of pre-neoplastic lesions in the stomach or in adenomas (Leung et al., 2000; Ottini et al., 1997; Semba et al., 1996; Tamura et al., 1995). The significance of this finding remains to be demonstrated but it suggests that at least some of these lesions are truly pre-malignant and that they have acquired pre-cancerous genetic alterations. Also of interest, MSI gastric cancers display intratumoral histologic and genetic heterogeneity consistent with a state of increased genomic instability (Chong et al., 1994; Chung et al., 1997, 1999; Ohue et al., 1996). TGFBR2 and BAX mutations occur most frequently throughout these genetically heterogeneous tumors, suggesting they occur early in the development of gastric adenocarcinomas and are important in the acquisition of the malignant phenotype (Chung et al., 1997; Ohue et al., 1996).
Cell cycle deregulation in neurodegenerative diseases
Published in International Journal of Neuroscience, 2023
Xiaobo Zhang, Shuxin Song, Wenpeng Peng
Accumulating evidence demonstrates that the inhibition of cell cycle regulators alleviates neuronal death in PD. Gallastegui et al. [63] firstly revealed a negative regulatory mechanism of α-SYN (Alpha-synuclein, which play an important role in AD) expression, suggesting a putative role for cell cycle regulators in PD. This regulation was performed by p27 in collaboration with p21 and mediated by p130/E2F4 repressor complexes. These results allow to postulate that this regulatory mechanism could be disrupted or altered in the process of induction or propagation of PD. Tsutomu Sasaki [64] found that necdin, a growth suppressor expressed predominantly in postmitotic neurons, interacting with transcription factors E2F1 and p53, promotes mitochondrial biogenesis mediated by stabilization of endogenous Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-la) protein. It aimed to enhance neuroprotection against neurodegenerative disease. Even until now we know a lot about the link between PD and cell cycle, the signal pathway in detail is unclear. We still have to research more in order to find an effective therapy.
Identification of key genes, regulatory factors, and drug target genes of recurrent implantation failure (RIF)
Published in Gynecological Endocrinology, 2020
A better understanding of the RIF mechanism requires the simultaneous consideration of regulatory factors and target elements containing miRNAs, TFs, and target genes. Based on the analysis in the methods, two TFs (E2F4 and Paired amphipathic helix protein Sin3a, SIN3A), 6 miRNAs (miRNA489, miRNA199A, miRNA369-3P, miRNA522, and so on), 74 TFs-target gene regulatory pairs, and 33 miRNA-target genes pairs were obtained. After integrating all these regulatory pairs, a miRNA-TF-DEGs network containing 87 nodes and 107 regulatory pairs was constructed. As shown in Figure 4, the targeted genes of E2F4 were obviously more than that of SIN3A with the degree of 56 versus 18. MiRNA-199A and miRNA-369-3P showed the important regulatory of DEGs with the degree of 7.
The transcriptomic revolution and radiation biology
Published in International Journal of Radiation Biology, 2022
A reanalysis of the same NCI-60 gene expression data using IPA is illustrated in Figure 2(C). In this case, IPA was first used to predict putative upstream regulators of the genes in the down-regulated cluster. IPA assumes a normal distribution of gene up- or down-regulation for each potential upstream regulator-gene connection, and calculates a z-score (number of standard deviations from the mean) to determine the significant over-representation of ‘activated’ or ‘inhibited’ predictions. For each potential regulator, a z-score of ≥2 is taken as significantly likely to be activated, and a z-score of ≤ −2 as significantly inhibited. E2F4 was again predicted to be activated by radiation, but additional transcription factors were also predicted as possible upstream regulators of the down-regulated genes. The strongest predictions were for activation of NUPR1 (z-score = 3.5) and inhibition of FOXM1 (z-score = −3.7). FOXM1 is a known regulator of cell cycle genes with roles in carcinogenesis (Myatt and Lam 2007), and its down-regulation may enhance radiosensitivity (Nagel et al. 2015; Xiu et al. 2018). Consistent with our prediction from the NCI-60 data, NUPR1 has been shown to be induced by multiple cellular stressors, including ionizing radiation (Gironella et al. 2009). We have also previously reported IPA-predicted activation of NUPR1 by direct irradiation with 123 keV/µm 4He ions, and inhibition in un-irradiated bystanders of the same cells (Ghandhi et al. 2014). This example illustrates the common finding that reanalysis of transcriptomic data using different or updated approaches generally confirms older findings, but also often suggests additional directions for further investigation.