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Garcinia indica (Kokum) and Ilex aquifolium (European Holly)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Dicson Sheeja Malar, Mani Iyer Prasanth, Tewin Tencomnao, James Michael Brimson, Anchalee Prasansuklab
Garcinol acts as a potent inhibitor of histone acetyltransferases, as it inhibited chromatin transcription and induced apoptosis in HeLa cells (Balasubramanyam et al., 2004). In addition, garcinol mediated downregulation of NF-kB signaling pathway aided in caspase-mediated apoptosis indicating its chemoprotective potential (Ahmad et al., 2010). Garcinol was reported to target signal transducer and activator of transcription-3 (STAT-3) signaling pathway both under in vitro and in vivo conditions to inhibit the tumor growth and invasion of breast cancer (Ahmad et al., 2012a). Further, it induced mesenchymal-to-epithelial transition (MET) in aggressive triple-negative MDA-MB-231 and BT-549 breast cancer cells, mediated by upregulation of epithelial marker E-cadherin and downregulation of mesenchymal markers vimentin, ZEB-1, and ZEB-2. This was mechanistically linked with the deregulation of miR-200s, let-7s, NF-kB, and Wnt signaling pathways, as confirmed in mice models as well (Ahmad et al., 2012b).
Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Metastasis is a complex process involving the spread of tumor cells from the primary tumor to distant sites where secondary and tertiary tumors can form (Figure 12.4). The Epithelial-Mesenchymal Transition (EMT) is an essential event in the initial phase of metastasis, a process which also occurs during normal embryonic development, tissue regeneration, and wound healing. However, the EMT process is often not completed in tumor cells which are frequently in multiple transitional states and expressing mixed epithelial and mesenchymal genes. These hybrid cells can move collectively as clusters and behave more aggressively than normal cells, with the transition in gene expression often triggered by complex signaling pathways such as those controlled by the transcription factors SNAI1/2, ZEB1/2, and Twist. However, the role of these transcription factors in EMT is complex, and their functions are not tissue specific.
Juvenile Polyposis Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Rafael Parra-Medina, Elizabeth E. Montgomery, Paula Quintero-Ronderos, Edgar Garavito
The fact that some tumor samples do not show expression of certain proteins, even though there is evidence of gene structural alteration, suggests epigenetic factors acting as a second hit. They may contribute to the inactivation of genes controlling cell cycle or promoting the activity of tumor progression genes [16]. The relationship of hypoxia with modification of cell behavior is also well described. When a tumor cell divides, the oxygen supply diminishes, thus activating the cell response to hypoxia which depends on the stability of hypoxia-inducible factor 1-alpha (HIF1a). HIF1a is a transcription factor that trans-activates the genes related to erythrocyte production, angiogenesis, and reprogramming of cell metabolism by the increase in aerobic glycolysis [19]. HIF1a also induces expression of genes associated with EMT such as Twist, Snail, Slug, and ZEB1/2, which act during tumor progression, invasion, and metastasis. Therefore, hypoxia modulates the cell behavior, increasing the survival and tumor progression [19]. Finally, the EMT is also related to epigenetic factors that alter the cadherin E expression due to its promoter methylation and the expression of Snail and Slug due to the DNA methylation in their first intronic region. Moreover, miRNAs such as miRNA-200, which is associated with epithelial differentiation, are inhibited by ZEB1 (an EMT activator). Contrarily, p53 increases the expression of miRNA-200. Therefore, a loss of function of this gene is associated with a greater EMT [22]. Any of these factors could be at play in the progression of juvenile polyps to carcinoma.
Possible role of Porphyromonas gingivalis in orodigestive cancers
Published in Journal of Oral Microbiology, 2019
Sztukowska et al. [54] found that infection of immortalized gingival epithelial cells (TIGK cells) with P. gingivalis induced expression and nuclear localization of the ZEB1 transcription factor that controls EMT. Porphyromonas gingivalis strains that lacked the FimA fimbrial protein had reduced ability to induce ZEB1 expression. Increased expression of ZEB1 was also caused by P. gingivalis in a dual species community with F. nucleatum or S. gordonii. The increased ZEB1 expression was associated with enhanced ZEB1 promoter activity. The levels of ZEB1 correlated with increased migration of mesenchymal markers including MMP-9 and vimentin, and with enhanced migration of epithelial cells into matrigel. Knockdown of ZEB1 with siRNA inhibited the P. gingivalis-induced enhancement of mesenchymal markers such as vimentin and MMP-9, and migration of epithelial cells into matrigel. In addition, knockdown of ZEB1 with siRNA inhibited the P. gingivalis-induced increase in mesenchymal markers and epithelial cell migration. Interestingly, in mice, oral infection with P. gingivalis enhanced ZEB1 levels in gingival tissues [54]. Porphyromonas gingivalis was also detected intracellularly by antibody staining in biopsies from OSCC [54]. Taken together, FimA-driven ZEB1 expression may, in part, explain a contribution of P. gingivalis to OSCC. The in vitro and in vivo studies listed above showed that P. gingivalis may contribute to a mesenchymal phenotype driving the progression of cancer in co-operation with other oral bacteria.
Analysis of candidate genes ZEB1 and LOXHD1 in late-onset Fuchs’ endothelial corneal dystrophy in an Indian cohort
Published in Ophthalmic Genetics, 2018
Bhavna S. Rao, Samdani Ansar, Tharigopala Arokiasamy, Rachapalli R. Sudhir, Vetrivel Umashankar, Rama Rajagopal, Nagasamy Soumittra
Four genes, namely SLC4A11, ZEB1, LOXHD1, and AGBL1, are identified as candidates for late-onset FECD so far. However, mutations in these genes contribute to small percentage of late-onset FECD cases. Our group has previously reported mutations in SLC4A11 in the same FECD cohort presented here (5). While mutations in SLC4A11 contribute to approximately 11% of the FECD cases in our cohort, in a Chinese cohort and in a study with multiple ethnicities, mutations contribute to only 3–4% of the cases (3,4). We have identified a reported mutation and a VUS in ZEB1 gene in our present study. A comparison of the role of ZEB1 across multiple ethnicities shows that the contribution of this gene in our population is concurrent with other reports (6,28–30).
Perfluorooctane sulfonate (PFOS) triggers migration and invasion of esophageal squamous cell carcinoma cells via regulation of Zeb1
Published in Drug and Chemical Toxicology, 2022
Yaqing Liu, Jian Li, Hui Ding, Dahe Ge, Juntao Wang, Chunjin Xu
Our data indicated that Zeb1 is essential for PFOS induced development of ESCC. Zeb1 is a transcriptional factor known to repress E-cad promoter and thus induce EMT (Goscinski et al. 2015). The expression of Zeb1 is associated with aggressive disease and poor prognosis including ESCC (Feng et al. 2014, Caramel et al. 2018). Suppression of Zeb1 can attenuate TGF-beta-induced EMT via suppression of cellular senescence programs (Ohashi et al. 2010). Our results showed that PFOS can increase the expression of Zeb1, while knockdown of Zeb1 can attenuate PFOS induced migration and invasion of ESCC cells. Mechanistically, PFOS can increase the transcription and proteins stability of Zeb1 in ESCC cells (Figure 7).