Altered metabolism is considered as a hallmark of cancer. Here we investigated expression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) 2 lyase (HMGCL), an essential enzyme in ketogenesis, which produces ketone bodies by the breakdown of fatty acids to supply energy, in nasopharyngeal carcinoma (NPC). The expression of HMGCL was silenced in NPC tissue. Downregulation of HMGCL in NPC was associated with low intracellular β-hydroxybutyrate (β-HB) production, thereby reducing reactive oxygen species (ROS) generation. Ectopic expression of HMGCL restored β-HB level, associated with suppressed proliferation and colony formation of NPC cells in vitro and decreased tumorigenicity in vivo. HMGCL suppressed the migration and invasion of NPC cells in vitro via mesenchymal-epithelial transition. Furthermore, extracellular β-HB supply suppressed the proliferation and migration of NPC cells. Both intra- and extracellular β-HB exerting a suppressive role in NPC depends on ROS generation. Ketogenesis may be impaired in NPC cells due to lack of HMGCL expression, suggesting that it may be a promising target in NPC therapy.
The abnormality of DNA methylation is one of the major epigenetic alterations in the human hepatocellular carcinoma (HCC). We have assessed the global genomic DNA methylation profiles in human HCC patients by using the Infinium Human Methylation27 BeadChip. A CpG loci of S100A8 was found to be significantly hypomethylated in HCC.Pooled meta-analysis of five validation public datasets demonstrated its methylation level was significantly lower for HCC compared to paired adjacent normal tissues. Quantitative pyrosequencing analysis also showed that the S100A8 methylation level was decreased in cancer tissues (31.90%±13.31%) than that in the paired adjacent normal tissues (65.33%±3.64%, p<0.01). The area under the ROC curve (AUC) value was 0.950 (p<0.01). Kaplan-Meier survival curves revealed that hypomethylation of S100A8 was associated with shortened overall survival (OS) and progression-free survival (PFS) (log rank p<0.05). Multivariate Cox proportional hazards model also indicated significantly shorter OS (HR, 1.709; 95 % CI, 1.127-2.591) and PFS (HR, 1.767; 95 % CI, 1.168-2.974) were observed in the low-methylation-level group compared to the high-methylation-level group. Furthermore, S100A8 overexpression in Huh7 and MHCC-97H hepatoma cell lines led to increased cell proliferation, migration, invasion, and tumor growth. These findings suggested S100A8 methylation to be served as potential diagnosis and prognosis marker for HCC. S100A8 also may play as a tumor promoter in HCC.
Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) promotes the motility of nasopharyngeal carcinoma (NPC) cells. Previously, we have shown that the localization of integrin β4 (ITGβ4) is regulated by LMP2A, with ITGβ4 concentrated at the cellular protrusions in LMP2A-expressing NPC cells. In the present study, we aim to further investigate mechanisms involved in this process and its contribution to cell motility. We show that expression of LMP2A was correlated with increased epidermal growth factor receptor (EGFR) activation, elevated levels of intracellular Ca2+, calpain activation and accelerated cleavage of ITGβ4. Activation of EGFR and calpain activity was responsible for a redistribution of ITGβ4 from the basal layer of NPC cells to peripheral membrane structures, which correlated with an increased migratory capacity of NPC cells. Furthermore, we demonstrated that the calpain inhibitor calpastatin was downregulated in NPC primary tumors. In conclusion, our results point to LMP2A-mediated targeting of the EGFR/Ca2+/calpain/ITGβ4 signaling system as a mechanism underlying the increased motility of NPC cells. We suggest that calpain-facilitated cleavage of ITGβ4 contributes to the malignant phenotype of NPC cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.