Aberrant inactivation of SCNN1G promotes the motility of head and neck squamous cell carcinoma.

The sodium channel epithelial 1 subunit gamma (SCNN1G) is mainly responsible for sodium entry and absorption. The dysfunction of SCNN1G has been widely studied in kidney-related diseases and chronic heart failure. However, its role in cancer remains unclear. Here, we found that SCNN1G was aberrantly downregulated in head and neck squamous cell cancer (HNSCC) tissues, which showed an efficifent diagnostic value according to the ROC curve analysis. The lower expression of SCNN1G was significantly correlated with lymphatic metastasis and a worse outcome of HNSCC patients. Ectopic overexpressing SCNN1G inhibited the invasive and migratory abilities of HNSCC cells, while knocking down SCNN1G showed an opposite effect. A positive correlation between SCNN1G and CDH1 expression was observed, which suggested that SCNN1G might impede HNSCC metastasis via strengthing cell-cell adherin. In addition, RAS signaling and ion channel transport signaling were enriched by SCNN1G in HNSCC using GSEA analysis, indicating that these signaling pathways might be the underlying mechanisms for SCNN1G as well. In addition, six sorts of immune infiltrate subtype cells were associated with SCNN1G expression. Our findings support that SCNN1G inactivation contributes to the metastasis of HNSCC. SCNN1G could serves as a valuable diagnostic and prognostic marker for HNSCC.

Integration Profiling Between Plasma Lipidomics, Epstein-Barr Virus and Clinical Phenomes in Nasopharyngeal Carcinoma Patients.

Plasma lipidomics has been commonly used for biomarker discovery. Studies in cancer have suggested a significant alteration of circulating metabolite profiles which is correlated with cancer characteristics and treatment outcome. However, the lipidomics characteristics of nasopharyngeal carcinoma (NPC) have rarely been studied. We previously described the phenomenon of lipid droplet accumulation in NPC cells and showed that such accumulation could be regulated by latent infection of Epstein-Barr virus (EBV). Here, we compared the plasma lipidome of NPC patients to that of healthy controls by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found 19 lipids (e.g., phosphatidylinositols 18:0/20:4 and 18:0/18:2 and free fatty acid 22:6) to be remarkably decreased, whereas 2 lipids (i.e., diacylglycerols 16:0/16:1 and 16:0/20:3) to be increased, in the plasma of NPC patients, compared with controls. Different lipid profiles were also observed between patients with different titers of EBV antibodies (e.g., EA-IgA and VCA-IgA) as well as between patients with and without lymph node or distant organ metastasis. In conclusion, plasma lipidomics might help to differentiate NPC cases from controls, whereas EBV infection might influence the risk and prognosis of NPC through modulating lipid metabolism in both tumor cells and peripheral blood.

Epigenetic inactivation of ACAT1 promotes epithelial-mesenchymal transition of clear cell renal cell carcinoma.

BACKGROUND: Acetyl-CoA acyltransferase 1 (ACAT1) is a key enzyme catalyzing the production of mitochondrial ketone bodies. We have shown that ACAT1 is down-regulated in kidney renal clear cell carcinoma (KIRC) previously. OBJECTIVE: To investigate the reasons for downregulation of ACAT1 in KIRC and explore the underlying mechanisms involved in metastatic inhibition regulated by ACAT1. METHODS: The Gene Expression Omnibus (GEO) database was queried for meta-analysis of ACAT1 mRNA expression in KIRC. The UALCAN website was used to compare the methylation levels of the ACAT1 promoter region in KIRC and normal tissues. RT-qPCR was used to quantitate ACAT1 transcription levels. The GCBI and Tarbase V.8 databases were used to predict miRNAs that may target the mRNA of ACAT1. The correlation between mRNA expression of ACAT1, MMP7 (matrix metallopeptidase 7), CDH1 (E-cadherin), EpCAM (epithelial cell adhesion molecule), and VIM (vimentin) was analyzed. Extracellular MMP7 protein was quantitated using an ELISA assay. RESULTS: The methylation level of the ACAT1 promoter region in KIRC was significantly higher than that in the normal kidney tissues. The ACAT1 mRNA expression in the KIRC cell lines was restored after treatment with 5-aza-dC (p < 0.05). MiR-21-5p is a conserved microRNA targeting ACAT1. It is expressed at a significantly higher level in KIRC than in normal tissues (p < 0.001). MiR-21-5p miRNA expression negatively correlates with ACAT1 mRNA expression. The expression of miR-21-5p is higher at the T3-T4 stages and in the histologic grades G3-G4. Patients with high miR-21-5p expression tended to have lower overall survival, suggesting that miR-21-5p could serve as a potentially valuable diagnostic biomarker for KIRC (AUC = 0.957; p < 0.001). A mimetic of miR-21-5p inhibited the expression of ACAT1 mRNA and protein. In addition, ACAT1 mRNA expression positively correlates with CDH1 and EpCAM but is negatively correlated with VIM. Overexpression of ACAT1 suppresses the secretion of MMP7 in KIRC cells. CONCLUSION: Expression of ACAT1 in KIRC is controlled at two levels, firstly by the hypermethylation of the ACAT1 promoter region and secondly by overexpression of miR-21-5p. Downregulation of ACAT1 expression correlates with epithelial-mesenchymal transition (EMT).

Epigenetic Inactivation of Acetyl-CoA Acetyltransferase 1 Promotes the Proliferation and Metastasis in Nasopharyngeal Carcinoma by Blocking Ketogenesis.

The dysregulation of epigenetic modification and energy metabolism cooperatively contribute to the tumorigenesis of nasopharyngeal carcinoma (NPC). However, the detailed mechanisms underlying their joint contribution to NPC development and progression remain unclear. Here, we investigate the role of Acy1 Coenzyme A Acyltransferases1 (ACAT1), a key enzyme in the metabolic pathway of ketone bodies, in the proliferation and metastasis of NPC and to elucidate the underlying molecular mechanisms. Ketogenesis, plays a critical role in tumorigenesis. Previously, we reported two enzymes involved in ketone body metabolism mediate epigenetic silencing and act as tumor suppressor genes in NPC. Here, we identify another key enzyme, Acetyl-CoA acetyltransferase 1 (ACAT1), and show that its transcriptional inactivation in NPC is due to promoter hypermethylation. Ectopic overexpression of ACAT1 significantly suppressed the proliferation and colony formation of NPC cells in vitro. The migratory and invasive capacity of NPC cells was inhibited by ACAT1. The tumorigenesis of NPC cells overexpressing ACAT1 was decreased in vivo. Elevated ACAT1 in NPC cells was accompanied by an elevated expression of CDH1 and a reduced expression of vimentin and SPARC, strongly indicating that ACAT1 is involved in regulating epithelial-mesenchymal transition (EMT). We also found that ACAT1 contributes to increased intracellular levels of ß-hydroxybutyrate (ß-HB). Exogenously supplied ß-HB significantly inhibits the growth of NPC cells in a dose-dependent manner. In summary, ACAT1 may function as a tumor suppressor via modulation of ketogenesis and could thus serve as a potential therapeutic target in NPC. In summary, our data suggest that regulation of ketogenesis may serve as adjuvant therapy in NPC.

Inverse correlation of miR-27a-3p and CDH5 expression serves as a diagnostic biomarker of proliferation and metastasis of clear cell renal carcinoma.

BACKGROUND: Cadherin-5 (CDH5) is aberrantly expressed in a variety of human cancers and plays an important role in angiogenesis. The present study provides further insight into the role of miR-27a-3p in the regulation of CDH5 expression in renal clear cell carcinoma (ccRCC). METHODS: Thedysregulation of CDH5 expression in ccRCC and its association with clinicopathological characteristics were analyzed using the TCGA database. A meta-analysis was performed to verify the alteration of CDH5 expression in ccRCC using the GEO database. Quantitative RT-PCR and immunohistochemical staining were applied to assess the transcriptional and protein levels of CDH5. TargetScan and Tarbase were employed to predict the miRNAs with the potential to target mRNA of CDH5. RESULTS: The mRNA level of CDH5 in ccRCCwas significantly higher than in normal tissue. CDH5 mRNA expression could therefore serve as a potential diagnostic biomarker for ccRCC (AUC = 0.844). However, the reduced CDH5 transcription levels were significantly correlated with patients in the T3-4 stage, lymph node, and distant metastasis, as well as with a worse clinical outcome. We further observed that CDH5, at the protein level, was almost absent in ccRCC samples. In addition, a few databases screen showed that mir-27a-3p is a highly conserved miRNA targeting CDH5. The expression of mir-27a-3p was significantly elevated in ccRCC tissues in contrast to normal tissues. Importantly, it was positively associated with the T3-4 stage and M stage, respectively, suggesting that the expression level of mir-27a-3p could serve as a diagnostic biomarker for ccRCC (AUC = 0.775). CONCLUSION: Our data suggest that thereduced translational level of CDH5 in ccRCC was related to the overexpression of mir-27a-3p. The higher mir-27a-3p and lower CDH5 expression significantly correlated with advanced clinical stages for ccRCC patients.

Downregulation of SLC27A6 by DNA Hypermethylation Promotes Proliferation but Suppresses Metastasis of Nasopharyngeal Carcinoma Through Modulating Lipid Metabolism.

Lipid is the building block and an important source of energy, contributing to the malignant behavior of tumor cells. Recent studies suggested that lipid droplets (LDs) accumulations were associated with nasopharyngeal carcinoma (NPC) progression. Solute carrier family 27 member 6 (SLC27A6) mediates the cellular uptake of long-chain fatty acid (LCFA), a necessary lipid component. However, the functions of SLC27A6 in NPC remain unknown. Here, we found a significant reduction of SLC27A6 mRNA in NPC tissues compared with normal nasopharyngeal epithelia (NNE). The promoter methylation ratio of SLC27A6 was greater in NPC than in non-cancerous tissues. The demethylation reagent 5-aza-2'-deoxycytidine (5-aza-dC) remarkably restored the mRNA expression of SLC27A6, suggesting that this gene was downregulated in NPC owing to DNA promoter hypermethylation. Furthermore, SLC27A6 overexpression level in NPC cell lines led to significant suppression of cell proliferation, clonogenicity in vitro, and tumorigenesis in vivo. Higher SLC27A6 expression, on the other hand, promoted NPC cell migration and invasion. In particular, re-expression of SLC27A6 faciliated epithelial-mesenchymal transition (EMT) signals in xenograft tumors. Furthermore, we observed that SLC27A6 enhanced the intracellular amount of triglyceride (TG) and total cholesterol (T-CHO) in NPC cells, contributing to lipid biosynthesis and increasing metastatic potential. Notably, the mRNA level of SLC27A6 was positively correlated with cancer stem cell (CSC) markers, CD24 and CD44. In summary, DNA promoter hypermethylation downregulated the expression of SLC27A6. Furthermore, re-expression of SLC27A6 inhibited the growth capacity of NPC cells but strengthened the CSC markers. Our findings revealed the dual role of SLC27A6 in NPC and shed novel light on the link between lipid metabolism and CSC maintenance.