Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Neurofilament heavy polypeptide regulates the Akt-beta-catenin pathway in human esophageal squamous cell carcinoma.

ABSTRACT: Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth. We observed promoter methylation and loss of expression in neurofilament heavy polypeptide (NEFH) in a significant proportion of primary esophageal squamous cell carcinoma (ESCC) samples that were of a high tumor grade and advanced stage. RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo, whereas forced expression of NEFH significantly inhibited cell growth and colony formation. Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase, via activation of the Akt/beta-catenin pathway, resulting in enhanced aerobic glycolysis and mitochondrial dysfunction. The acceleration of glycolysis and mitochondrial dysfunction in NEFH-knockdown cells was suppressed in the absence of beta-catenin expression, and was decreased by the treatment of 2-Deoxyglucose, a glycolytic inhibitor, or API-2, an Akt inhibitor. Loss of NEFH activates the Akt/beta-catenin pathway and increases glycolysis and mitochondrial dysfunction. Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways.

SUBMITTER: Kim MS

PROVIDER: S-EPMC2815775 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

TGIF1 plays a carcinogenic role in esophageal squamous cell carcinoma through the Wnt/β‑catenin and Akt/mTOR signaling pathways.

Project description:TGFB induced factor homeobox 1 (TGIF1), a transcriptional corepressor, has been reported to be involved in tumorigenesis and cancer development. However, the role of TGIF1 in the growth and metastasis of esophageal cancer is poorly studied. In the present study, it was found that TGIF1 was highly expressed in esophageal cancer tissues and cell lines. The silencing of TGIF1 by siRNA interference significantly inhibited the proliferation, migration, invasion and epithelial‑mesenchymal transition (EMT) process of KYSE‑150 esophageal cancer cells, and promoted cell apoptosis. Correspondingly, the upregulation of TGIF1 significantly promoted the proliferation and metastatic potential of Eca‑109 cells, and reduced apoptosis. Furthermore, the data indicated that the Wnt/β‑catenin and Akt/mammalian target of rapamycin (mTOR) signaling pathways were inhibited by TGIF1 knockdown, and were promoted by the overexpression of TGIF1. It was also confirmed that TGIF1 knockdown reduced tumor growth, inhibited Wnt/β‑catenin and Akt/mTOR pathway activation, and reversed the TGF‑β1‑mediated EMT process in a tumor xenograft model. Taken together, the data of the present study suggest that TGIF1 plays an oncogenic role in the progression of esophageal cancer. It may carry out this role by regulating the Wnt/β‑catenin and Akt/mTOR signaling pathways.

| S-EPMC7951946 | biostudies-literature

NHE9 induces chemoradiotherapy resistance in esophageal squamous cell carcinoma by upregulating the Src/Akt/β-catenin pathway and Bcl-2 expression.

Project description:Recently, we found that NHE9 mRNA was upregulated in chemoradiotherapy (CRT)-resistant esophageal squamous cell carcinoma (ESCC); however, the underlying mechanisms were unclear. Here, we aimed to clarify the functional contribution of NHE9 to CRT resistance, understand the molecular basis of NHE9-dependent resistance in ESCC, and identify potential therapeutic targets. Our results showed that NHE9 prevented CRT-induced apoptosis. Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling. Moreover, upregulated Bcl-2 protein was also observed in cells exhibiting NHE9-induced CRT resistance. A higher NHE9 level was associated with a poor response to CRT and less decrease in T and N stage in ESCC patients. Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression. Taken together, our findings demonstrate that NHE9 can be an effective predictor of CRT response and may be useful in the development of targeted therapies for CRT-resistant ESCC.

| S-EPMC4494947 | biostudies-literature

MiRNA-146a/AKT/β-Catenin Activation Regulates Cancer Stem Cell Phenotype in Oral Squamous Cell Carcinoma by Targeting CD24

Project description:CD44highCD24low population has been previously reported as cancer stem cells (CSCs) in Oral Squamous Cell Carcinoma (OSCC). Increasing evidence suggests potential involvement of microRNA (miRNA) network in modulation of CSC properties. MiRNAs have thus emerged as crucial players in tumor development and maintenance. However, their role in maintenance of OSCC stem cells remains unclear. Here we report an elevated expression of miR-146a in the CD44highCD24low population within OSCC cells and primary HNSCC tumors. Moreover, over-expression of miR-146a results in enhanced stemness phenotype by augmenting the CD44highCD24low population. We demonstrate that miR-146a stabilizes β-catenin with concomitant loss of E-cadherin and CD24. Interestingly, CD24 is identified as a novel functional target of miR-146a and ectopic expression of CD24 abrogates miR-146a driven potential CSC phenotype. Mechanistic analysis reveals that higher CD24 levels inhibit AKT phosphorylation leading to β-catenin degradation. Using stably expressing miR-146a/CD24 OSCC cell lines, we also validate that the miR-146a/CD24/AKT loop significantly alters tumorigenic ability in vivo. Furthermore, we confirmed that β-catenin trans-activates miR-146a, thereby forming a positive feedback loop contributing to stem cell maintenance. Collectively, our study demonstrates that miR-146a regulates CSCs in OSCC through CD24-AKT-β-catenin axis.

| S-EPMC8546321 | biostudies-literature

Elevated DHODH expression promotes cell proliferation via stabilizing β-catenin in esophageal squamous cell carcinoma.

Project description:As a key enzyme in de novo pyrimidine biosynthesis, the expression level of dihydroorotate dehydrogenase (DHODH) has been reported to be elevated in various types of malignant tumors and its tumor-promoting effect was considered to relate to its pyrimidine synthesis function. Here, we revealed one intriguing potential mechanism that DHODH modulated β-catenin signaling in esophageal squamous cell carcinoma (ESCC). We demonstrated that DHODH directly bound to the NH2 terminal of β-catenin, thereby, interrupting the interaction of GSK3β with β-catenin and leading to the abrogation of β-catenin degradation and accumulation of β-catenin in the nucleus, which in turn, resulted in the activation of β-catenin downstream genes, including CCND1, E2F3, Nanog, and OCT4. We further demonstrated that the regulation of β-catenin by DHODH was independent of DHODH catalyzing activity. Univariate and multivariate analyses suggested that DHODH expression might be an independent prognostic factor for ESCC patients. Collectively, our study highlights the pivotal role of DHODH mediated β-catenin signaling and indicates that DHODH may act as a multi-functional switcher from catalyzing pyrimidine metabolism to regulating tumor-related signaling pathways in ESCC.

| S-EPMC7566478 | biostudies-literature

Aurora-A enhances malignant development of esophageal squamous cell carcinoma (ESCC) by phosphorylating β-catenin.

Project description:The Aurora-A gene encodes a serine/threonine protein kinase that is frequently overexpressed in several types of human tumors. The overexpression of Aurora-A has been observed to associate with the grades of differentiation, invasive capability and distant lymph node metastasis of esophageal squamous cell carcinoma (ESCC). However, the molecular mechanism by which Aurora-A promotes malignant development of ESCC is still largely unknown. In this study, we show that Aurora-A overexpression enhances tumor cell invasion and metastatic potential in vitro and in vivo. Furthermore, Aurora-A overexpression inhibits the degradation of β-catenin, promotes its dissociation from cell-cell contacts and increases its nuclear translocation. We also demonstrate for the first time that Aurora-A directly interacts with β-catenin and phosphorylates β-catenin at Ser552 and Ser675. Substitutions of serine residue with alanine at single or both positions substantially attenuate Aurora-A-mediated stabilization of β-catenin, abolish its cytosolic and nuclear localization as well as transcriptional activity. In addition, Aurora-A overexpression is significantly correlated with increased cytoplasmic β-catenin expression in ESCC tissues. In view of our results, we propose that Aurora-A-mediated phosphorylation of β-catenin is a novel mechanism of malignancy development of tumor.

| S-EPMC5528673 | biostudies-literature

Demethylzelasteral inhibits proliferation and EMT via repressing Wnt/β-catenin signaling in esophageal squamous cell carcinoma.

Project description:As a kind of tumor commonly seen, no effective treatment is available for esophageal squamous cell carcinoma (ESCC). Therefore, seeking a new treatment is urgent. Demethylzeylasteral (T-96) isolated from Tripterygium wilfordii root bark embraces outstanding good antitumor activity. However, as for the mechanism of T-96 work on ESCC cells, it is rarely reported. In this study, we found that T-96 has inhibition when ESCC cells are proliferating, migrating and cloning. Moreover, relevant effects are influenced by dose and time. And T-96 can result in the stop of G2/M phase and induce apoptosis of ESCC cells. In addition, the expressions of Cyclin B1, Cyclin D1, Bcl-2, PARP1 and Survivin were decreased after starch demethylation. Despite of this, Bax and PARP1's expressions went up. To add up, there was an obvious increase in the expression of E-cadherin, while that of N-cadherin, Vimentin and MMP9 decreased after T-96 treatment. Moreover, the expression of Wnt/β-Catenin pathway, which concerns proteins β-Catenin, c-Myc and Wnt3a decreased. Our study shows that T-96 inhibits the proliferation and migration of esophageal cancer cells through Wnt/β-catenin pathway. Moreover, it gives rise to cell cycle arrest and apoptosis. According to the research results, T-96 tends to be put into use when treating ESCC patients, thus laying the experimental foundation for clinical research.

| S-EPMC8176255 | biostudies-literature

SP4 Facilitates Esophageal Squamous Cell Carcinoma Progression by Activating PHF14 Transcription and Wnt/Β-Catenin Signaling.

Project description:Specificity protein 4 transcription factor (SP4), a member of the Sp/Krüppel-like family (KLF), could bind to GT and GC box promoters, and plays an essential role in transcriptional activating. Despite SP4 having been detected to be highly expressed in a variety of human tumors, its biological effect and underlying molecular mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. Our research discovered that high SP4 expression is detected in primary ESCC specimens and cell lines and is strongly associated with the ESCC tumor grade and poor prognosis. In vitro, knockdown of SP4 suppressed cell proliferation and cell-cycle progression and promoted apoptosis, whereas overexpression of SP4 did the opposite. In vivo, inhibiting SP4 expression in ESCC cells suppresses tumor growth. Subsequently, we demonstrated that SP4 acts as the transcriptional upstream of PHF14, which binds to PHF14 promoter region, thus promoting PHF14 transcription. PHF14 was also significantly expressed in patient tissues and various ESCC cell lines and its expression promoted cell proliferation and inhibited apoptosis. Moreover, knockdown of SP4 inhibited the Wnt/β-catenin signaling pathway, whereas overexpression of PHF14 eliminated the effects of SP4 knockdown in ESCC cells. These results demonstrate that SP4 activates the Wnt/β-catenin signaling pathway by driving PHF14 transcription, thereby promoting ESCC progression, which indicates that SP4 might act as a prospective prognostic indicator or therapeutic target for patients with ESCC.ImplicationsThis study identified SP4/PH14 axis as a new mechanism to promote the progression of ESCC, which may serve as a novel therapeutic target for patients with ESCC.

| S-EPMC10758695 | biostudies-literature

SAMD9 Promotes Postoperative Recurrence of Esophageal Squamous Cell Carcinoma by Stimulating MYH9-Mediated GSK3β/β-Catenin Signaling.

Project description:Recurrence is a challenge to survival after the initial treatment of esophageal squamous cell carcinoma (ESCC). But, its mechanism remains elusive and there are currently no biomarkers to predict postoperative recurrence. Here, the possibility of sterile alpha motif domain-containing protein 9 (SAMD9) as a predictor of postoperative recurrence of ESCC is evaluated and the molecular mechanisms by which SAMD9 promotes ESCC recurrence are elucidated. The authors found that the high level of SAMD9 is correlated with postoperative recurrence and poor prognosis of ESCC. Overexpression of SAMD9 promotes tumor stemness, angiogenesis, and EMT, while downregulation of SAMD9 reduced these phenotypes. Mechanistically, it is found that SAMD9 stimulated ubiquitination-mediated glycogen synthase kinase-3 beta (GSK-3β) degradation by interaction with myosin-9 (MYH9) and TNF receptor-associated factor 6 (TRAF6), which in turn activated Wnt/β-catenin pathway. Further, the authors demonstrated that silencing SAMD9 inhibited lung metastasis and tumor formation in vivo. Finally, the authors found that silencing MYH9 or β-catenin, or overexpressing GSK-3β inhibited SAMD9-stimulated ESCC cell stemness, EMT, angiogenesis, metastasis, and tumorigenicity. Together, the findings indicate that the SAMD9/MYH9/GSK3β/β-catenin axis promotes ESCC postoperative recurrence and that SAMD9 is a crucial target for ESCC therapy. Additionally, SAMD9 has the potential as a predictor of postoperative recurrence in ESCC.

| S-EPMC10104667 | biostudies-literature

BANCR Regulates The Cell Invasion And Migration In Esophageal Squamous Cell Carcinoma Through Wnt/?-Catenin Signaling Pathway.

Project description:Objective:To explore the regulation of long-chain noncoding BANCR on cell invasion and migration of esophageal squamous carcinoma cells and related mechanisms. Method:The mRNA expression of BANCR in esophageal squamous carcinoma cells and esophageal squamous cells was detected by quantitative PCR . The relationship between the expression of BANCR and the survival rate of patients with esophageal squamous cell carcinoma (ESCC) was analyzed by Kaplan-Meier method. The BANCR pair was detected by Transwell invasion and scratch test. In ESCC cell lines, the cells had invasion and migration ability; Western blot was applied to detect the expression of proteins involved in the Wnt/?-catenin signaling pathway. Results:BANCR revealed relatively high expression in esophageal squamous carcinoma cells, and the higher the expression of BANCR was, the lower the survival rate of patients with ESCC was. Inhibition of BANCR expression could effectively reduce the invasion and migration ability of esophageal squamous cell carcinoma. After silencing BANCR, the expression of wnt3a, survivin, ?-catenin and c-myc protein was downregulated compared with the negative control group (p<0.05). Conclusion:Long-chain noncoding BANCR was highly expressed in patients with ESCC and was negatively correlated with patients' survival time. It was of the capability to modulate the cell migration and invasion of ESCC cells through inducing Wnt/?-catenin signaling pathway.

| S-EPMC6847997 | biostudies-literature

Long noncoding RNA MALAT1 promotes malignant development of esophageal squamous cell carcinoma by targeting β-catenin via Ezh2.

Project description:Evidences have shown that lncRNAs involve in the initiation and progression of various cancers including esophageal squamous cell carcinoma (ESCC). The aberrant expression of lncRNA MALAT1 was investigated in 106 paired ESCC tissues and adjacent non-cancerous tissues by qRT-PCR. Down-regulated MALAT1 and Ezh2 over-expression plasmid were constructed respectively to analyze the expression of β-catenin, Lin28 and Ezh2 genes. We found that the MALAT1 expression level was higher in human ESCC tissues (P=0.0011), which was closely correlated with WHO grade (P=0.0395, P=0.0331), lymph node metastasis (P=0.0213) and prognosis (P=0.0294). Silencing of MALAT1 expression inhibited cell proliferation, migration and tumor sphere formation, while increasing cell apoptosis of esophageal cancer in vitro. Down-regulation of MALAT1 decreased the expression of β-catenin, Lin28 and Ezh2 genes, while over-expressed Ezh2 combined with MALAT1 down-regulation completely reversed the si-MALAT1-mediated repression of β-catenin and Lin28 in esophageal cancer cells. Animal experiments showed that knockdown of MALAT1 decreased tumor formation and improved survival. MALAT1 promotes the initiation and progression of ESCC, suggesting that inhibition of MALAT1 might be a potential target for treatment of ESCC.

| S-EPMC5041935 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data