Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0546837 (esophageal cancer)
 8,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Esophageal cancer is difficult to treat because of its rapid progression, and more effective therapeutic approaches are needed. The PPARgamma is a nuclear receptor superfamily member that is expressed in many cancers. PPARgamma expression is a feature of esophageal cancer cell lines, and in the present investigation, the PPARgamma antagonists T0070907 and GW9662 could induce loss of invasion but could not induce growth reduction or apoptosis at low concentrations (< 10 mM). A high concentration of antagonists (50 microM) inhibited cell growth and induced apoptosis, but these effects did not explain our result at the low concentration. Morphological change, decreased expression of the cell signaling pathway and inhibition of cancer cell invasion were observed in the low concentration. This suggested that PPARgamma antagonists inhibited esophageal cancer cell invasion as well as cell adherence, most likely due to alteration in the FAK-MAPK pathway, and this was independent of apoptosis. These results suggested that PPARgamma plays an important role in cancer cell invasion and that it might be a novel target for therapy of esophageal cancer.
 ...
PMID:Inhibition of peroxisome proliferator-activated receptor gamma activity in esophageal carcinoma cells results in a drastic decrease of invasive properties. 1680 24

Esophageal cancer is one of the most aggressive cancers in the world. Novel preventive and therapeutic strategies tend to target the key molecules involved in the signaling transduction pathways for cell growth. It is known that FAK and mTOR are important controllers of cell growth. TAE226, a novel small molecule compound, is a potent ATP competitive inhibitor of FAK and IGF-IR. TAE226 can block FAK and IGF-IR signaling pathways. The purpose of this study was to explore the inhibitory effects on mTOR signaling and the mechanism of cell growth suppression by TAE226. We examined the expression of mTOR and S6 in esophageal cancer cells (SEG-1) and normal esophageal epithelial cells (KOB-13) and the efficacy of TAE226 against SEG-1 cells. mTOR and S6 were overexpressed in SEG-1 cells compared with KOB-13 cells. TAE226 inhibited the expression of mTOR, Akt, p70S6K and S6 as well as the phosphorylation of mTOR (Ser2448), Akt (Ser473), p70S6K (Thr389) and S6 (Ser240/244). As a result, TAE226 induced a dose-dependent decrease in cell growth (number) and damage in the cell shape. Together, these data show that TAE226 has potent inhibitory effects on mTOR signaling and esophageal cancer cell growth indicating that TAE226 has potential application in esophageal cancer treatment.
 ...
PMID:TAE226, a dual inhibitor for FAK and IGF-IR, has inhibitory effects on mTOR signaling in esophageal cancer cells. 1902 Jul 30

Drugs in clinical use with indole structure exhibit side effects. Therefore, to search for indole compounds with more efficacy and less side effect for cancer therapy, we developed a novel indole compound SK228 and examined its effects and mechanisms on antitumor growth and invasion inhibition in cell and tumor xenografts in nude mice models. SK228 significantly inhibited growth of different lung and esophageal cancer cell lines at sub-micromolar range, but not normal lung cells. SK228 induced DNA damages mainly by producing reactive oxygen species (ROS) resulting in apoptosis. SK228 treatment increased the release of cytochrome c into the cytosol along with the increased activity of caspase-3 and -9 without affecting caspase-8, whereas these effects were attenuated by ROS inhibitor. The expression levels of BCL-2 family regulators were also affected. Moreover, low-dose SK228 significantly reduced the invasion of cancer cells. The active phosphorylated form of FAK/Paxillin signaling pathway proteins and active form of RhoA were decreased. Moreover, the F-actin cytoskeleton was disrupted after low-dose SK228 treatment. Growth of an A549 tumor cell xenograft was markedly inhibited without significant side effects. SK228-induced apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry of cleaved caspase-3 in tumors from treated mice. Our study provides the first evidence that SK228 exhibits cancer cell-specific cytotoxicity by inducing mitochondria-mediated apoptosis. In addition, SK228 inhibits cancer cell invasion via FAK/Paxillin disruption at noncytotoxic doses. SK228 can be further tested as a pharmaceutical compound for cancer treatment.
 ...
PMID:The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse. 2201 44

Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK-Raf-MEK1/2-ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment.
 ...
PMID:Rab25 is a tumor suppressor gene with antiangiogenic and anti-invasive activities in esophageal squamous cell carcinoma. 2299 5

Tumor endothelial cells have been found to be associated with metastasis and cancer progression. In this study, we reported that human esophageal cancer endothelial cells (HECEC), unlike corresponding human esophageal normal endothelial cells (HENEC) displayed several distinct feature couple with unique gene expression profile. Further studies showed that HECEC can enhance migration, invasion and self-renewal properties of esophageal carcinoma cell in vitro by a direct cell-cell interaction. In vivo assay demonstrated that HECEC could significantly enhance the invasion and lung metastasis of esophageal cancer cells. To elucidate the molecular mechanisms of HECEC in esophageal carcinoma progression, we employed the microarray to analyze the gene expression profiles before and after treating with HECEC, HENEC or conditioned meium from HECEC. Among the highly expressed HECEC-regulated genes, we focused on Epiregulin (EREG). Further studies demonstrated that overexpression of EREG in EC9706 or Kyse30 cells can induce actin reorganization, sphere formation ability and a significantly enrichment of CD44+ cancer stem-like cells. Moreover, up-regulation of EREG in esophageal cancer cells could enhance lung metastasis and decrease the survival time in vivo. Further study indicated that EREG could induce activation of the Src and FAK. In addition, all these effects could also be inhibited by the function-blocking anti-EREG antibody in a dose dependent manner. Immunohistochemical analysis revealed that high level of EREG was significantly correlated with lymph node metastases and poor prognosis. In summary, HECEC play key roles in enhancing the invasion, migration, cancer stem cell phenotype and metastatic potential of esophageal cancer cells through Epiregulin.
 ...
PMID:Tumor endothelial cells promote metastasis and cancer stem cell-like phenotype through elevated Epiregulin in esophageal cancer. 2782 17

Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer. Long noncoding RNAs (lncRNAs) are thought to play a critical role in cancer development. Recently, lncRNA CASC9 was shown to be dysregulated in many cancer types, but the mechanisms whereby this occurs remain largely unknown. In this study, we found that CASC9 was significantly upregulated in ESCC tissues, with further analysis revealing that elevated CASC9 expression was associated with ESCC prognosis and metastasis. Furthermore, we found that CASC9 knockdown significantly repressed ESCC migration and invasion in vitro and metastasis in nude mice in vivo. A microarray analysis and mechanical experiments indicated that CASC9 preferentially affected gene expression linked to ECM-integrin interactions, including LAMC2, an upstream inducer of the integrin pathway. We demonstrated that LAMC2 was consistently upregulated in ESCC and promoted ESCC metastasis. LAMC2 overexpression partially compromised the decrease of cell migration and invasion capacity in CASC9 knockdowns. In addition, we found that both CASC9 and LAMC2 depletion reduced the phosphorylation of FAK, PI3K, and Akt, which are downstream effectors of the integrin pathway. Moreover, the reduction in phosphorylation caused by CASC9 depletion was rescued by LAMC2 overexpression, further confirming that CASC9 exerts a pro-metastatic role through LAMC2. Mechanistically, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assay indicated that CASC9 could bind with the transcriptional coactivator CREB-binding protein (CBP) in the nucleus. Chromatin immunoprecipitation (ChIP) assay additionally illustrated that CASC9 increased the enrichment of CBP and H3K27 acetylation in the LAMC2 promoter, thereby upregulating LAMC2 expression. In conclusion, we demonstrate that CASC9 upregulates LAMC2 expression by binding with CBP and modifying histone acetylation. Our research reveals the prognostic and pro-metastatic roles for CASC9 in ESCC, suggesting that CASC9 could serve as a biomarker for prognosis and a target for metastasis treatment.
 ...
PMID:LncRNA CASC9 promotes esophageal squamous cell carcinoma metastasis through upregulating LAMC2 expression by interacting with the CREB-binding protein. 2951 40

The direct anti-proliferative and pro-apoptotic effects of local anesthetics have been well documented in various cancers. However, whether local anesthetics affect cancer metastasis and their underlying molecular mechanisms are not well understood. In this work, we show that ropivacaine at the clinically relevant concentration significantly inhibits esophageal cancer cell migration. Interestingly, ropivacaine at the same concentration does not display inhibitory effects on esophageal cancer cell growth and survival. We further demonstrate that ropivacaine significantly decreases activities of GTPases including RhoA, Rac1 and Ras, and inhibits prenylation in esophageal cancer cells. In addition, the inhibitory effects of ropivacaine on GTPases activities and migration are abolished in the presence of geranylgeraniol and farnesol, demonstrating that ropivacaine inhibits GTPases activities via prenylation inhibition. Finally, we demonstrate that ropivacaine-inhibited esophageal cancer cell inhibition occurs independently of sodium channel but via suppressing Rac1/JNK/paxillin/FAK pathway. Our work demonstrates the potent anti-migratory effect of ropivacaine in esophageal cancer by attenuating prenylation-dependent migratory signalling events. These findings provide significant insight into the potential mechanisms by which local anaesthetics may negatively affect metastasis.
 ...
PMID:Ropivacaine inhibits the migration of esophageal cancer cells via sodium-channel-independent but prenylation-dependent inhibition of Rac1/JNK/paxillin/FAK. 2977 1