Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. The specific cellular gene alterations responsible for hepatocarcinogenesis are not well known. Cytokine-induced antiapoptotic molecule (CIAPIN1), a recently reported antiapoptotic molecule which plays an essential role in mouse definitive hematopoiesis, is considered a downstream effecter of the receptor tyrosine kinase-Ras signaling pathway. However, the exact function of this gene in tumors is not clear. In this study, we reported that CIAPIN1 is highly expressed in HCC as compared with non-tumor hepatic tissue (P < 0.05). We employed adenovirus-mediated RNA interference technique to knock down CIAPIN1 expression in HCC cells and observed its effects on HCC cell growth in vitro and in vivo. Among the four HCC and one normal human liver cell lines we analyzed, CIAPIN1 was highly expressed in HCC cells. Knock down of CIAPIN1 could inhibit HCC cell proliferation by inhibiting the cell cycle S-phase entry. Soft agar colony formation assay indicated that the colony-forming ability of SMMC-7721 cells decreased by approximately 70% after adenovirus AdH1-small interfering RNA (siRNA)/CIAPIN1 infection. In vivo experiments showed that adenovirus AdH1-siRNA/CIAPIN1 inhibited the tumorigenicity of SMMC-7721 cells and significantly suppressed tumor growth when injected directly into tumors. These results suggest that knock down of CIAPIN1 by adenovirus-delivered siRNA may be a potential therapeutic strategy for treatment of HCC in which CIAPIN1 is overexpressed.
Carcinogenesis 2008 Aug
PMID:Adenovirus-delivered CIAPIN1 small interfering RNA inhibits HCC growth in vitro and in vivo. 1829 78

Molecularly targeted therapies aim to interfere with molecular mechanisms, selectively involved in carcinogenesis and tumor growth in order to optimize the efficacy and minimize the side effects of anticancer treatment. In the last decade, several receptor tyrosine kinase inhibitors (TKIs) have become approved for therapeutic use in hematological malignancies as well as solid tumors. However, a major challenge remains in the selection of patients most likely to respond to these agents. Successful examples of personalizing molecularly targeted therapies based on biomarkers include the use of trastuzumab in HER-2 overexpressing breast cancer and imatinib in c-KIT expressing gastrointestinal stromal tumor. In contrast, EGFR and anti-angiogenic TKIs have mostly been evaluated in unselected patient groups and so far no biomarkers that predict or reflect the efficacy of these TKIs have been validated in clinical practice. Nevertheless, potential biomarkers, including EGFR gene copy number and the absence of K-ras mutations for anti-EGFR agents, and functional imaging for anti-angiogenic agents, have been identified. These biomarkers await validation in randomized phase III trials to confirm their value in predicting drug efficacy. In order to maximize efficiency in the search for valid predictive biomarkers, there is an urgent need for the standardization of their assessment, as well as the techniques employed in their assays. This article will focus on studies that address biomarker discovery or validation for EGFR and anti-angiogenic TKIs, differentiating those markers that predict for drug efficacy (predictive markers) from those that reflect drug mechanisms of action or effects (pharmacodynamic markers).
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PMID:Progress and challenges in the identification of biomarkers for EGFR and VEGFR targeting anticancer agents. 1851 76

Blockade of the transient receptor potential channel vanilloid subfamily 1 (TRPV1) is suggested as a therapeutic approach to pain relief. However, TRPV1 is a widely expressed protein whose function might be critical in various nonneuronal physiologic conditions. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is overexpressed in many human epithelial cancers and is a potential target for anticancer drugs. Here, we show that TRPV1 interacts with EGFR, leading to EGFR degradation. Notably, the absence of TRPV1 in mice results in a striking increase in skin carcinogenesis. The TRPV1 is the first membrane receptor shown to have a tumor-suppressing effect associated with the down-regulation of another membrane receptor. The data suggest that, although a great deal of interest has focused on TRPV1 as a target for pain relief, the chronic blockade of this pain receptor might increase the risk for cancer development.
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PMID:Transient receptor potential type vanilloid 1 suppresses skin carcinogenesis. 1915 96

Two standardized anthocyanin-rich mixtures were investigated for their ability to inhibit the receptor tyrosine kinases (RTKs) EGFR, ErbB2, ErbB3, VEGFR-2, and VEGFR-3. Both mixtures reduced the kinase activity of recombinant kinase domains of each RTK at concentrations <or=12.9 microg/mL, with preferential inhibition of VEGFR-2 and EGFR (<or=3.4 microg/mL). Similarly, ligand-induced autophosphorylation of these RTKs in human vulva carcinoma or porcine aortic endothelial cells was suppressed by both mixtures, with ErbB3 and VEGFR-3 being preferentially inhibited. Anthocyanin-rich extracts completely abrogated VEGFR-3 phosphorylation at concentrations of >or=50 microg/mL. These results indicate that anthocyanin-rich mixtures can inhibit RTKs with low specificity. The rank order of inhibitory efficacy against the tested RTKs in intact cells was VEGFR-3 >> VEGFR-2 > ErbB3 > EGFR > ErbB2. Considering the important role of RTKs in carcinogenesis, their inhibition by anthocyanin-rich mixtures suggests that they may serve as biomarkers of the pharmacological efficacy of anthocyanins in future chemoprevention experiments and in clinical intervention studies.
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PMID:Suppression of the kinase activity of receptor tyrosine kinases by anthocyanin-rich mixtures extracted from bilberries and grapes. 1932 6

Met, the receptor for hepatocyte growth factor (HGF), is a receptor tyrosine kinase that has recently emerged as an important contributor to human neoplasia. In physiological and pathological conditions, Met triggers various cellular functions related to cell proliferation, cell migration and the inhibition of apoptosis, and also regulates a genetic program leading to coagulation. Since medulloblastomas (MBs) express high levels of tissue factor (TF), the main initiator of blood coagulation, we therefore examined the link between Met and TF expression in these pediatric tumors. We observed that stimulation of the MB cell line DAOY with HGF led to a marked increase of TF expression and procoagulant activity, in agreement with analysis of clinical MB tumor specimens, in which tumors expressing high levels of Met also showed high levels of TF. The HGF-dependent increase in TF expression and activity required Src family kinases and led to the translocation of TF to actin-rich structures at the cell periphery, suggesting a role of the protein in cell migration. Accordingly, addition of physiological concentrations of the TF activator factor VIIa (FVII) to HGF-stimulated DAOY cells promoted a marked increase in the migratory potential of these cells. Overall, these results suggest that HGF-induced activation of the Met receptor results in TF expression by MB cells and that this event probably contribute to tumor proliferation by enabling the formation of a provisional fibrin matrix. In addition, TF-mediated non-hemostatic functions, such as migration toward FVIIa, may also play a central role in MB aggressiveness.
Carcinogenesis 2009 Jul
PMID:c-Met activation in medulloblastoma induces tissue factor expression and activity: effects on cell migration. 1935 92

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm associated with asbestos exposure. Although expression and activation of receptor tyrosine kinases (RTKs), including MET, have been reported in most MPM, specific RTK inhibitors showed less than the expected response in MPM cells. To determine whether the lack of response of MET inhibitors was due to cooperation with other RTKs, we determined activation status of MET and other RTKs, including epidermal growth factor receptor (EGFR) family of 20 MPM cell lines, and tested whether dual RTK inhibition is an effective therapeutic strategy. We detected MET upregulation and phosphorylation (thus indicating activation) in 14 (70%) and 13 (65%) cell lines, but treatment with MET-specific inhibitors showed weak or modest effect of suppression in most of the cell lines. Phospho-RTK array analysis revealed that MET was simultaneously activated with other RTKs, including EGFR, ErbB2, ErbB3 and platelet-derived growth factor receptor-beta. Combination of MET and EGFR inhibitors triggered stronger inhibition on cell proliferation and invasion of MPM cells than that of each in vitro. These results indicated that coactivation of RTKs was essential in mesothelioma cell proliferation and/or survival, thus suggesting that simultaneous inhibition of RTKs may be a more effective strategy for the development of molecular target therapy for MPM.
Carcinogenesis 2009 Jul
PMID:Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells. 1938 May 21

The non-steroidal anti-inflammatory drug tolfenamic acid (TA) inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with half-maximal growth inhibitory concentration values of 36 and 48 muM, respectively. TA also increased Annexin V staining in both cell lines, indicative of proapoptotic activity. Treatment of SEG-1 and BIC-1 cells with TA for up to 72 h decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and this was accompanied by decreased expression of the well-characterized Sp-regulated genes cyclin D1, vascular endothelial growth factor and survivin. TA also decreased hepatocyte growth factor receptor, (c-Met), a receptor tyrosine kinase that is overexpressed in esophageal cancer cells and tumors and is an important drug target. Knockdown of Sp1, Sp3 and Sp4 by RNA interference in SEG-1 and BIC-1 cells also decreased c-Met expression, demonstrating that c-Met is an Sp-regulated gene in esophageal cancer cells. Sp1 was overexpressed in esophageal cancer cells and tumors and increased Sp1 staining was observed in esophageal tumors from patients. TA (20 mg/kg/day) also decreased tumor growth and weight in athymic nude mice bearing SEG-1 cells as xenografts and this was accompanied by increased apoptosis and decreased Sp1 and c-Met staining in tumors from treated mice. Thus, TA-dependent downregulation of Sp transcription factors and c-Met defines a novel chemotherapeutic approach for treatment of esophageal cancer.
Carcinogenesis 2009 Jul
PMID:Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met. 1940 33

GLI family members are zinc-finger transcription factors, which are involved in embryogenesis and carcinogenesis through transcription regulation of GLI1, CCND1, CCND2, FOXA2, FOXC2, RUNX2, SFRP1, and JAG2. GLI1 transcription is upregulated in a variety of human tumors, such as basal cell carcinoma, lung cancer, breast cancer, gastric cancer, pancreatic cancer, and esophageal cancer. Hedgehog signaling via Smoothened cascade and receptor tyrosine kinase (RTK) signaling via PI3K-AKT cascade induce stabilization of GLI1 protein, whereas G-protein coupled receptor (GPCR) signaling via Gs-PKA cascade induces degradation of GLI1 protein. Here we report integrative genomic analyses of the GLI1 gene. The GLI1 and ARHGAP9 genes are located in a tail-to-tail manner with overlapping 3'-ends. ARHGAP9 was expressed in bone marrow, spleen, thymus, monocytes, and macrophages, whereas GLI1 was almost undetectable in normal tissues or cells with predominant ARHGAP9 expression. Because overlapping sense and anti-sense transcripts are annealed to each other to give rise to double-stranded RNAs functioning as endogenous RNAi, GLI1 expression might be negatively regulated by ARHGAP9 transcripts. GLI-binding element with one base substitution at the +1589-bp position from the transcriptional start site (TSS) of the human GLI1 gene was completely conserved in chimpanzee GLI1, mouse Gli1, and rat Gli1 genes. Ten Smad-binding elements, double E-boxes for EMT regulators, and double N-boxes for HES/HEY family members within intron 1 of the human GLI1 gene were also conserved in mammalian GLI1 orthologs. GLI1 transcription is upregulated due to Hedgehog, and TGFbeta signaling activation, whereas GLI1 transcription is downregulated due to Snail/Slug, and Notch signaling activation. Together these facts indicate that Hedgehog, TGFbeta, and RTK signals positively regulate GLI1, and that Notch, and GsPCR signals negatively regulate the GLI1.
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PMID:Integrative genomic analyses on GLI1: positive regulation of GLI1 by Hedgehog-GLI, TGFbeta-Smads, and RTK-PI3K-AKT signals, and negative regulation of GLI1 by Notch-CSL-HES/HEY, and GPCR-Gs-PKA signals. 1951 67

The expression of proteinase-activated receptor (PAR)(2) in human hepatocellular carcinoma (HCC) was established by reverse transcription-polymerase chain reaction, confocal immunofluorescence and electron microscopy in permanent cell lines, primary HCC cell cultures and HCC tumor tissue. Stimulation of HCC cells with trypsin and the PAR(2)-selective activating peptide, 2-furoyl-LIGRLO-NH(2), increased cell invasion across Matrigel. Both effects were blocked by a PAR(2)-selective pepducin antagonist peptide (pal-PAR(2)) and by PAR(2) silencing with specific small interfering RNA (siRNA). PAR(2)-initiated HCC cell invasion was also blocked by inhibiting the hepatocyte growth factor receptor (Met receptor tyrosine kinase) with the receptor-targeted kinase inhibitors, SU 11274 and PHA 665752, or by downregulation of Met with specific siRNA. The involvement of Met in PAR(2)-mediated HCC invasive signaling was further supported by the finding that treatment of HCC cells with trypsin or the PAR(2)-selective agonist peptide, 2-furoyl-LIGRLO-NH(2), stimulated Met activation-phosphorylation. In addition, Met-dependent stimulation of p42/p44 mitogen-activated protein Kinases was found to be critical for the PAR(2)-Met receptor tyrosine kinase-invasive signaling axis in HCC cells. Our study establishes an important link between the PAR(2) and Met receptor tyrosine kinase signaling in promoting HCC cell invasion.
Carcinogenesis 2009 Sep
PMID:Met receptor tyrosine kinase transactivation is involved in proteinase-activated receptor-2-mediated hepatocellular carcinoma cell invasion. 1954 60

EphA5 is a member of the Eph receptor tyrosine kinase family, which plays a critical role in the regulation of carcinogenesis. Our previous DNA methylation microarray results suggested that the CpG islands in the EphA5 promoter exhibited higher methylation levels in breast cancer tissues. In this study, we further analyzed EphA5 gene expression profiles, methylation status, and clinical implications in breast cancer. We found that the level of EphA5 mRNA was dramatically decreased in 5 different breast cancer cell lines. After treating the cell lines with 5-aza-2'-deoxycytidine (5-aza-dC, a demethylation agent), the levels of EphA5 mRNA and protein were significantly increased. Bisulfite sequencing and methylation-specific polymerase chain reaction detection showed that decreased expression of EphA5 was associated with its methylation status. We also found a significant correlation (P = .017) between the reduction of EphA5 mRNA levels and aberrant methylation of EphA5 in 31 paired tissue samples. In clinical samples, EphA5 methylation was detected in 64.1% (75/117) of breast tumors and 28.2% (33/117) of paired normal tissues (P < .001), which was associated with higher tumor grade (P = .024), lymph node metastasis (P = .004), and progesterone receptor-negative status (P = .008). Our data indicate that EphA5 might be a potential target for epigenetic silencing in primary breast cancer and a valuable molecular marker for breast cancer carcinogenesis and progression.
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PMID:Frequent epigenetic inactivation of the receptor tyrosine kinase EphA5 by promoter methylation in human breast cancer. 1973 95


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