Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence suggests that multiple tumors, including pancreatic adenocarcinoma, display heterogeneity in parameters that are critical for tumor formation, progression and metastasis. Understanding heterogeneity in solid tumors is increasingly providing a plethora of new diagnostic and therapeutic approaches. In this study, a particular focus was put on identifying a subpopulation of stem cell-like, slow cycling tumor cells in a pancreas adenocarcinoma cell lines. Using a label retention technique a subpopulation of slow cycling cells (DiI+/SCC) was identified and further evaluated in the BxPC-3 and Panc03.27 cell lines. These slowly cycling cells managed to retain the lipophilic labeling dye DiI, while the bulk of the cells (>94%) did not. The DiI+/SCC population, showed only a partial overlap with the CSC markers CD24(+)/CD44(+), CD133(+) and ALDH but they survived chemotherapeutic treatment, and were able to recreate the initial heterogeneous tumor cell population. DiI+/SCCs exhibited an increased invasive potential as compared with their non-label retaining, faster cycling cells (DiI-/FCC). They also had increased tumorigenic potential and morphological changes resembling cells that have undergone an epithelial to mesenchymal transition (EMT). Analysis of DiI+/SCC cells by real time PCR revealed a selective up-regulation of tell tale components of the Hedgehog/TGFbeta pathways, as well as a down-regulation of EGFR, combined with a shift in crucial components implied in EMT. The presented findings offer an expanded mechanistic understanding that associates tumor initiating potential with cycling speed and EMT in pancreatic cancer cell lines.
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PMID:Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma. 1942 80

Cervical displasia are classified as CIN-I, CIN-II and CIN-III. It has been observed that in at least 60% of CIN-I and CIN-II, the pathology disappears spontaneously, while around 30% persist at 24 months, 10% progress to CIN-III and 1% develops as a SCC. The factors involved in the evolution of the pathology are not defined, although infection of HPV is a necessary condition, but not the only one. For this reason, the identification of genetic changes is an essential element for understanding the carcinogenic process. It can also serve as a helpful tool for identifying patients who may be susceptible to its evolution and treatment, from patients whose lesions could regress spontaneous and for whom periodic follow-ups would be enough. Fifty three cervical biopsies from patients with dysplasia and ISCC were included in the study. These biopsies were set into nine macroarrays. Eight genes and five proteins were examined in each samples (hTERT, PIK3CA, hTERC, MYC, CCND1, BCL2, ZNF217 and p16) by fluorescence in situ hybridization (FISH) and/or immunohistochemistry (IHC). The results reflected that the genetic alterations of PIK3CA, ZNF217 and CCND1 were associated with the evolution of normal tissue to CIN I, those of hTERC and ERBB with the evolution of LSIL to HSIL, those of hTERT and MYC with the evolution of CIN-II/CIN-III to ISCC, and those of BCL-2 with the inception of ISCC. With regards to proteins, the expression of MYC and CCND1 in the initial stages of the illness would help in the acquisition of the altered cellular phenotype.
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PMID:Analysis of gene status in cervical dysplastic lesions and squamous cell carcinoma using tissue microarrays. 1947 28

It is established that tumor cell-derived VEGF acts on endothelial cells to promote angiogenesis and tumor growth. Here, we demonstrate that in K5-SOS-dependent mouse skin tumors, autocrine VEGF is required for tumor cell proliferation in a cell-autonomous and angiogenesis-independent manner. VEGF is upregulated in SOS-expressing tumors, and its deletion in epidermal cells delays tumorigenesis by suppressing angiogenesis and tumor cell proliferation. Epidermis-specific Flt1 deletion also impairs tumorigenesis and proliferation. Surprisingly, complete tumor inhibition occurs in the absence of VEGF in EGFR mutant mice, demonstrating that VEGFR and EGFR synergize in neoplastic cells to promote tumor growth. Mechanistically, K5-SOS upregulates VEGF, Flt1, and Neuropilin-1 in an Erk-dependent manner, thereby activating an autocrine proliferation loop, whereas EGFR prevents tumor cells from apoptosis. Moreover, Flt1 is upregulated in human SCC, and its inhibition in SCC cells impairs proliferation. Thus, in addition to regulating angiogenesis, VEGF has to be considered as a potent growth factor for epidermal tumors.
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PMID:Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. 2014 40

Aberrant promoter methylation of the checkpoint gene with forkhead-associated domain and ring finger (CHFR) gene is frequently detected in human cancer. We previously demonstrated that diminished CHFR expression was significantly correlated with both poor prognosis and heavy smoking in nonsmall cell lung cancer (NSCLC). Conversely, epidermal growth receptor (EGFR) mutation is detected in NSCLC among those who have never smoked or smoked lightly. To address the frequency of CHFR hypermethylation as well as differences in the distributions and clinicopathologic backgrounds against EGFR mutation in NSCLC, we investigated a large group of 208 NSCLC patients, including 165 with adenocarcinoma (ADC), 40 with squamous cell carcinoma and three others. We found that CHFR hypermethylation and EGFR mutation are mutually exclusive and have contrastive clinicopathologic backgrounds in NSCLC. Methylation-specific polymerase chain reaction (MSP) and direct DNA sequencing were performed to detect CHFR hypermethylation and EGFR mutation, respectively. CHFR hypermethylation was found in 29 cases (14%) (16 ADC (8%), 12 SCC (6%) and one adenosquamous carcinoma), while EGFR mutation was detected in 48 (23%) cases, all of which were ADC. CHFR hypermethylation and EGFR mutation were mutually exclusive (p = 0.004). NSCLC with altered CHFR was significantly correlated with smoking history, poor differentiation, lymphatic invasion, and poor prognosis; this contrasted sharply with EGFR mutation, which had statistically better clinical outcomes. Our results demonstrate that CHFR loss might be critical for the tumorigenesis of NSCLC in patients with a history of smoking and induces tumors of a more malignant phenotype than the EGFR mutation. Thus, CHFR alteration should be considered a therapeutic target against NSCLC in patients with poor prognoses.
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PMID:CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non-small cell lung cancer. 2047 35

The purpose of the study was to analyse the influence of HPV infection on the outcome of a randomized clinical trial of conventional (CF) versus 7-days-a-week postoperative radiotherapy (p-CAIR) for squamous cell cancer of the head and neck (SCCHN). Between 2001 and 2004, 279 patients with high-risk SCC of the larynx or cancer of the oral cavity/oropharynx were randomized to receive 63 Gy in fractions of 1.8 Gy given 5 days a week or 7 days a week (Radiother Oncol 87:155-163, 2008). The presence of HPV DNA in 131 archival paraffin blocks was assessed with multiplex quantitative real-time PCR using five consensus primers for the conservative L1 region and molecular beacon probes targeting 14 high-risk HPV subtypes. Following the RT-PCR procedure, we could determine the presence and type of HPV16, HPV18 and the other 12 less frequent oncogenic subtypes. Out of 131 samples, 9 were positive for HPV infection (6.9%), all of them with HPV16 subtype. None of the 65 laryngeal tumours was HPV positive. The 5-year LRC in HPV-positive patients was 100%, compared to 58% in the HPV-negative group (p = 0.02, log-rank test). Amongst 122 patients with HPV-negative tumours, 5-year LRC was 50.3% in p-CF versus 65.2 in p-CAIR (p = 0.37). HPV infection was associated with low expression of EGFR and cyclin D. This study demonstrates a favourable outcome for HPV-positive patients with SCCHN treated with postoperative radiotherapy. While considering the small number of HPV+ tumours, the data set can be considered as hypothesis generating only, the outcome raises new questions on the necessity of aggressive postoperative treatment in HPV+ patients.
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PMID:Impact of HPV infection on the clinical outcome of p-CAIR trial in head and neck cancer. 2093 70

The aim of this study was to develop poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lac(n))) core-crosslinked thermosensitive biodegradable polymeric micelles suitable for active tumor targeting, by coupling the anti-EGFR (epidermal growth factor receptor) EGa1 nanobody to their surface. To this end, PEG was functionalized with N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) to yield a PDP-PEG-b-p(HPMAm-Lac(n)) block copolymer. Micelles composed of 80% mPEG-b-p(HPMAm-Lac(n)) and 20% PDP-PEG-b-p(HPMAm-Lac(n)) were prepared and lysozyme (as a model protein) was modified with N-succinimidyl-S-acetylthioacetate, deprotected with hydroxylamine hydrochloride and subsequently coupled to the micellar surface. The micellar conjugates were characterized using SDS-PAGE and gel permeation chromatography (GPC). Using the knowledge obtained with lysozyme conjugation, the EGa1 nanobody was coupled to mPEG/PDP-PEG micelles and the conjugation was successful as demonstrated by western blot and dot blot analysis. Rhodamine labeled EGa1-micelles showed substantially higher binding as well as uptake by EGFR over-expressing cancer cells (A431 and UM-SCC-14C) than untargeted rhodamine labeled micelles. Interestingly, no binding of the nanobody micelles was observed to EGFR negative cells (3T3) as well as to14C cells in the presence of an excess of free nanobody. This demonstrates that the binding of the nanobody micelles is indeed by interaction with the EGF receptor. In conclusion, EGa1 decorated (mPEG/PDP-PEG)-b-(pHPMAm-Lac(n)) polymeric micelles are highly promising systems for active drug targeting.
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PMID:Nanobody-shell functionalized thermosensitive core-crosslinked polymeric micelles for active drug targeting. 2168 29

Hepatocyte growth factor (HGF) and c-Met have recently attracted a great deal of attention as prognostic indicators of patient outcome, and they are important in the control of tumor growth and invasion. Epigallocatechin-3-gallate (EGCG) has been shown to modulate multiple signal pathways in a manner that controls the unwanted proliferation and invasion of cells, thereby imparting cancer chemopreventive and therapeutic effects. In this study, we investigated the effects of EGCG in inhibiting HGF-induced tumor growth and invasion of oral cancer in vitro and in vivo. We examined the effects of EGCG on HGF-induced cell proliferation, migration, invasion, induction of apoptosis and modulation of HGF/c-Met signaling pathway in the KB oral cancer cell line. We investigated the antitumor effect and inhibition of c-Met expression by EGCG in a syngeneic mouse model (C3H/HeJ mice, SCC VII/SF cell line). HGF promoted cell proliferation, migration, invasion and induction of MMP (matrix metalloproteinase)-2 and MMP-9 in KB cells. EGCG significantly inhibited HGF-induced phosphorylation of Met and cell growth, invasion and expression of MMP-2 and MMP-9. EGCG blocked HGF-induced phosphorylation of c-Met and that of the downstream kinases AKT and ERK, and inhibition of p-AKT and p-ERK by EGCG was associated with marked increases in the phosphorylation of p38, JNK, cleaved caspase-3 and poly-ADP-ribose polymerase. In C3H/HeJ syngeneic mice, as an in vivo model, tumor growth was suppressed and apoptosis was increased by EGCG. Our results suggest that EGCG may be a potential therapeutic agent to inhibit HGF-induced tumor growth and invasion in oral cancer.
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PMID:Green tea (-)-epigallocatechin-3-gallate inhibits HGF-induced progression in oral cavity cancer through suppression of HGF/c-Met. 2129 66

Green tea and its major active component, epigallocatechin-3-gallate (EGCG), have been reported to have anticancer activity on various cancers. However, the exact molecular mechanism of its anticancer activity is still not well understood. We investigated the anticancer activity of green tea extract (GTE) and EGCG on 3 human squamous carcinoma cell lines (CAL-27, SCC-25, and KB) in vitro. We also examined the effects of GTE and EGCG on cell signaling networks using our newly developed Pathway Array technology, which is an innovative proteomic assay to globally screen changes in protein expression and phosphorylation. Our results demonstrated that GTE and EGCG inhibited all 3 squamous carcinoma cells' growth via S and G(2)/M phase arrest, but different sensitivities to GTE and EGCG in different cell lines were observed: CAL-27 cells were more sensitive to the both agents than SCC-25 and KB cells, and GTE at an EGCG equivalent concentration displayed a stronger inhibition than EGCG alone. The Pathway Array assessment of 107 proteins indicated that different signaling pathways were activated in different cell lines, suggesting heterogeneity at the signaling network level. After treatment with GTE or EGCG, a total of 21 proteins and phosphorylations altered significantly in all 3 cell lines based on analysis of variance (ANOVA) (P < 0.05). The major signaling pathways affected by GTE and EGCG were EGFR and Notch pathways, which, in turn, affected cell cycle-related networks. These results suggested that GTE and EGCG target multiple pathways or global networks in cancer cells, which resulted in collective inhibition of cancer cell growth. The finding pointed out the future direction to study the underlying mechanism of the chemotherapeutic and chemopreventive activities of EGCG and GTE.
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PMID:The effect of green tea extract and EGCG on the signaling network in squamous cell carcinoma. 2139 Nov 27

This study investigated different methods of EGFR (Epithelial Growth Factor Receptor) targeting in feline squamous cell carcinoma with the ultimate aim of establishing a large animal model of human head and neck cancer. Both small molecule receptor tyrosine kinase inhibitor (TKI) and RNA interference (RNAi) techniques were employed to target the feline EGFR. We demonstrated that the human drug gefitinib caused a reduction in cell proliferation and migration in a feline cell line. However, we also document the development of resistance that was not associated with mutation in the kinase domain. RNAi caused a potent reduction in EGFR activity and was able to overcome acquired gefitinib resistance. In addition, RNAi targeting of EGFR, but not gefitinib, caused an additive effect on cell killing when combined with radiation. These results support the use of feline SCC as a model of head and neck cancer in man in the search for novel and effective treatments for both tumors.
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PMID:Studies on the inhibition of feline EGFR in squamous cell carcinoma: enhancement of radiosensitivity and rescue of resistance to small molecule inhibitors. 2146 10

5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent that inhibits the growth and initiates the apoptosis of epithelial tumors, including squamous cell carcinoma of the head and neck region. However, resistance to this drug is often observed in a clinical setting. The primary mode of action of 5-FU is believed to be the inhibition of thymidylate synthase. Overexpression of the enzymes involved in thymidine synthesis has been shown in some cases to be associated with resistance. However, the detailed mechanisms of resistance of squamous cell carcinoma are not fully understood. In the present study, we examined the involvement of survival signaling pathways in the resistance of squamous carcinoma cells to 5-FU. 5-FU induced the activation of the ERK and Akt kinases in UM-SCC-23 human squamous carcinoma cells, indicating that this anticancer drug activates survival signaling pathways as well as apoptotic signals. In 5-FU-resistant UM-SCC-23 cells established by our group, ERK and Akt signals were constitutively activated. U0126 is an inhibitor of MEK, which is an upstream activator for ERK. U0126 failed to sensitize resistant UM-SCC-23 cells to 5-FU-induced apoptotic cell death. This is in sharp contrast to LY294002, which is an inhibitor of phosphatidylinositol 3-kinase, an upstream activator for Akt. LY294002 drastically enhanced 5-FU-induced apoptotic cell death in resistant UM-SCC-23 cells. These results indicate that the Akt survival signal plays an important role in the resistance of squamous carcinoma cells to 5-FU treatment, and suggest that the modification of Akt activity might provide a new strategy for human 5-FU-resistant squamous carcinoma therapy.
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PMID:AKT plays a pivotal role in the acquisition of resistance to 5-fluorouracil in human squamous carcinoma cells. 2147 74


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