Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endoplasmic reticulum protein 29 (ERp29) is a novel endoplasmic reticulum (ER) secretion factor that facilitates the transport of secretory proteins in the early secretory pathway. Recently, it was found to be overexpressed in several cancers; however, little is known regarding its function in breast cancer progression. In this study, we show that the expression of ERp29 was reduced with tumor progression in clinical specimens of breast cancer, and that overexpression of ERp29 resulted in G(0)/G(1) arrest and inhibited cell proliferation in MDA-MB-231 cells. Importantly, overexpression of ERp29 in MDA-MB-231 cells led to a phenotypic change and mesenchymal-epithelial transition (MET) characterized by cytoskeletal reorganization with loss of stress fibers, reduction of fibronectin (FN), reactivation of epithelial cell marker E-cadherin and loss of mesenchymal cell marker vimentin. Knockdown of ERp29 by shRNA in MCF-7 cells reduced E-cadherin, but increased vimentin expression. Furthermore, ERp29 overexpression in MDA-MB-231 and SKBr3 cells decreased cell migration/invasion and reduced cell transformation, whereas silencing of ERp29 in MCF-7 cells enhanced cell aggressive behavior. Significantly, expression of ERp29 in MDA-MB-231 cells suppressed tumor formation in nude mice by repressing the cell proliferative index (Ki-67 positivity). Transcriptional profiling analysis showed that ERp29 acts as a central regulator by upregulating a group of genes with tumor suppressive function, for example, E-cadherin (CDH1), cyclin-dependent kinase inhibitor (CDKN2B) and spleen tyrosine kinase (SYK), and by downregulating a group of genes that regulate cell proliferation (eg, FN, epidermal growth factor receptor (EGFR) and plasminogen activator receptor (uPAR)). It is noteworthy that ERp29 significantly attenuated the overall ERK cascade, whereas the ratio of p-ERK1 to p-ERK2 was highly increased. Taken together, our results showed that ERp29 is a novel regulator leading to cell growth arrest and cell transition from a proliferative to a quiescent state, and reprogramming molecular portraits to suppress the tumor growth of MDA--MB--231 breast cancer cells.
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PMID:Overexpression of endoplasmic reticulum protein 29 regulates mesenchymal-epithelial transition and suppresses xenograft tumor growth of invasive breast cancer cells. 1986 66

The LGI1 gene has been implicated in tumor cell invasion through regulation of the ERK pathway. To determine whether human prostate cancer cells (PC3, 22RV, Du145) are similarly affected by exposure to LGI1, we conducted scratch wound assays and demonstrated that the secreted LGI1 protein can reduce cell motility, an essential component of invasion and metastasis. These studies have now been extended to an in vivo mouse model of prostate cancer. Using a BAC transgenic mouse expressing a GFP reporter gene under the control of cis regulatory elements, we demonstrated that LGI1 is highly expressed in the normal prostate epithelium. To determine whether loss of LGI1 expression is associated with development and progression of murine prostate cancer, we bred the GFP reporter BAC transgenic mice with TRAMP mice which undergo early hyperplasia and progressive stages of prostate cancer. In the F1 animals, although the surrounding normal prostate epithelium expressed high levels of LGI1 in the double transgenic mice, the LGI1 gene had been inactivated even at the earliest stages of hyperplasia. This observation supports the suggestion that inactivation of LGI1 in certain cell types is related to tumor progression. Taken together these results suggest that LGI1 may be an important molecule for the arrest of prostate cancer cell invasion and possibly as a biomarker for early detection of prostate hyperplasia.
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PMID:Inactivation of LGI1 expression accompanies early stage hyperplasia of prostate epithelium in the TRAMP murine model of prostate cancer. 1977 37

Human LATS1 and LATS2) (LATS1/2) are tumor suppressors that have been shown to be mutated or downregulated in several human cancers including leukemia, lung, prostate and breast cancers. However, the precise mechanisms and the proteins modulated by LATS1/2 that are responsible for these events remain largely unknown. To elucidate potential signaling pathways, the current study investigated the expression profile in HeLa cells with reduced expression of LATS1/2. Using RNA-mediated interference, both LATS1 and LATS2 were substantially knocked-down, and accordingly, this lead to an increase in multiple phenotypes associated with tumor progression, including enhanced cell proliferation, resistance to drug-induced cell death, and increased cell migration. Using whole human genome Oligo (60-mer) arrays (Agilent), genes modulated by loss of LATS1/2 were identified and functionally grouped into categories including cell proliferation, cell death, cell adhesion and motility, as well as cell communication. Selected genes, including known tumor suppressor genes and oncogenes such as CDKN1A, WISP2, SLIT2, TP53INP1, BIRC4BP, SPRY2, SPRY4, SPRED1, FAT4, and CYR61 were confirmed by qRT-PCR to be significantly differentially expressed. Importantly, the collection of genes identified suggests that LATS1/2 function through diverse mechanisms and multiple signaling pathways including the Hippo signaling pathway, as well as the p53, Ras-ERK, or WNT networks, to inhibit tumor progression.
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PMID:Identification of LATS transcriptional targets in HeLa cells using whole human genome oligonucleotide microarray. 1979 73

The extracellular matrix (ECM), in collaboration with intracellular signal, plays a critical role in the modulation of cellular behavior and function. Herein, we investigated the influence of fibronectin (FN) and tumor necrosis factor-alpha (TNF-alpha) on OPN expression in HN-22, a human head and neck squamous cell carcinoma (HNSCC) cell line. The data showed that TNF-alpha significantly increased OPN expression only in the FN-coated condition. Application of function-blocking antibody directed against beta1 integrin abolished this OPN induction. Moreover, TNF-alpha when added together with activating beta1 integrin antibody is sufficient to induced OPN expression. The combination effect of FN and TNF-alpha was significantly deteriorated by a MEK inhibitor, but not NF-kappaB inhibitor. We further demonstrated that the phosphorylation of ERK1/2 was strongly enhanced by TNF-alpha and FN compared to the application of either one alone. Synergistic effect on ERK1/2 phosphorylation was also detected by TNF-alpha and activating beta1 integrin antibody, whereas inhibitory antibody to beta1 integrin attenuated FN and TNF-alpha-induced phosphorylation of ERK1/2. Our results indicate that FN coordinates TNF-alpha-mediated OPN induction via beta1 integrin-dependent signaling mechanism that activates ERK. The results suggest the critical role of tumor micro-environment signaling networks on the regulation of cytokine expression profiles during tumor progression.
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PMID:Fibronectin supports TNF-alpha-induced osteopontin expression through beta1 integrin and ERK in HN-22 cells. 2005 94

Kiss-1 has been identified as a putative metastasis suppressor gene in various human malignancies. However, there is little information about its possible role in gastric carcinoma. In this study, we determined whether the Kiss-1 gene negatively regulates MMP-9 expression. cDNA microarray technology was used to identify the genes associated with metastasis by hepatocyte growth factor (HGF) in the gastric cancer cell lines, NUGC-3 and MKN-28. The levels of Kiss-1 RNA and protein were confirmed to be upregulated in HGF-treated gastric cancer cells. HGF induced Kiss-1 and MMP-9 production in a dose-dependent manner. In order to investigate roles of HGF signaling in tumor progression and metastasis, we measured effects of a specific MEK1 inhibitor (PD 098059) and a p38 kinase inhibitor (SB 203580) on HGF-mediated cell proliferation and MMP-9. Pretreatment with PD 098059 reduced MMP-9 and HGF-mediated cell proliferation, but increased Kiss-I expression. In contrast, SB 203580 pretreatment enhanced MMP-9 and cell prolifera-tion, but decreased Kiss-1 expression. Cotreatment of PD098059 and SB203580 increased the p38 phosphorylation stimulated by HGF. These results suggest that the HGF-mediated Kiss-1 overexpression is regulated mainly by the p38 activation and, furthermore, the activation of ERK might affect HGF-mediated Kiss-1 expression indirectly by the regulation of p38 kinase. Consistent with this result, p38 phosphorylation was strongly repressed by the knock-down of Kiss-1. Downregulation of Kiss-1 using Kiss-1 shRNA also increased in vitro cell invasion. In conclusion, Kiss-1 suppresses MMP-9 expression by activating the p38 MAP kinase signaling pathway.
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PMID:Kiss-1 suppresses MMP-9 expression by activating p38 MAP kinase in human stomach cancer. 2006

Angiogenesis is observed in many diseases, such as tumor progression, diabetes and rheumatoid arthritis; it is a process that involves proliferation, migration, differentiation and tube formation of endothelial cells. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis by induction of these endothelial functions. Thus, inhibition of these critical angiogenic steps is a practical therapeutic strategy for those diseases. NP-184 is a substituted benzimidazole analogue which exhibits a potent anti-thrombotic activity. In this report, NP-184 inhibited the viability of human umbilical vascular endothelial cells (HUVEC) in a concentration-dependent manner, and caused cell apoptosis as examined by cell-cycle analysis and Annexin V staining with flow cytometry. NP-184 also concentration-dependently inhibited the HUVEC migration, tube formation on Matrigel, and rat aortic ring sprouting stimulated by VEGF. Regarding the intracellular signal transduction, NP-184 concentration-dependently interfered with the activation of AKT, ERK and the nuclear translocation of NF-kappaB. In vivo study showed that NP-184 dose-dependently reduced angiogenesis in Matrigel plug assay. These results indicate that NP-184 is a potential candidate for developing the treatment of angiogenesis related-diseases.
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PMID:A novel compound, NP-184, inhibits the vascular endothelial growth factor induced angiogenesis. 2006 87

Tumor and stromal interactions in the tumor microenvironment are critical for oncogenesis and cancer progression. Our understanding of the molecular events by which reactive stromal fibroblasts-myofibroblast or cancer-associated fibroblasts (CAF)-affect the growth and invasion of prostate cancer remains unclear. Laser capture microdissection and cDNA microarray analysis of CAFs in prostate tumors revealed strong upregulation of phosphoglycerate kinase-1 (PGK1), an ATP-generating glycolytic enzyme that forms part of the glycolytic pathway and is directly involved in CXCL12-CXCR4 signaling. Normal fibroblasts overexpressing PGK1 resembled myofibroblasts in their expression of smooth muscle alpha-actin, vimentin, and high levels of CXCL12. These cells also displayed a higher proliferative index and the capability to contribute to prostate tumor cell invasion in vitro, possibly through expression of MMP-2 and MMP-3 and activation of the AKT and ERK pathways. Coimplantation of PGK1-overexpressing fibroblasts with prostate tumor cells promoted tumor cell growth in vivo. Collectively, these observations suggest that PGK1 helps support the interactions between cancer and its microenvironment.
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PMID:Characterization of phosphoglycerate kinase-1 expression of stromal cells derived from tumor microenvironment in prostate cancer progression. 2006 85

We describe a mechanism of tumorigenesis mediated by kinase-dead BRAF in the presence of oncogenic RAS. We show that drugs that selectively inhibit BRAF drive RAS-dependent BRAF binding to CRAF, CRAF activation, and MEK-ERK signaling. This does not occur when oncogenic BRAF is inhibited, demonstrating that BRAF inhibition per se does not drive pathway activation; it only occurs when BRAF is inhibited in the presence of oncogenic RAS. Kinase-dead BRAF mimics the effects of the BRAF-selective drugs and kinase-dead Braf and oncogenic Ras cooperate to induce melanoma in mice. Our data reveal another paradigm of BRAF-mediated signaling that promotes tumor progression. They highlight the importance of understanding pathway signaling in clinical practice and of genotyping tumors prior to administering BRAF-selective drugs, to identify patients who are likely to respond and also to identify patients who may experience adverse effects.
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PMID:Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. 2053 44

Activating mutations in NRAS and BRAF are found frequently in cutaneous melanomas. Because concurrent mutations of both BRAF and RAS are extremely rare, it is thought that transformation by RAS and BRAF occurs through a common mechanism. Also, there is evidence for a relationship of synthetic lethality between NRAS and BRAF oncogenes that leads to selection against cells with a hyperactive mitogen-activated protein kinase (MAPK) pathway. However, it is not known whether the hyperactivation of the MAPK pathway by overexpression of either oncogene alone could also inhibit melanoma tumorigenesis. Here, we show that in melanoma cells with oncogenic BRAF (mBRAF), high levels of mBRAF induce hyperactivation of ERK and senescence-like phenotype and trigger autophagy by inhibiting the mammalian target of rapamycin complex signaling. Growth inhibition and cell death caused by high mBRAF levels are partially rescued by downregulation of BRAF protein or inhibition of autophagy, but not by inhibition of the MAPK or apoptotic pathways. In nude mice, growth of mBRAF-overexpressing tumors is inhibited. Quantitative immunohistochemical analysis of human melanomas and cell lines showed a significant positive correlation between the levels of BRAF protein and autophagy marker light chain 3. Our data suggest that high oncogenic BRAF levels trigger autophagy, which may have a role in melanoma tumor progression.
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PMID:Induction of autophagy and inhibition of melanoma growth in vitro and in vivo by hyperactivation of oncogenic BRAF. 2018 46

Early growth response-1 (Egr-1) is overexpressed in human prostate tumors and contributes to cancer progression. On the other hand, mutation of p53 is associated with advanced prostate cancer, as well as with metastasis and hormone independence. This study shows that in prostate cell lines in culture, Egr-1 overexpression correlated with an alteration of p53 activity because of the expression of SV40 large T-antigen or because of a mutation in the TP53 gene. In cells containing altered p53 activity, Egr-1 expression was abolished by pharmacological inhibition or RNAi silencing of p53. Although forced expression of wild-type p53 was not sufficient to trigger Egr-1 transcription, four different mutants of p53 were shown to induce Egr-1. Direct binding of p53 to the EGR1 promoter could not be detected. Instead, Egr-1 transcription was driven by the ERK1/2 pathway, as it was abrogated by specific inhibitors of MEK. Egr-1 increased the transcription of HB-EGF (epidermal growth factor), amphiregulin and epiregulin, resulting in autocrine activation of the EGF receptor (EGFR) and downstream MEK/ERK cascade. Thus, mutant p53 initiates a feedback loop that involves ERK1/2-mediated transactivation of Egr-1, which in turn increases the secretion of EGFR ligands and stimulates the EGFR signaling pathway. Finally, p53 may further regulate this feedback loop by altering the level of EGFR expression.
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PMID:Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells. 2019 Aug 20


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