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

Certain forms of hexavalent chromium [Cr(VI)] are human carcinogens. Our recent work has shown that a broad range protein tyrosine phosphatase (PTP) inhibitor, sodium orthovanadate (SOV), abrogated both Cr(VI)-induced growth arrest and clonogenic lethality. Notably, SOV enhanced Cr(VI) mutation frequency, ostensibly through forced survival of genetically damaged cells. In the present study, co-treatment with this PTP inhibitor bypassed the Cr(VI)-induced G(1)/S checkpoint arrest in diploid human lung fibroblasts (HLF). Moreover, the PTP inhibitor abrogated the Cr(VI)-induced decrease in the expression of key effectors of the G(1)/S checkpoint [Cyclin D1, phospho Ser 807/811 Rb (pRB), p27]. Cr(VI)-induced G(1) arrest was associated with the cytoplasmic appearance of pRb and the nuclear localization of p27, both of which were reversed by the PTP inhibitor. The PTP inhibitor's reversal of G(1)/S checkpoint effector localization after Cr exposure was found to be Akt1-dependent, as this was abrogated by transfection with either akt1 siRNA or an Akt1-kinase dead plasmid. Furthermore, Akt1 activation alone was sufficient to induce G(1)/S checkpoint bypass and to prevent Cr(VI)-induced changes in pRb and p27 localization. In conclusion, this work establishes Akt1 activation to be both sufficient to bypass the Cr(VI)-induced G(1)/S checkpoint, as well as necessary for the observed PTP inhibitor effects on key mediators of the G(1)/S transition. The potential for Akt to bypass G(1)/S checkpoint arrest in the face of genotoxic damage could increase genomic instability, which is a hallmark of neoplastic progression.
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PMID:AKT1 mediates bypass of the G1/S checkpoint after genotoxic stress in normal human cells. 1937 90

MicroRNAs are noncoding, endogenous small RNAs that regulate target genes by cleavage of the targeted mRNA or translational repression. We investigated the microRNAome using 2-color microarrays in a highly invasive human breast cancer cell line, MDA-MB-231 (subline 4175) and a noninvasive breast epithelial cell line, MCF10A. We found 13 microRNAs that were up-regulated, and nine were down-regulated significantly in 4175 cells (p < 0.05, -fold change >2) compared with MCF10A cells. Interestingly, miR-27b and its putative target gene, ST14 (suppressor of tumorigenicity 14), had inverse expression pattern in breast cancer cells. The 3'-untranslated region of ST14 contains a regulatory element for miR-27b, and our luciferase experiments indicate that antisense miR-27b enhances ST14 expression in cancer cells. Furthermore, antagomir of miR-27b suppressed cell invasion in 4175 cells, whereas pre-miR-27b stimulated invasion in moderately invasive ZR75 breast cancer cells. In addition, ST14 reduces cell proliferation as well as cell migration and invasion. Analysis of human breast tumors revealed that miR-27b expression increases during cancer progression, paralleling a decrease in ST14 expression. Furthermore, our data indicate that ST14 inhibits cells from entering into S phase by up-regulating p27, which results in down-regulation of cyclin E-CDK2 complexes, suggesting ST14 reduces cell growth through its effects on cell cycle-related proteins. Introduction of miR-27b into ST14-expressing cells did not suppress the effect on cell growth. These findings suggest that ST14 plays an important role in several biological processes, and some effects are not completely dependent on miR-27b regulation.
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PMID:ST14 (suppression of tumorigenicity 14) gene is a target for miR-27b, and the inhibitory effect of ST14 on cell growth is independent of miR-27b regulation. 1954 20

Parathyroid hormone-related protein (PTHrP), a paraneoplastic protein expressed by two-thirds of human non-small cell lung cancers, has been reported to slow progression of lung carcinomas in mouse models and to lengthen survival of patients with lung cancer. This study investigated the effects of ectopic expression of PTHrP on proliferation and cell cycle progression of two human lung adenocarcinoma cell lines that are normally PTHrP negative. Stable transfection with PTHrP decreased H1944 cell DNA synthesis, measured by thymidine incorporation, bromodeoxyuridine uptake, and MTT proliferation assay. A substantial fraction of PTHrP-positive cells was arrested in or slowly progressing through G1. Cyclin D2 and cyclin A2 protein levels were 60-70% lower in PTHrP-expressing cells compared with control cells (P < 0.05, N = 3 independent clones per group), while expression of p27(Kip1), a cyclin-dependent kinase inhibitor, was increased by 35 +/- 9% (mean +/- SE, P < 0.05) in the presence of PTHrP. Expression of other cyclins, including cyclins D1 and D3, and cyclin-dependent kinases was unaffected by PTHrP. PTHrP did not alter the phosphorylation state of Rb, but decreased cyclin-dependent kinase (CDK) 2-cyclin A2 complex formation. Ectopic expression of PTHrP stimulated ERK phosphorylation. In MV522 cells, PTHrP had similar effects on DNA synthesis, cyclin A2 expression, pRb levels, CDK2-cyclin A2 association, and ERK activation. In summary, PTHrP appears to slow progression of lung cancer cells into S phase, possibly by decreasing activation of CDK2. Slower cancer cell proliferation could contribute to slower tumor progression and increased survival of patients with PTHrP-positive lung cancer.
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PMID:Cell cycle actions of parathyroid hormone-related protein in non-small cell lung carcinoma. 1963 68

p27(kip1) (p27) is a cell cycle inhibitor and tumor suppressor whose expression is highly regulated in the cell. Low levels of p27 have been associated with poor prognosis in cancer. Recently, several microRNAs have been described to control p27 expression in various tumor types. In this chapter, we will provide an overview on the role of microRNAs in cancer, and will discuss how microRNAs regulate p27 expression and the implications for tumor progression.
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PMID:Regulation of p27(kip1) mRNA expression by microRNAs. 1984 81

The Kaposi sarcoma-associated herpes virus-G protein-coupled receptor is a key molecule in the pathogenesis of Kaposi sarcoma, playing a central role in promoting vascular endothelial growth factor-driven angiogenesis and spindle cell proliferation. We studied the effects of 1 alpha,25-dihydroxyvitamin D(3) [1 alpha,25(OH)(2)D(3)] and the analog TX527 on the proliferation of endothelial cells (SVECs) and SVECs transformed by the viral G protein-coupled receptor (SVEC-vGPCR). 1 alpha,25(OH)(2)D(3) and TX527 decreased SVEC-vGPCR and SVEC numbers, the response being time dependent and similar in both cell lines. Vitamin D receptor (VDR) levels increased on treatment with 10 nm 1 alpha,25(OH)(2)D(3) or 1 nm TX527 in a time-dependent manner (1.5-24 h) in SVECs and SVEC-vGPCR. Basal VDR levels were increased in SVEC-vGPCR. The antiproliferative effects were accompanied by reduction in cyclin D1 and accumulation of p27 in SVECs but not SVEC-vGPCR. Induction of VDR was blocked by transfection of short hairpin RNA against VDR in SVEC-vGPCR and the antiproliferative effects of 1 alpha,25(OH)(2)D(3) and TX527 were decreased, involving the VDR genomic pathway in the hormone and analog mechanism of action. In vivo experiments showed that 1 alpha,25(OH)(2)D(3) and TX527 decreased SVEC-vGPCR tumor progression when the tumor cells were implanted in nude mice. In conclusion, we have demonstrated that 1 alpha,25(OH)(2)D(3) and its TX527 analog have antiproliferative effects on the growth of endothelial cells transformed by the vGPCR in vitro and in vivo, the vitamin D receptor being part of the inhibitory mechanism of action.
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PMID:1 Alpha,25-dihydroxyvitamin D3 and its TX527 analog inhibit the growth of endothelial cells transformed by Kaposi sarcoma-associated herpes virus G protein-coupled receptor in vitro and in vivo. 1991 63

The malignant transformation of breast epithelium involves a number of cellular pathways, including those dependent on signaling from TGF beta. Tranilast [N-(3, 4-dimethoxycinnamonyl)-anthranilic acid] is a drug that is used in Japan to control allergic disorders in patients, and its mechanism of action involves TGF beta. In view of the multiple roles of TGF beta in tumor progression, we hypothesized in this study that tranilast impacts cell proliferation, apoptosis, and migration. Using the mouse breast cancer cell line 4T1, our studies showed that tranilast increases AKT1 phosphorylation and decreases ERK1/2 phosphorylation. Alterations in the cell cycle mediators' cyclin D1, p27, cyclin A, pRB, cyclin B, and Cdc2 were observed after exposure to tranilast, favoring cell arrest beyond the G1/S phase. Tranilast reduced tumor cell proliferation even when it was amplified by exogenous TGF beta. TGF beta-neutralizing antibody did not cause a significant decrease in cell proliferation. Tranilast treatment upregulates p53, induces PARP cleavage in vitro, consistent with a promotion of tumor cell apoptosis. TGF beta-neutralizing antibody downregulates endoglin and matrix metalloproteinases (MMP)-9 levels in vitro indicating that the tranilast effect is mediated through TGF beta modulation. Tranilast treatment results in the inhibition of cell migration and invasion. Western blot analysis of tumor lysates from tranilast-treated mice shows decreased levels of TGF beta1, endoglin, and significantly higher levels of p53 and cleaved PARP. Cleaved caspase 3 expression is significantly elevated in tranilast-treated mouse breast tumors. To conclude, tranilast induces cellular and molecular changes in murine breast cancer that can be exploited in preclinical therapeutic trials.
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PMID:Tranilast inhibits cell proliferation and migration and promotes apoptosis in murine breast cancer. 2014 38

Identification of the molecular characteristics of intramucosal (IMCs) and submucosal cancers (SMCs) is essential to our understanding of early gastric carcinogenesis. However, little is known regarding the differences between the 2 lesions. One hundred and forty-eight patients with primary early gastric cancer [IMC, 106; SMC, 42] were characterized for expression of cell cycle-related proteins and loss of heterozygosity (LOH). We also examined microsatellite instability (MSI) and methylation status. For LOH and methylation studies, we used a panel of 17 microsatellite markers (3p, 4p, 5q, 9p. 13q, 17p, 18q and 22q) and promoter regions of 9 genes (MLH-1, RUNX3, p16, HPP1, RASSF2A, SFRP1, DKK-1, ZFP64 and SALL4) that are frequently altered or methylated in gastric cancers. Overexpression of p53 and cyclin D1 was observed in SMC. In addition, low expression of p27 was more frequent in SMC than in IMC. Frequencies of 4p, 9p, 13q and 22q were significantly higher in SMC than in IMC. The SALL4 gene was frequently methylated in SMC compared with IMC. However, other gene methylations were common in both IMC and SMC. The frequency of LOH-high status/methylation-low status was significantly higher in SMC than in IMC. However, LOH-low status/methylation-high status in SMC was more frequently found in IMC. Our data confirm that methylation of cancer-related genes plays a major role in the development of IMCs. Importantly, the results also show that gastric submucosal progression is characterized by the accumulation of specific genetic alterations. In addition, changes of cell cycle-related proteins are associated with cancer progression.
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PMID:Molecular analysis of gastric differentiated-type intramucosal and submucosal cancers. 2017 4

p27(Kip1) is a cyclin dependent kinase inhibitor that functions as a tumor suppressor in a variety of different cancers. While p27 has a well established role in regulating the cell cycle, it has also been shown to regulate cellular migration by influencing the activation state of the small GTPase RhoA. We recently demonstrated that loss of p27 enhances tumor progression and leads to a dramatic decrease in survival in PDGF-induced oligodendrogliomas. Here we show that p27 deficient PDGF-expressing glial cells contained elevated levels of Rho-GTP and were less migratory than wild type cells. Migration defects in p27 deficient cells were rescued by either Rho kinase inhibition or expression of p27 or CK(-), a mutant of p27 that cannot bind cyclins/cdks. The RCAS/tv-a retroviral system was used to specifically induce PDGF-expressing gliomas in mice. Many of the p27 deficient mice died earlier than wild type mice and displayed hydrocephalus which was associated with periventricular tumors that failed to invade the normal brain parenchyma. Invasion failure was reversed by co-expression of PDGF with either the GAP domain of p190(RhoGAP), a negative regulator of Rho, or p27, or CK(-). These results suggest that p27 mediated regulation of the Rho pathway is cell cycle independent and demonstrate for the first time a migration defect in cancer cells that is associated with p27 deficiency in vivo in a mouse tumor model.
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PMID:p27 deficiency is associated with migration defects in PDGF-expressing gliomas in vivo. 2042 14

The genes encoding microRNAs of the human miR-200 family map to fragile chromosomal regions and are frequently downregulated upon tumor progression. Although having been reported to regulate epithelial-to-mesenchymal transition and transforming growth factor-beta-driven cell invasion, the role of the miR-200 family in EGF-driven breast cancer cell invasion, viability, apoptosis and cell cycle progression is still unknown. In particular, there is no study comparing the roles of the two clusters of this miRNA family. In this study, we show for the first time that miR-200 family members differentially regulate EGF-driven invasion, viability, apoptosis and cell cycle progression of breast cancer cells. We showed that, all miR-200 family members regulate EGF-driven invasion, with the miR-200bc/429 cluster showing stronger effects than the miR-200a/141 cluster. Furthermore, expression of the miR-200a/141 cluster results in G1 arrest supported by increased p27/Kip1 and decreased cyclin dependent kinase 6 expression. In contrast, expression of the 200bc/429 cluster decreases G1 population and increases G2/M phase, in line with the observed reduction of p27/Kip1 and upregulation of the inhibitory phosphorylation of Cdc25C, respectively. To test the hypothesis that phenotypical differences observed between the two clusters are caused by differential targeting spectrums, we performed genome-wide microarray profiling in combination with gain-of-function studies. This identified phospholipase C gamma 1 (PLCG1), which was downregulated only by the miR-200bc/429 cluster, as a potential candidate contributing to these phenotypical differences. Luciferase reporter assays validated PLCG1 as a direct functional target of miR-200bc/429 cluster, but not of miR-200a/141 cluster. Finally, loss of PLCG1 in part mimicked the effect of miR-200bc/429 overexpression in viability, apoptosis and EGF-driven cell invasion of breast cancer cells. Our results suggest that the miR-200 family has a tumor-suppressor function by negatively regulating EGF-driven cell invasion, viability and cell cycle progression in breast cancer.
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PMID:miR-200bc/429 cluster targets PLCgamma1 and differentially regulates proliferation and EGF-driven invasion than miR-200a/141 in breast cancer. 2051 23

Prostate cancers that are resistant to hormone therapy are more invasive and have greater ability to spread to other organs than androgen-dependent prostate cancers. Furthermore, this type of prostate cancer is also highly resistant to current forms of chemotherapy. This study analyzed CXCL5/ENA78, which is highly expressed in androgen-independent prostate cancers, and is responsible for cell migration and epithelial-to-mesenchymal transition in two androgen-independent prostate cancer cell lines. Inducement of PC-3 and DU145 cancer progression by CXCL5/ENA78 is associated with increased Raf/MEK/ERK activation, and the upregulation of early growth response-1 (Egr-1) and Snail. Blockade of Egr-1 decreased Snail upregulation and cell migration, indicating that Egr-1 is required in CXCL5/ENA78-mediated Snail enhancement and cell migration. In addition, Egr-1 siRNA also decreased the effect of CXCL5/ENA78 on p27 inhibition, Cdk4 induction and cell proliferation, suggesting Egr-1 is also involved in CXCL5/ENA78-mediated cell growth. Moreover, blocking ERK1/2 by siRNA suppressed CXCL5/ENA78-induced Egr-1 enhancement, cell migration, and proliferation. Our study suggests that inhibition of CXCL5/ENA78-mediated ERK/Egr-1/Snail signaling is an attractive therapeutic target for androgen-independent prostate cancer.
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PMID:CXCL5/ENA78 increased cell migration and epithelial-to-mesenchymal transition of hormone-independent prostate cancer by early growth response-1/snail signaling pathway. 2094 84


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