UMLS:C0699790 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have purified a protein from serum-free conditioned medium of the HT29 human colon adenocarcinoma cell line based on its ability to inhibit the proliferation of the same cell line. The purification procedure consisted of acid gel permeation, semipreparative, and analytical reversed-phase chromatographies. The high-pressure liquid chromatography-purified colon cancer cell growth inhibitor migrates as a single band of 27 and 34 kDa on sodium dodecyl sulfate/polyacrylamide gels under nonreducing and reducing conditions, respectively. NH2-terminal amino acid sequence analysis of the first 32 residues has demonstrated that this protein belongs to the insulin-like growth factor-binding protein (IGFBP) family. More precisely, this growth inhibitor appeared to be identical to the recently cloned human IGFBP-4. This IGFBP (HT29-IGFBP) has been characterized by performing ligand blotting and competitive binding experiments. The affinity of HT29-IGFBP for insulin-like growth factor (IGF) II (approximately 3.4 x 10(10) M-1) is slightly greater than its affinity for IGF-I (approximately 1.4 x 10(10) M-1). HT29 cells also produce two other isoforms (28 and 31 kDa, nonreduced) of the HT29-IGFBP having the same partial NH2-terminal amino acid sequence as the 27-kDa protein. The monoclonal antibody alpha IR-3 is known to block the mitogenic actions of IGFs. alpha IR-3 inhibited the growth of HT29 cells, thus suggesting that IGFs are required for the growth of these colon cancer cells.
...
PMID:Purification of a colon cancer cell growth inhibitor and its identification as an insulin-like growth factor binding protein. 170 85

The extent to which the insulin-like growth factor (IGF) system contributes to the initiation and progression of colon cancer remains poorly defined. We recently reported that a majority of human colon cancers express and secrete the potent mitogen IGF-II and at least two inhibitory binding proteins, IGFBP-2 and IGFBP-4. In the present study we measured the expression and secretion of IGF-II, IGFBP-2, and IGFBP-4 in relation to growth and differentiation of CaCo2 human colon cancer cells, which undergo spontaneous enterocytic differentiation in culture. Under the conditions of the present study, CaCo2 cells demonstrated an initial rapid phase of growth between Day 2 through days 7-9 of culture, followed by a significant retardation in the growth between days 9-13. Alkaline phosphatase (ALP) activity, a marker of enterocytic differentiation, progressively increased between Days 7-13 in culture, temporally correlating with post-confluent phase of negligible growth. These changes in growth and differentiation were accompanied by > 80% decline in the relative concentration of IGF-II messenger RNA (mRNA) between Days 2-13. In contrast, the relative mRNA concentrations of inhibitory binding proteins (IGFBP-2 and IGFBP-4) increased rapidly to 200% of Day 2 values by Days 5-7 before returning to baseline levels by Day 13. The relative protein concentrations of the three factors measured in the conditioned media of the cells followed a pattern very similar to that measured for the mRNA levels. While the changes in the relative protein concentrations and mRNA levels of IGF-II and IGFBP-4 were statistically significant, the changes measured in the RNA and protein levels of IGFBP-2 were not, as a result of large inter experimental variations. Thus these results suggested that CaCo2 cell differentiation may require an attenuation of IGF-II effects. To confirm the latter possibility, additional studies were conducted with a specific neutralizing antibody against IGF-II. Incubation of CaCo2 cells with anti-IGF-II antibodies from Day 0 through Day 7 significantly retarded the growth of the cells and was accompanied by a significant increase in the concentration of Alkaline phosphatase activity per 10(6) cells. Recently, we reported a potent inhibitory role of IGFBP-4 in the growth of colon cancer cells. In the present studies, a possible important role of IGF-II is illustrated not only in the growth but also in the differentiation of colonic cells. Our studies thus suggest that differential expression of IGF-II and IGFBPs may be playing a critical role in both proliferation and differentiation of colonocytes.
...
PMID:Proliferation and differentiation of a human colon cancer cell line (CaCo2) is associated with significant changes in the expression and secretion of insulin-like growth factor (IGF) IGF-II and IGF binding protein-4: role of IGF-II. 861 13

The majority of the colon cancers analyzed to-date express insulin-like growth factor binding protein (IGFBP)-4, and antisense inhibition of IGFBP-4 messenger RNA (mRNA) confers a growth advantage to the cells in response to endogenous and exogenous IGFs. We recently reported a significant up-regulation of IGFBP-4 expression in a human colon cancer cell line (CaCo2) on spontaneous differentiation of the cells in culture. This suggests that the expression of IGFBP-4 may be related to growth and differentiation of colon cancer cells. To study the endogenous factors involved in the transcriptional regulation of IGFBP-4, we have isolated and sequenced the human (h) IGFBP-4 promoter. The approximately 1.3 kilobase pair (kb) 5' flanking region of the IGFBP-4 gene is GC rich and possesses several potential regulatory elements. These elements include a typical TATA box with sequence TATAA, located -299 nt from the initiation ATG codon. The cap site is located 14 nt downstream of the TATA box as determined by primer extension analysis. A 1.4-kb DNA fragment including the 1.254 kb 5' flanking region of the hIGFBP-4 gene was subcloned into a luciferase reporter vector (pGL-2 basic) either in the sense (BP-4-S-pGL) (S) or antisense (BP-4-AS-pGL) (AS) (negative control) orientation, relative to the luciferase coding sequence in the vector. CaCo2 cells were transfected with either the S or the AS vectors on days 2-10 of culture; cotransfection with the SV40-beta-Galactidose (Gal) vector was used to correct for transfection efficiency. The ratio of luciferase/beta-Gal expression by CaCo2 cells transfected with the S vectors increased significantly from days 3 and 4 to days 5 and 6 of culture, followed by a sharp decline on days 7-9, resembling the pattern of endogenous expression of IGFBP-4 by the cells; the expression of luciferase by the AS vectors remained low and insignificant. These results thus suggest that the approximately 1.4 kb 5' flanking region of the IGFBP-4 gene contains the cis elements required for regulation of the IGFBP-4 gene. Cloning and sequencing of the functional hIGFBP-4 promoter will enable us, for the first time, to study the endogenous factors/mechanisms responsible for the growth/differentiation (cell density) associated regulation of IGFBP-4 expression in colonic epithelial cells.
...
PMID:Cloning of the functional promoter for human insulin-like growth factor binding protein-4 gene: endogenous regulation. 897 21

We have compared the expression of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in ten paired samples of normal and tumour colonic tissue with regard to both mRNA and protein. We have compared sensitivity of these tissues to IGF-I using primary cultures of epithelial cells of colonic mucosa, and we have examined the production of IGFs and IGFBPs by these cells. In the tissues, IGFBP-2 mRNA was expressed in all normal and cancer samples but other IGFBPs showed variable expression. mRNAs for IGF-I were expressed in all normal and cancer tissues but IGF-II mRNA was only detected in cancer tissue (3 out of 10). Immunostaining of sections of normal and cancer tissue was negative for IGF-I and IGF-II; IGFBP-2 was positive in 2 out of 10 cancer tissues and 7 out of 10 normal tissues; IGFBP-3 was positive in 7 out of 10 cancer tissues and 7 out of 10 normal tissues; and IGFBP-4 was positive in 5 out of 10 cancer tissues and 6 out of 10 normal tissues. In the cells in culture, cancer cells showed increased incorporation of [35S]methionine into protein and [3H]thymidine into DNA (P < 0.02) when treated with IGF-I. Western blotting of serum-free conditioned media from cells in culture showed that 8 out of 10 normal and 3 out of 10 cancer cultures produced a 32-kDa immunoreactive IGFBP-2. No IGFBP-3 was secreted by any culture but 24-kDa IGFBP-4 was found in 3 out of 10 normal and 5 out of 10 cancer tissues. Because of the discrepancy between mRNA and protein expression for IGFBP-2, degradation of native IGFBPs was assessed using tissue extracts. Colon cancer extracts were able to degrade exogenous IGFBP-2, IGFBP-3 and IGFBP-4, whereas normal tissue extracts were without effect on IGFBP-2. We conclude that IGFBPs are synthesized and secreted by cells of the colonic mucosa but that proteolysis of secreted IGFBP-2 occurs in colon cancer tissue. This selective degradation may confer a growth advantage.
...
PMID:Insulin-like growth factors and their binding proteins in human colonocytes: preferential degradation of insulin-like growth factor binding protein 2 in colonic cancers. 921 34

Human colon cancer cell lines COLO205, HT29 and SW620 are known to secrete insulin-like growth factor II (IGF-II) and its modulatory binding proteins (IGFBPs). We have characterised the sensitivity of these cell lines to exogenous IGF-I and have examined the effects of their autocrine IGFBPs on these responses. Cells cultured in serum-free medium were treated with 1-100 ng/ml IGF-I, or des(1,3)IGF-I, a truncated IGF-I with low affinity for IGFBPs. DNA synthesis was determined by 24 h incorporation of 3H-thymidine. Experiments were repeated in the presence of 24 h cell-conditioned media containing endogenous IGFBPs. In all 3 cell lines, cell-conditioned media reduced sensitivity to IGF-I but not to des(1,3)IGF-I suggesting that IGFBPs in the cell-conditioned media of colon cells inhibit IGF-I action. IGFBPs in the cell layer and 24 h cell-conditioned media were identified by Western ligand and antibody analyses. IGFBP-4 was secreted by all cell lines and IGFBP-2 from the COLO205 and SW620 cells lines but not the HT29 cells. No IGFBP-3 was secreted by any of the cell lines but IGFBP-3 was found in the cell layer in all of the cell lines. When endogenous secreted IGFBPs were removed, cell lines were consistently more sensitive to IGF-I than des(1,3)IGF-I suggesting that IGFBP-3 associated with the cell layer enhances responses to IGF-I. This is in contrast to the effects of the secreted IGFBPs. Differential modulating actions of IGFBPs may be important in regulating colon cell turnover.
...
PMID:Insulin-like growth factor binding proteins as mediators of IGF-I effects on colon cancer cell proliferation. 938 91

We investigated the role of insulin-like growth factor (IGF)-I and IGF-binding proteins (IGFBPs) in the regulation of vascular endothelial growth factor (VEGF) expression in colon cancer cells and the mechanism by which this regulation occurs. HT29 human colon cancer cells were treated with IGF-I for various time periods. VEGF mRNA expression increased within 2 h and peaked at 24 h. SW620 colon cancer cells exhibited a peak induction of VEGF mRNA 8 h after IGF-I treatment. IGF-I induction of VEGF was confirmed at the protein level. In experiments using transient transfection of VEGF promoter-reporter constructs into HT29 cells, IGF-I increased the activity of the VEGF promoter, and pretreatment of HT29 cells with dactinomycin abrogated the induction of VEGF mRNA by IGF-I. The half-life of VEGF mRNA was not prolonged by treatment with IGF-I. Blocking the activity of IGFBP-4 did not significantly modulate the effect of IGF-I induction of VEGF mRNA in HT29 cells. Treating cells with des-(1-3)-IGF-I (an active derivative of IGF-I that does not bind to binding proteins) had effects on VEGF mRNA expression that were similar to those of IGF-I. These findings suggest that IGF-I regulates VEGF expression in human colon cancer cells by induction of transcription of the VEGF gene. IGFBPs do not significantly affect IGF-I induction of VEGF.
...
PMID:Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I. 973 15

The present study examined the effects of all-trans retinoic acid (tRA) on proliferation and expression of the IGF system in Caco-2 human colon adenocarcinoma cells. tRA inhibited Caco-2 cell proliferation in a dose-dependent manner, with a 40 +/- 2% decrease in cell number observed 48 h after the addition of 1 microM tRA. Ligand blot analysis of IGFBPs in conditioned media revealed that Caco-2 cells produced three IGFBPs of M(r): 34,000 (IGFBP-2), 24,000 (IGFBP-4), and 32,000 (IGFBP-6). The concentrations of IGFBP-2 and IGFBP-4 decreased by 48 +/- 6 and 70 +/- 13%, respectively, whereas that of IGFBP-6 increased by 698 +/- 20% with 1 microM tRA. tRA decreased mRNA levels of IGFBP-2 and IGFBP-4 by 20 +/- 3 and 50 +/- 8%, respectively, whereas tRA increased IGFBP-6 mRNA by 660 +/- 20%. tRA did not alter levels of IGF-II mRNA or peptide. To examine if endogenous IGFBP-6 inhibits cell proliferation, Caco-2 cells were transfected with an IGFBP-6 cDNA expression construct or pcDNA3 vector only and stable clones were selected. Clones overexpressing IGFBP-6 grew more slowly than vector controls and achieved final densities 30-55% lower than those of vector controls. Accumulation of IGFBP-6 mRNA and concentrations of IGFBP-6 peptide in conditioned media were increased by 200-250 and 220-250%, respectively, in the IGFBP-6 clones compared with controls. Increased expression of IGFBP-6, which has a high binding affinity for IGF-II, following tRA treatment suggests that the decreased proliferation caused by tRA may result, at least in part, from IGFBP-6-mediated disruption of the IGF-II autocrine loop in these colon cancer cells.
...
PMID:Inhibition of Caco-2 cell proliferation by all-trans retinoic acid: role of insulin-like growth factor binding protein-6. 1180 15

We previously demonstrated that a mixture of conjugated linoleic acid (CLA) isomers decreases colon cancer incidence in rats treated with 1,2-dimethylhydrazine. Our in vitro studies have also shown that CLA inhibits the growth of HT-29 cells, a human colon cancer cell line. When we compared the individual potencies of the two main isomers found in the mixture of CLA isomers (e.g., cis-9, trans-11 [c9t11] and trans-10, cis-12 [t10c12]), t10c12 CLA decreased viable cell numbers in a dose-dependent manner. By contrast, c9t11 CLA had no effect. Therefore, the present study examined whether the decreased cell growth is related to changes in secretion of insulin-like growth factor (IGF)-II and/or IGF-binding proteins (IGFBPs) that have been shown to regulate HT-29 cell proliferation. Cells were incubated in serum-free medium with various concentrations of the individual CLA isomers, and immunoblot analysis of 24-hour, serum-free, conditioned media using a monoclonal anti-IGF-II antibody was performed. HT-29 cells secreted both mature 7,500 apparent molecular weight (M(r)) and higher-M(r) forms of IGF-II. t10c12 CLA decreased the levels of the higher-M(r) and the mature form of IGF-II in a dose-dependent manner, whereas c9t11 CLA had no effect. Ligand blot analysis of conditioned medium using (125)I-IGF-II revealed that the production of IGFBP-2 and IGFBP-4 was also decreased by t10c12 CLA, whereas c9t11 CLA had no effect. Exogenous IGF-II abrogated the growth inhibition induced by t10c12 CLA. These results indicate that inhibition of HT-29 cell growth by t10c12 CLA may be mediated by decreasing IGF-II secretion in these cells.
...
PMID:trans-10, cis-12 conjugated linoleic acid reduces insulin-like growth factor-II secretion in HT-29 human colon cancer cells. 1458 85

The imbalance in systemic mediators of inflammation, such as leptin, is thought to be involved in obesity-associated cancers. In addition, systemic endocrine signals can influence the local autocrine/paracrine factors produced within this microenvironment to influence epithelial cell fate. We previously demonstrated that leptin preferentially promotes the survival and proliferation of colon epithelial cells possessing an Apc mutation (IMCE) but not model normal cells (YAMC). Therefore, the purpose of this study was to identify leptin-induced functional gene family changes which characterize the response of colon epithelial cells possessing an Apc mutation but not normal cells. Consistent with our knowledge of colon carcinogenesis, genes regulating the Wnt/beta-catenin-mediated pathway including Mdm2, Pik3r1, and Rb1 were upregulated by leptin. Importantly, leptin induced IGF-mediated pathway gene expression changes and their protein products in IMCE cells. In the IMCE cells IGFBP-6, IGF-1, and Crim1 expression was upregulated, while IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-5, and Nov expression was downregulated by leptin treatment. These data establish a biologically plausible mechanistic link between the elevated levels of growth factors and the increased risk of colon cancer associated with obesity.
...
PMID:Microarray analysis reveals that leptin induces autocrine/paracrine cascades to promote survival and proliferation of colon epithelial cells in an Apc genotype-dependent fashion. 1762 Mar 8

SOX9 regulates cell lineage specification by directly regulating target genes in a discrete number of tissues, and previous reports have shown cell proliferative and suppressive roles for SOX9. Although SOX9 is expressed in colorectal cancer, only a few direct targets have been identified in intestinal epithelial cells. We previously demonstrated increased proliferation in Sox9-deficient crypts through loss-of-function studies, indicating that SOX9 suppresses cell proliferation. In this study, crypt epithelial cells isolated from Sox9-deficient mice were used to identify potential target genes of SOX9. Insulin-like growth factor (IGF)-binding protein 4 (IGFBP-4), an inhibitor of the IGF/IGF receptor pathway, was significantly downregulated in Sox9-deficient intestinal epithelial cells and adenoma cells of Sox9-deficient ApcMin/+ mice. Immunolocalization experiments revealed that IGFBP-4 colocalized with SOX9 in mouse and human intestinal epithelial cells and in specimens from patients with primary colorectal cancer. Reporter assays and chromatin immunoprecipitation demonstrated direct binding of SOX9 to the IGFBP-4 promoter. Overexpression of SOX9 attenuated cell proliferation, which was restored following treatment with a neutralizing antibody against IGFBP-4. These results suggest that SOX9 regulates cell proliferation, at least in part via IGFBP-4. Furthermore, the antiproliferative effect of SOX9 was confirmed in vivo using Sox9-deficient mice, which showed increased tumor burden when bred with ApcMin/+ mice. Our results demonstrate, for the first time, that SOX9 is a transcriptional regulator of IGFBP-4 and that SOX9-induced activation of IGFBP-4 may be one of the mechanisms by which SOX9 suppresses cell proliferation and progression of colon cancer.
...
PMID:SOX9 directly regulates IGFBP-4 in the intestinal epithelium. 2366 May

1 2 Next >>