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

The insulin receptor substrate-1 (IRS-1), a docking protein for both the type 1 insulin-like growth factor receptor (IGF-IR) and the insulin receptor, is known to send a mitogenic, anti-apoptotic, and anti-differentiation signal. Several micro RNAs (miRs) are suggested by the data base as possible candidates for targeting IRS-1. We show here that one of the miRs predicted by the data base, miR145, whether transfected as a synthetic oligonucleotide or expressed from a plasmid, causes down-regulation of IRS-1 in human colon cancer cells. IRS-1 mRNA is not decreased by miR145, while it is down-regulated by an siRNA targeting IRS-1. Targeting of the IRS-1 3'-untranslated region (UTR) by miR145 was confirmed using a reporter gene (luciferase) expressing the miR145 binding sites of the IRS-1 3'-UTR. In agreement with the role of IRS-1 in cell proliferation, we show that treatment of human colon cancer cells with miR145 causes growth arrest comparable to the use of an siRNA against IRS-1. Taken together, these results identify miR145 as a micro RNA that down-regulates the IRS-1 protein, and inhibits the growth of human cancer cells.
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PMID:Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. 1782 56

The increased mortality associated with acromegaly was first demonstrated in early epidemiological studies. Since the seminal paper by Wright et al. in 1970, nearly 20 studies have analyzed mortality rates in over 5,000 patients with acromegaly. Overall standardized mortality rates are approximately two times higher than in the general population, relating to an average reduction in life expectancy of around 10 years. The excess deaths are due predominantly to cardiovascular, cerebrovascular and respiratory disease. Malignancy deaths have been high in some studies but not others; in the largest series looking at cancer mortality in acromegaly, overall cancer deaths were not increased, but colon cancer mortality was higher than expected. In 1993, Bates et al. first demonstrated that outcome was related to the latest measurable growth hormone (GH), and treatment to reduce GH levels led to improved outcomes. Other factors predicting poor outcome include the presence of hypertension and diabetes. On the basis of current evidence, a latest GH of less than 2-2.5 mug/L is a better predictor of good outcome than a normal insulin-like growth factor-1 (IGF-1), possibly due to discrepancy between GH and IGF-1 at low GH levels. There is some evidence to suggest a more stringent GH cut-off (less than 1 mug/L) may yield additional benefit but further studies are required to investigate any added risk of increased mortality from hypopituitarism. Radiotherapy has been linked specifically to cerebrovascular mortality and its use in patients with acromegaly must involve a careful risk-benefit analysis in each case.
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PMID:Does acromegaly enhance mortality? 1807 87

An impressive body of epidemiologic data collected over the past decade indicates that the risk of colon cancer is elevated in those with metabolic syndrome. This evidence includes studies that examined the risk of colon cancer or adenoma in relation to determinants of the metabolic syndrome (obesity, abdominal distribution of adiposity, and physical inactivity), clinical consequences of this syndrome (type 2 diabetes and hypertension), plasma or serum components of the definition of metabolic syndrome (hypertriglyceridemia, hyperglycemia, and low HDL cholesterol), and markers of hyperinsulinemia or insulin resistance (insulin and C-peptide), which is the underlying metabolic defect of the metabolic syndrome. The mechanism underlying these associations is unknown but may involve the influence of hyperinsulinemia in enhancing free or bioavailable concentrations of insulin-like growth factor-1. Future studies should also be based on better measurements of insulin resistance, beta-cell depletion, and insulin responses to better assess which aspects of insulin resistance are most closely related to the risk of colon neoplasia.
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PMID:Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. 1826 77

Large bowel cancer is one of the leading causes of deaths from cancer in Western countries, and the incidence of colorectal cancer is increasing with the steady increase in life expectancy. Modification of diet and lifestyle provide measures of reducing the risk of developing colon cancer. Evidence suggests that the components of the insulin-like growth factor (IGF) system may be appropriate targets for cancer prevention and therapy. A positive correlation was found between dietary and lifestyle, plasma IGF-I, and colon cancer incidence rates. Diet, nutrition, and other lifestyle features affect the expression and production of IGF-1 and other members of the IGF family. The purpose of this review is to examine current evidence obtained from our recent studies and others that investigated the role of dietary components in the regulation of the IGF system and colon cancer cell growth.
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PMID:Inhibition of colon cancer cell growth by dietary components: role of the insulin-like growth factor (IGF) system. 1829 50

This study identifies a novel cross-talk paradigm between the type I insulin-like growth factor receptor (IGF1R) and epidermal growth factor receptor (EGFR) in colon cancer cells. IGF1R activation by ligand exposure in growth factor-deprived cells induces Akt activation in the FET, CBS, and GEO colon cancer cell lines. Investigation of IGF1R-mediated signaling pathways using small interfering RNA approaches indicated that, as expected, phosphatidylinositol 3'-kinase (PI3K) was activated by IGF1R. Mitogen-activated protein kinase (MAPK) activity as reflected by phospho-extracellular signal-regulated kinase (ERK) induction was not significantly activated until later times following release of these cells from growth factor deprivation stress. The appearance of phospho-ERK was proximal to EGFR activation. Treatment of cells with the PI3K inhibitor LY294002 before release from stress resulted in a concentration-dependent loss of EGFR activation, whereas treatment with the MAPK inhibitor PD98059 did not block EGFR activation, indicating that EGFR activation was downstream of the IGF1R/PI3K pathway. PD98059 inhibition of MAPK was associated with a concentration-dependent reduction in EGFR-mediated phospho-ERK. EGFR inhibitor blocked induction of phospho-ERK, showing that MAPK activity was a consequence of EGFR-mediated signaling. On the other hand, a small-molecule IGF1R inhibitor, PQIP, blocked Akt phosphorylation. The divergent signaling functions of IGF1R and EGFR suggested the potential for synergism by a combination of therapy directed at the two receptors. Combination treatment with PQIP and EGFR inhibitor Tarceva resulted in synergistic effects as indicated by combination index analysis in all three cell lines tested.
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PMID:Heterogeneity of receptor function in colon carcinoma cells determined by cross-talk between type I insulin-like growth factor receptor and epidermal growth factor receptor. 1882 58

We previously described the novel zinc finger protein ZKSCAN3 as a new "driver" of colon cancer progression. To investigate the underlying mechanism and because the predicted structural features (tandem zinc fingers) are often present in transcription factors, we hypothesized that ZKSCAN3 regulates the expression of a gene(s) favoring tumor progression. We employed unbiased screening to identify a DNA binding motif and candidate downstream genes. Cyclic amplification and selection of targets using a random oligonucleotide library and ZKSCAN3 protein identified KRDGGG as the DNA recognition motif. In expression profiling, 204 genes were induced 2-29-fold, and 76 genes reduced 2-5-fold by ZKSCAN3. To enrich for direct targets, we eliminated genes under-represented (<3) for the ZKSCAN3 binding motif (identified by CAST-ing) in 2 kilobases of regulatory sequence. Up-regulated putative downstream targets included genes contributing to growth (c-Met-related tyrosine kinase (MST1R), MEK2; the guanine nucleotide exchanger RasGRP2, insulin-like growth factor-2, integrin beta 4), cell migration (MST1R), angiogenesis (vascular endothelial growth factor), and proteolysis (MMP26; cathepsin D; PRSS3 (protease serine 3)). We pursued integrin beta 4 (induced up to 6-fold) as a candidate target because it promotes breast cancer tumorigenicity and stimulates phosphatidyl 3-kinase implicated in colorectal cancer progression. ZKSCAN3 overexpression/silencing modulated integrin beta 4 expression, confirming the array analysis. Moreover, ZKSCAN3 bound to the integrin beta 4 promoter in vitro and in vivo, and the integrin beta 4-derived ZKSCAN3 motif fused upstream of a tk-Luc reporter conferred ZKSCAN3 sensitivity. Integrin beta 4 knockdown by short hairpin RNA countered ZKSCAN3-augmented anchorage-independent colony formation. We also demonstrate vascular endothelial growth factor as a direct ZKSCAN3 target. Thus, ZKSCAN3 regulates the expression of several genes favoring tumor progression including integrin beta 4.
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PMID:Unbiased screening for transcriptional targets of ZKSCAN3 identifies integrin beta 4 and vascular endothelial growth factor as downstream targets. 1894 Aug 3

Obesity is rapidly becoming a global phenomenon. This is more than a cosmetic issue as obesity is associated with several life-threatening diseases, including colon cancer. Insulin resistance and inflammation, underlying factors in obesity-related diseases, promote colonocyte proliferation and suppress programmed cell death, or apoptosis, by activating the insulin-like growth factor (IGF) and prostaglandin pathways. These pathways converge on the Wnt pathway, which is implicated in colon carcinogenesis. Despite tremendous advances in our understanding of the molecular mechanisms involved in colon carcinogenesis, mortality due to colon cancer world-wide is unacceptably high. Even though conventional therapies can prolong a patient's life-span a few years, they cause serious side effects. Thus, there is growing interest in functional foods and dietary bioactive compounds with chemopreventive properties. This search is fueled by the epidemiological studies indicating that plant-based diets are protective against several types of cancers. This review provides a brief summary of the IGF and prostaglandin pathways, which are implicated in obesity-enhanced colon cancer, and some of the functional foods/dietary compounds that target these pathways. It is essential to understand the molecular mechanisms involved in chemoprevention before providing appropriate science-based dietary recommendations to prevent colon cancer in both obese and non-obese individuals.
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PMID:Obesity-enhanced colon cancer: functional food compounds and their mechanisms of action. 1899 70

Obesity and diabetes mellitus are risk factors for colon cancer. The activation of the insulin-like growth factor (IGF)/IGF-IR axis plays a critical role in this carcinogenesis. (-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, seems to have both antiobesity and antidiabetic effects. This study examined the effects of EGCG on the development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes mellitus. Male db/db mice were given four weekly s.c. injections of azoxymethane (15 mg/kg body weight) and then they received drinking water containing 0.01% or 0.1% EGCG for 7 weeks. At sacrifice, drinking water with EGCG caused a significant decrease in the number of total aberrant crypt foci, large aberrant crypt foci, and beta-catenin accumulated crypts in these mice, all of which are premalignant lesions of the colon. The colonic mucosa of db/db mice expressed high levels of the IGF-IR, phosphorylated form of IGF-IR (p-IGF-IR), p-GSK-3beta, beta-catenin, cyclooxygenase-2, and cyclin D1 proteins, and EGCG in drinking water caused a marked decrease in the expression of these proteins. Treating these mice with EGCG also caused an increase in the serum level of IGFBP-3 while conversely decreasing the serum levels of IGF-I, insulin, triglyceride, cholesterol, and leptin. EGCG overcomes the activation of the IGF/IGF-IR axis, thereby inhibiting the development of colonic premalignant lesions in an obesity-related colon cancer model, which was also associated with hyperlipidemia, hyperinsulinemia, and hyperleptinemia. EGCG may be, therefore, useful in the chemoprevention or treatment of obesity-related colorectal cancer.
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PMID:(-)-Epigallocatechin gallate suppresses azoxymethane-induced colonic premalignant lesions in male C57BL/KsJ-db/db mice. 1913 73

Colon cancer patients frequently show increased levels of serum insulin-like growth factor-binding protein-2 (IGFBP-2), however, the pathogenetic relevance of this phenomenon for colorectal cancer is unclear. Therefore, we have used IGFBP-2 transgenic animals which overexpress IGFBP-2 systemically and locally in the intestine to study its role in chemically induced colorectal carcinogenesis. Mice received intraperitoneal injections of 1,2-dimethylhydrazine (DMH) (40 mg/kg body weight) once a week for 6 weeks to selectively induce aberrant crypt foci (ACF) and tumors in the colon. While tumor incidence was comparable in transgenic and control mice, the volume of adenomas in IGFBP-2 transgenic mice was reduced more than 2-fold. Furthermore, serum IGFBP-2 levels negatively correlated with tumor volume in the IGFBP-2 transgenic group. Histological examination showed that IGFBP-2 transgenic mice developed significantly less dysplastic ACF with a high potential to progress to advanced stages. The reduced tumor volume in IGFBP-2 transgenic animals was due to significantly reduced proliferative capacity, evidenced by a lower proportion of cells positive for Ki67. Our results demonstrate for the first time in an experimental model that IGFBP-2 overabundance prior to the onset and during colorectal carcinogenesis reduces tumor growth by inhibition of cell proliferation.
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PMID:IGFBP-2 overexpression reduces the appearance of dysplastic aberrant crypt foci and inhibits growth of adenomas in chemically induced colorectal carcinogenesis. 1914 66

MicroRNA 145 (miR145) has been proposed as a tumor suppressor. It was previously shown that miR145 targets the 3' UTR of the insulin receptor substrate-1 (IRS-1) and dramatically inhibits the growth of colon cancer cells. miR145 also targets the type 1 insulin-like growth factor receptor (IGF-IR). We show here that an IRS-1 lacking its 3' UTR is no longer down-regulated by miR145 and rescues colon cancer cells from miR145-induced inhibition of growth. An IGF-IR resistant to miR145 (again by elimination of its 3' UTR) is not down-regulated by miR145 but fails to rescue colon cancer cells from growth inhibition. These and other results, taken together, indicate that down-regulation of IRS-1 plays a significant role in the tumor suppressor activity of miR145.
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PMID:Mechanism of growth inhibition by MicroRNA 145: the role of the IGF-I receptor signaling pathway. 1939 Nov 7


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