Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin-like growth factor (IGF) axis is a complex system composed of two mitogenic ligands, IGF-I and IGF-II, two receptors, IGF-IR and IGF-IIR, and six binding proteins, IGFBP1 to IGFBP6. The IGFBPs exert their actions through their regulation of IGF bioavailability for IGF receptors. The present study evaluated the correlation between IGFBP2 expression and clinicopathologic parameters and cell proliferation in cancer by using surgically resected tissue specimens from 97 patients with gastric carcinoma treated at our hospital. Immunohistochemical staining was performed using IGFBP2 and Ki-67 monoclonal antibody. An obvious difference existed in the IGFBP2 expression between carcinomas and normal mucosa. Correlation between IGFBP2 expression and the depth of penetration, lymph node metastasis, and clinical stage were observed. There was positive correlation between IGFBP2 expression and Ki-67 expression. We conclude that IGFBP2 may be involved in carcinogenesis and progression of gastric carcinoma by promoting cell proliferation.
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PMID:Expression of IGFBP2 in gastric carcinoma and relationship with clinicopathologic parameters and cell proliferation. 1717 34

Calcitriol, the hormonally active form of Vitamin D, inhibits the growth and development of many cancers through multiple mechanisms. Our recent research supports the contributory role of several new and diverse pathways that add to the mechanisms already established as playing a role in the actions of calcitriol to inhibit the development and progression of prostate cancer (PCa). Calcitriol increases the expression of insulin-like growth factor binding protein-3 (IGFBP-3), which plays a critical role in the inhibition of PCa cell growth by increasing the expression of the cell cycle inhibitor p21. Calcitriol inhibits the prostaglandin (PG) pathway by three actions: (i) the inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (ii) the induction of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs and (iii) decreasing the expression of EP and FP PG receptors that are essential for PG signaling. Since PGs have been shown to promote carcinogenesis and progression of multiple cancers, the inhibition of the PG pathway may add to the ability of calcitriol to prevent and inhibit PCa development and growth. The combination of calcitriol and non-steroidal anti-inflammatory drugs (NSAIDs) result in a synergistic inhibition of PCa cell growth and offers a potential therapeutic strategy. Mitogen activated protein kinase phosphatase 5 (MKP5) is a member of a family of phosphatases that are negative regulators of MAP kinases. Calcitriol induces MKP5 expression in prostate cells leading to the selective dephosphorylation and inactivation of the stress-activated kinase p38. Since p38 activation is pro-carcinogenic and is a mediator of inflammation, this calcitriol action, especially coupled with the inhibition of the PG pathway, contributes to the chemopreventive activity of calcitriol in PCa. Mullerian Inhibiting Substance (MIS) has been evaluated for its inhibitory effects in cancers of the reproductive tissues and is in development as an anti-cancer drug. Calcitriol induces MIS expression in prostate cells revealing yet another mechanism contributing to the anti-cancer activity of calcitriol in PCa. Thus, we conclude that calcitriol regulates myriad pathways that contribute to the potential chemopreventive and therapeutic utility of calcitriol in PCa.
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PMID:Novel pathways that contribute to the anti-proliferative and chemopreventive activities of calcitriol in prostate cancer. 1722 71

To better understand the underlying pathways of cervical carcinogenesis, cDNA microarray analysis was performed on 2 sets of squamous cell carcinomas (SCCs) and their adjacent normal squamous epithelia. Consistently altered expression was detected for 32 genes. Real-time RT-PCR analysis was conducted on a selected subset of these genes (S100A2, GPC4, p72, IGFBP-5, TRIM2 and NAB2) for 14 additional SCCs and 10 normal epithelia. This found that, of the 6 candidate genes, only the insulin-like growth factor binding protein-5 (IGFBP-5) mRNA was generally and significantly under-expressed in SCCs (p < 0.001). All normal cervical epithelia (30 of 30) stained positively for IGFBP-5 protein, with 70% showing strong staining, whereas 65% (17/26) of SCC had complete loss of IGFBP-5, and only 8% (2/26) SCC retained strong expression (p < 0.001). Immunohistochemistry of premalignant cervical intraepithelial neoplasia (CIN) lesions shows a significantly weaker or negative staining in advanced CIN3 lesions compared with normal squamous epithelia (p = 0.001). This is the first study to show that down-regulation of IGFBP-5 protein correlates with cervical carcinogenesis and does so at a preneoplastic stage.
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PMID:Down-regulation of insulin-like growth factor binding protein-5 (IGFBP-5): novel marker for cervical carcinogenesis. 1729 Apr 7

Anabolic steroid and peptide hormones or growth factors are utilized to increase the performance of athletes of professional or amateur sports. Despite their well-documented adverse effects, the use of some of these agents has significantly grown and has been extended also to non-athletes with the aim to improve appearance or to counteract ageing. Pre-clinical studies and epidemiological observations in patients with an excess of hormone production or in patients chronically treated with hormones/growth factors for various pathologies have warned about the potential risk of cancer development and progression which may be also associated to the use of certain doping agents. Anabolic steroids have been described to provoke liver tumours; growth hormone or high levels of its mediator insulin-like growth factor-1 (IGF-1) have been associated with colon, breast, and prostate cancers. Actually, IGF-1 promotes cell cycle progression and inhibits apoptosis either by triggering other growth factors or by interacting with pathways which have an established role in carcinogenesis and cancer promotion. More recently, the finding that erythropoietin (Epo) may promote angiogenesis and inhibit apoptosis or modulate chemo- or radiosensitivity in cancer cells expressing the Epo receptor, raised the concern that the use of recombinant Epo to increase tissue oxygenation might favour tumour survival and aggressiveness. Cancer risk associated to doping might be higher than that of patients using hormones/growth factors as replacement therapy, since enormous doses are taken by the athletes often for a long period of time. Moreover, these substances are often used in combination with other licit or illicit drugs and this renders almost unpredictable all the possible adverse effects including cancer. Anyway, athletes should be made aware that long-term treatment with doping agents might increase the risk of developing cancer.
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PMID:Doping with growth hormone/IGF-1, anabolic steroids or erythropoietin: is there a cancer risk? 1734 98

Current dogma suggests that the positive correlation between obesity and cancer is driven by white adipose tissue that accompanies obesity, possibly through excess secretion of adipokines. Recent studies in fatless A-Zip/F1 mice, which have undetectable adipokine levels but display accelerated tumor formation, suggest that adipokines are not required for the enhanced tumor development. The A-Zip/F-1 mice are also diabetic and display elevated circulating levels of other factors frequently associated with obesity (insulin, insulin-like growth factor-1, and proinflammatory cytokines) and activation of several signaling pathways associated with carcinogenesis. In view of this information, the risk factors underlying the obesity-cancer link need to be revisited. We postulate that the pathways associated with insulin resistance and inflammation, rather than adipocyte-derived factors, may represent key prevention and therapeutic targets for disrupting the obesity-cancer link.
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PMID:The obesity-cancer link: lessons learned from a fatless mouse. 1736 54

Tumor suppression by insulin-like growth factor-binding protein-3 (IGFBP-3) has been demonstrated to occur via insulin-like growth factor-dependent and -independent mechanisms in vitro and in vivo. We have recently described IGFBP-3-induced mitochondrial translocation of the nuclear receptors RXRalpha/Nur77 in the induction of prostate cancer (CaP) cell apoptosis. Herein, we demonstrate that IGFBP-3 and Nur77 associate in the cytoplasmic compartment in 22RV1 CaP cells. Nur77 is a major component of IGFBP-3-induced apoptosis as shown by utilizing mouse embryonic fibroblasts (MEFs) derived from Nur77 wild-type and knockout (KO) mice. However, dose-response experiments revealed that a small component of IGFBP-3-induced apoptosis is Nur77 independent. Reintroduction of Nur77 into Nur77 KO MEFs restores full responsiveness to IGFBP-3. IGFBP-3 induces phosphorylation of Jun N-terminal kinase and inhibition of Akt phosphorylation and activity, which have been associated with Nur77 translocation. Finally, IGFBP-3 administration to CaP xenografts on SCID mice induced apoptosis and translocated Nur77 out of the nucleus. Taken together, our results verify an important role for the orphan nuclear receptor Nur77 in the apoptotic actions of IGFBP-3.
Carcinogenesis 2007 Aug
PMID:Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3. 1743 20

Medulloblastomas are malignant brain tumors that arise in the cerebellum in children. Aberrant activation of the Sonic hedgehog (Shh) signaling pathway, which normally stimulates proliferation of granule neuron precursors (GNP) during cerebellar development, induces tumors in mice that closely mimic human medulloblastomas. Shh-dependent medulloblastoma formation is enhanced by hyperactive insulin-like growth factor (IGF) signaling and ectopic expression of Myc oncogenes. This enhanced tumorigenesis stems from the sensitivity of GNPs to IGF and Myc levels in regulating proliferation. An emerging theme in cancer research is that oncogene-induced cell proliferation cannot initiate neoplastic transformation unless cellular programs that mediate apoptosis are disabled. Here, we report a high frequency of medulloblastoma formation in mice after postnatal overexpression of the antiapoptotic protein Bcl-2 in cooperation with Shh. Ectopic expression of Bcl-2 alone or in combination with N-Myc did not induce tumors, indicating that Shh has essential transforming functions in GNPs not supplied by the mitogenic stimulus of N-Myc combined with a strong antiapoptotic signal provided by Bcl-2. Expression of endogenous Bcl-2 was not up-regulated in Shh-induced tumors. Instead, elevated levels of phosphorylated Akt were found, suggesting that activated phosphatidylinositol 3-kinase signaling is one intrinsic mechanism for suppressing apoptosis in Shh-dependent medulloblastomas. Thus, blockade of apoptosis cooperates with Shh-stimulated proliferation to transform GNPs and induce aggressive medulloblastomas. These findings provide insights into the molecular signals that initiate medulloblastoma formation and they support the importance of blocking apoptosis in carcinogenesis.
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PMID:Apoptosis suppression by somatic cell transfer of Bcl-2 promotes Sonic hedgehog-dependent medulloblastoma formation in mice. 1754 97

Resveratrol, a natural polyphenolic phytochemical, has been reported to act as an antioxidant and provide anticancer activities. We hypothesized that resveratrol would exert a chemopreventive effect against prostate cancer via regulation of sex steroid receptor and growth factor signaling pathways. In the current study, Transgenic Adenocarcinoma Mouse Prostate males were fed resveratrol (625 mg resveratrol per kg AIN-76A diet) or phytoestrogen-free, control diet (AIN-76A) starting at 5 weeks of age. Mechanisms of action and histopathology studies were conducted at 12 and 28 weeks of age, respectively. Resveratrol in the diet significantly reduced the incidence of poorly differentiated prostatic adenocarcinoma by 7.7-fold. In the dorsolateral prostate, resveratrol significantly inhibited cell proliferation, increased androgen receptor, estrogen receptor-beta, and insulin-like growth factor-1 receptor, and significantly decreased insulin-like growth factor (IGF)-1 and phospho-extracellular regulating kinase 1 (phospho-ERK 1). In the ventral prostate, resveratrol significantly reduced cell proliferation and phospho-ERKs 1 and 2, but did not significantly alter insulin-like growth factor-1 receptor and IGF-1. Serum total testosterone, free testosterone, estradiol, dihydrotestosterone and sex hormone-binding globulin (SHBG) concentrations and Simian Virus-40 large T antigen expression in the prostate were not altered in resveratrol-treated mice. Total resveratrol concentration in the blood serum of 12-week-old mice treated for 3 weeks with 625 mg resveratrol per kg diet was 52 +/- 18 nM. The decrease in cell proliferation and the potent growth factor, IGF-1, the down-regulation of downstream effectors, phospho-ERKs 1 and 2 and the increase in the putative tumor suppressor, estrogen receptor-beta, provide a biochemical basis for resveratrol suppressing prostate cancer development.
Carcinogenesis 2007 Sep
PMID:Resveratrol suppresses prostate cancer progression in transgenic mice. 1767 39

The E7 protein encoded by the oncogenic human papillomavirus type 16 has been shown to bind and inactivate insulin-like growth factor-binding protein-3 (IGFBP-3), the pro-apoptotic product of a tumour suppressor gene; however, the molecular mechanism underlying E7-induced inactivation of IGFBP-3 remained uncertain. In this study, we map the IGFBP-3-binding domain for E7 to the nuclear localization signal in the conserved C-terminal domain of IGFBP-3. Moreover, we demonstrate that both proteins interact in the nucleus and that E7 induces polyubiquitination and proteasome-dependent proteolysis of nuclear IGFBP-3 in cervical cancer cells. This leads to a dramatic shortening of the half-life of nuclear IGFBP-3, whereas the stability of an E7-non-binding IGFBP-3 mutant is not affected by E7. Finally, we show that E7-mediated destruction of nuclear IGFBP-3 correlates with the inhibition of IGFBP-3-induced apoptotic cell death. These data are consistent with E7-induced ubiquitin/proteasome-dependent inactivation of nuclear IGFBP-3.
Carcinogenesis 2007 Dec
PMID:Human papillomavirus type 16 E7 oncoprotein inhibits apoptosis mediated by nuclear insulin-like growth factor-binding protein-3 by enhancing its ubiquitin/proteasome-dependent degradation. 1782 6

Chemoprevention is an upcoming approach to control cancer including prostate cancer (PCa). Here, we studied the efficacy and associated mechanisms of a chemopreventive agent silibinin against ectopically growing and established advanced human prostate carcinoma PC-3 tumor xenografts in athymic nude mice. Dietary silibinin (0.5%, w/w) did not show any adverse health effect in mice. In first protocol, silibinin started 1 week prior to xenograft implantation and continued for 60 additional days, whereas in the second protocol, silibinin treatment was started after 25 days of established tumors for 4, 8 and 16 days. Silibinin inhibited tumor growth rate in both protocols showing up to 35% (P = 0.010) and 18-56% (P = 0.002 to <0.001) decrease in tumor volume per mouse and 27% (P < 0.01) and 44% (P = 0.014) decrease in tumor weight per mouse, respectively. In first protocol, silibinin decreased (P < 0.001) tumor cell proliferation and microvessel density but increased (P < 0.001) apoptosis. An increase in insulin-like growth factor-binding protein-3 (IGFBP-3) expression with a concomitant decrease in vascular endothelial growth factor (VEGF) expression was noted. Silibinin strongly increased phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), Cip1/p21 and Kip1/p27 (cyclin-dependent kinase inhibitors) levels but moderately decreased Bcl-2 and survivin levels. In established tumors, similar biomarkers and molecular changes were observed due to silibinin corresponding to its antitumor efficacy. These findings identified in vivo antitumor efficacy of silibinin against PC-3 human PCa in both intervention protocols accompanied with its anti-proliferative, pro-apoptotic and anti-angiogenic activities. At molecular level, silibinin increased IGFBP-3, Cip1/p21, Kip1/p27 levels and ERK1/2 activation and decreased Bcl-2, survivin and VEGF levels in tumors.
Carcinogenesis 2007 Dec
PMID:Silibinin suppresses in vivo growth of human prostate carcinoma PC-3 tumor xenograft. 1791 9


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