Molecular markers and targets for colorectal cancer prevention

AbstractColorectal cancer is the third most prevalent cancer in the world. If detected at an early stage, treatment often might lead to cure. As prevention is better than cure, epidemiological studies reveal that having a healthy diet often protects from promoting/developing cancer. An important consideration in evaluating new drugs and devices is determining whether a product can effectively treat a targeted disease. There are quite a number of biomarkers making their way into clinical trials and few are awaiting the preclinical efficacy and safety results to enter into clinical trials. Researchers are facing challenges in modifying trial design and defining the right control population, validating biomarker assays from the biological and analytical perspective and using biomarker data as a guideline for decision making. In spite of following all guidelines, the results are disappointing from many of the large clinical trials. To avoid these disappointments, selection of biomarkers and its target drug needs to be evaluated in appropriate animal models for its toxicities and efficacies. The focus of this review is on the few of the potential molecular targets and their biomarkers in colorectal cancers. Strengths and limitations of biomarkers/surrogate endpoints are also discussed. Various pathways involved in tumor cells and the specific agents to target the altered molecular biomarker in biomolecular pathway are elucidated. Importance of emerging new platforms siRNAs and miRNAs technology for colorectal cancer therapeutics is reviewed.

[1]  Graeme J. Poston,et al.  β‐catenin expression in primary and metastatic colorectal carcinoma , 1999 .

[2]  B. Calvo,et al.  Expression of 15-lipoxygenase-1 in human colorectal cancer. , 1999, Cancer research.

[3]  Michael Z Michael,et al.  Reduced accumulation of specific microRNAs in colorectal neoplasia. , 2003, Molecular cancer research : MCR.

[4]  M. Brandi,et al.  Growth response of colon cancer cell lines to selective estrogen receptor modulators. , 2003, Anticancer research.

[5]  Rivat Christine,et al.  Implication of STAT3 Signaling in Human Colonic Cancer Cells during Intestinal Trefoil Factor 3 (TFF3) – and Vascular Endothelial Growth Factor–Mediated Cellular Invasion and Tumor Growth , 2005, Cancer Research.

[6]  Henk-Jan Guchelaar,et al.  The risk of cancer in users of statins. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  C. Croce,et al.  MicroRNA gene expression deregulation in human breast cancer. , 2005, Cancer research.

[8]  C. Rao,et al.  Modulation of cyclooxygenase-2 activities by the combined action of celecoxib and decosahexaenoic acid: novel strategies for colon cancer prevention and treatment. , 2004, Molecular cancer therapeutics.

[9]  G. Crosthwaite,et al.  Proton pump inhibitors for Barrett's oesophagus , 2000, Gut.

[10]  D. Witte,et al.  Estrogen receptor β is expressed in human colorectal adenocarcinoma , 2001 .

[11]  J M Alvaro-Gracia,et al.  Licofelone--clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis. , 2004, Rheumatology.

[12]  F. Russo,et al.  Prognostic value of cytosolic estrogen receptors in human colorectal carcinoma and surrounding mucosa , 1994, Digestive Diseases and Sciences.

[13]  A. Lewis,et al.  Oestrogen-induced apoptosis in colonocytes expressing oestrogen receptor beta. , 2002, The Journal of endocrinology.

[14]  D. Ritchie,et al.  Effects of tepoxalin, a dual inhibitor of cyclooxygenase/5-lipoxygenase, on events associated with NSAID-induced gastrointestinal inflammation. , 1997, Prostaglandins, leukotrienes, and essential fatty acids.

[15]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[16]  R. Bernards,et al.  Stable suppression of tumorigenicity by virus-mediated RNA interference. , 2002, Cancer cell.

[17]  Elizabeth L. Barry,et al.  Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. , 2007, JAMA.

[18]  F. Traganos,et al.  Nitric Oxide-Donating Nonsteroidal Anti-Inflammatory Drugs Inhibit the Growth of Various Cultured Human Cancer Cells: Evidence of a Tissue Type-Independent Effect , 2002, Journal of Pharmacology and Experimental Therapeutics.

[19]  P. Lakatos,et al.  Oestrogen and vitamin D receptor (VDR) genotypes and the expression of ErbB-2 and EGF receptor in human rectal cancers. , 2001, European journal of cancer.

[20]  J. Mason Statins and their role in vascular protection. , 2003, Clinical science.

[21]  Ronit Almog,et al.  Statins and the risk of colorectal cancer. , 2005, The New England journal of medicine.

[22]  H. Herschman Prostaglandin synthase 2. , 1996, Biochimica et biophysica acta.

[23]  Y. Kawasaki,et al.  Wnt/β-Catenin and Estrogen Signaling Converge in Vivo* , 2004, Journal of Biological Chemistry.

[24]  D. Levy,et al.  What does Stat3 do? , 2002, The Journal of clinical investigation.

[25]  R. DuBois,et al.  Cyclooxygenase, NSAIDs, and colorectal cancer , 1996, Journal of Gastroenterology.

[26]  M. Gottardis,et al.  Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma. , 1998, Cancer research.

[27]  I. J. Lynch,et al.  Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer. , 2001, Cancer research.

[28]  F. Grodstein,et al.  Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. , 1999, The American journal of medicine.

[29]  R. Evans,et al.  Nuclear receptors and lipid physiology: opening the X-files. , 2001, Science.

[30]  V. Steele,et al.  Is inducible nitric oxide synthase a target for chemoprevention? , 2003, Molecular cancer therapeutics.

[31]  5-Lipoxygenase, a marker for early pancreatic intraepithelial neoplastic lesions. , 2005 .

[32]  R. DuBois,et al.  Cyclooxygenase Regulates Angiogenesis Induced by Colon Cancer Cells , 1998, Cell.

[33]  Xi He,et al.  Adenomatous Polyposis Coli (APC) Differentially Regulates β-Catenin Phosphorylation and Ubiquitination in Colon Cancer Cells* , 2006, Journal of Biological Chemistry.

[34]  H. Paulson,et al.  RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia , 2004, Nature Medicine.

[35]  K. Shirai,et al.  [HMG-CoA reductase]. , 2001, Nihon rinsho. Japanese journal of clinical medicine.

[36]  C. la Vecchia,et al.  Hormone replacement therapy and risk of colon and rectal cancer. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[37]  T. P. Pretlow,et al.  Aberrant crypts in human colonic mucosa: Putative preneoplastic lesions , 1992, Journal of cellular biochemistry. Supplement.

[38]  Shan Wang,et al.  Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma. , 2004, World journal of gastroenterology.

[39]  L. Hamann,et al.  Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists , 1997, Nature.

[40]  M. Shinoda,et al.  Effects of ER-34122, a novel dual 5-lipoxygenase/cyclooxygenase inhibitor, on indices of early articular lesion in MRL/MpJ-lpr/lpr mice , 1999, Inflammation Research.

[41]  R. Poulsom,et al.  Lack of inducible nitric oxide synthase promotes intestinal tumorigenesis in the Apc(Min/+) mouse. , 2001, Gastroenterology.

[42]  N. Pommery,et al.  COX-2/5-LOX dual acting anti-inflammatory drugs in cancer chemotherapy. , 2007, Current topics in medicinal chemistry.

[43]  M. Thun,et al.  Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women. , 1995, Journal of the National Cancer Institute.

[44]  Michael A. Beer,et al.  Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. , 2007, Molecular cell.

[45]  M. Kitagawa,et al.  Geranylgeranylated Rho Small GTPase(s) Are Essential for the Degradation of p27Kip1 and Facilitate the Progression from G1 to S Phase in Growth-stimulated Rat FRTL-5 Cells* , 1997, The Journal of Biological Chemistry.

[46]  S. Singh,et al.  Oestrogen and colonic epithelial cell growth. , 1995, Gut.

[47]  Bert Vogelstein,et al.  Mutational Analysis of the APC/β-Catenin/Tcf Pathway in Colorectal Cancer , 1998 .

[48]  P. Opolon,et al.  Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo. , 2002, Biochemical and biophysical research communications.

[49]  L. Patterson,et al.  Effects of conjugated equine estrogen in postmenopausal women with hysterectomy , 2004, Journal of Family Planning and Reproductive Health Care.

[50]  Norman Wolmark,et al.  Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. , 2006, JAMA.

[51]  M. Morrow Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial , 2007 .

[52]  S. Schwartz,et al.  Colorectal cancer following tamoxifen therapy for breast cancer (United States) , 2001, Cancer Causes & Control.

[53]  G. Landberg,et al.  Expression of the leukotriene D4 receptor CysLT1, COX-2, and other cell survival factors in colorectal adenocarcinomas. , 2003, Gastroenterology.

[54]  Xiao-Fan Wang,et al.  Inhibition of the 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Pathway Induces p53-independent Transcriptional Regulation of p21 WAF1/CIP1 in Human Prostate Carcinoma Cells* , 1998, The Journal of Biological Chemistry.

[55]  H Jick,et al.  Statin use and cancer risk in the General Practice Research Database , 2004, British Journal of Cancer.

[56]  J. Abbruzzese,et al.  Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis , 2003, Oncogene.

[57]  R. Chandraratna,et al.  Adenomatous Polyposis Coli (APC)-independent Regulation of β-Catenin Degradation via a Retinoid X Receptor-mediated Pathway* , 2003, Journal of Biological Chemistry.

[58]  J. Turkson,et al.  Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. , 2001, The Journal of clinical investigation.

[59]  J. Potter,et al.  Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, case-control study in the United States , 1997, Cancer Causes & Control.

[60]  Walter Birchmeier,et al.  Hot papers in cell biology - J. Behrens, J.P. von Kries, M. Kuehl, L. Bruhn, D. Wedlich, R. Grosschedl, W. Birchmeier: "Functional interaction of beta-catenin with the transcription factor LEF-1" - Comments by Walter Birchmeier , 1999 .

[61]  Analysis of gene expression profile in colon cancer using the Cancer Genome Anatomy Project and RNA interference. , 2006, Chinese journal of digestive diseases.

[62]  Jianjun Gao,et al.  Nitric oxide-donating aspirin prevents pancreatic cancer in a hamster tumor model. , 2006, Cancer research.

[63]  Tom S. Price,et al.  Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2. , 2006, Gastroenterology.

[64]  B. Rigas,et al.  Altered eicosanoid levels in human colon cancer. , 1993, The Journal of laboratory and clinical medicine.

[65]  A. Sjölander,et al.  Leukotrienes induce cell-survival signaling in intestinal epithelial cells. , 2000, Gastroenterology.

[66]  A. Ford-hutchinson,et al.  Expression of mRNA for cyclooxygenase‐1 and cyclooxygenase‐2 in human tissues , 1993, FEBS letters.

[67]  T. Hoey,et al.  G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the β-catenin pathway , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[68]  S. Cummings,et al.  Skeletal Effects of Raloxifene After 8 Years: Results from the Continuing Outcomes Relevant to Evista (CORE) Study , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[69]  M. Sporn,et al.  Chemoprevention: an essential approach to controlling cancer , 2002, Nature Reviews Cancer.

[70]  C. Harris,et al.  Nitric oxide in cancer and chemoprevention. , 2003, Free radical biology & medicine.

[71]  J. Gustafsson,et al.  Role of estrogen receptor β in colonic epithelium , 2006 .

[72]  Roy Garcia,et al.  STATs in oncogenesis , 2000, Oncogene.

[73]  J. Fraumeni,et al.  A prospective study of menopausal hormones and risk of colorectal cancer (United States) , 1997, Cancer Causes & Control.

[74]  R. Frairia,et al.  Sex steroid receptors, secondary bile acids and colorectal cancer. A possible mechanism of interaction. , 2003, Panminerva medica.

[75]  Michael Kühl,et al.  Functional interaction of β-catenin with the transcription factor LEF-1 , 1996, Nature.

[76]  J. Castle,et al.  Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs , 2005, Nature.

[77]  J. Barkin The Use of Aspirin for Primary Prevention of Colorectal Cancer: A Systematic Review Prepared for the U.S. Preventive Services Task Force , 2008 .

[78]  C. Watson,et al.  Membrane estrogen receptor-α levels predict estrogen-induced ERK1/2 activation in MCF-7 cells , 2004, Breast Cancer Research.

[79]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[80]  V. Steele,et al.  Nitric oxide–releasing aspirin and indomethacin are potent inhibitors against colon cancer in azoxymethane-treated rats: effects on molecular targets , 2006, Molecular Cancer Therapeutics.

[81]  L. Looijenga,et al.  Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas , 2002, Oncogene.

[82]  C. Shou,et al.  Expression of hiwi gene in human gastric cancer was associated with proliferation of cancer cells , 2006, International journal of cancer.

[83]  Akira Kikuchi,et al.  Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK‐3β and β‐catenin and promotes GSK‐3β‐dependent phosphorylation of β‐catenin , 1998 .

[84]  C. Croce,et al.  MicroRNA-cancer connection: the beginning of a new tale. , 2006, Cancer research.

[85]  M. von Knebel Doeberitz,et al.  Wnt/β‐catenin‐pathway as a molecular target for future anti‐cancer therapeutics , 2005 .

[86]  Frank Petersen,et al.  Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex , 2004 .

[87]  Chao Zhang,et al.  RNAi technology: a revolutionary tool for the colorectal cancer therapeutics. , 2006, World journal of gastroenterology.

[88]  N. Pommery,et al.  Mechanisms leading to COX-2 expression and COX-2 induced tumorigenesis: topical therapeutic strategies targeting COX-2 expression and activity. , 2006, Anti-cancer agents in medicinal chemistry.

[89]  Richard G. W. Anderson,et al.  ERβ Has Nongenomic Action in Caveolae , 2002 .

[90]  B. Rigas,et al.  The Role of NSAIDs in the Prevention of Colon Cancer , 2002, Cancer investigation.

[91]  Wei Jiang,et al.  Wnt/beta-catenin signaling pathway as a novel cancer drug target. , 2004, Current cancer drug targets.

[92]  Robert A Hegele,et al.  Retinoid X receptor heterodimers in the metabolic syndrome. , 2005, The New England journal of medicine.

[93]  J. Darnell,et al.  Constitutively activated Stat3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated Stat1. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[94]  Shuji Ogino,et al.  Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. , 2007, The New England journal of medicine.

[95]  S. Hart,et al.  Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. , 1992, The Journal of biological chemistry.

[96]  W. Smith Prostanoid biosynthesis and mechanisms of action. , 1992, The American journal of physiology.

[97]  A. Papavassiliou,et al.  Oestrogen receptor beta (ERbeta) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour's dedifferentiation. , 2003, European journal of cancer.

[98]  C. Rao,et al.  Chemopreventive effect of farnesol and lanosterol on colon carcinogenesis. , 2002, Cancer detection and prevention.

[99]  H. Johansson,et al.  Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast Cancer Study Group. , 1995, Journal of the National Cancer Institute.

[100]  Wei Zhang,et al.  Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. , 2005, The American journal of pathology.

[101]  L. Ellis,et al.  Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis , 2002, Oncogene.

[102]  B. Katzenellenbogen,et al.  Estrogen receptors: selective ligands, partners, and distinctive pharmacology. , 2000, Recent progress in hormone research.

[103]  S. Rutberg,et al.  Loss of retinoic acid receptors in mouse skin and skin tumors is associated with activation of the ras(Ha) oncogene and high risk for premalignant progression. , 1996, Cancer research.

[104]  W. Birchmeier,et al.  New aspects of Wnt signaling pathways in higher vertebrates. , 2001, Current opinion in genetics & development.

[105]  Amy A. Caudy,et al.  Post-transcriptional gene silencing by double-stranded RNA , 2001, Nature Reviews Genetics.

[106]  R. DuBois,et al.  Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors. , 1996, Gastroenterology.

[107]  A. Hatzigeorgiou,et al.  A combined computational-experimental approach predicts human microRNA targets. , 2004, Genes & development.

[108]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[109]  K. Kashfi,et al.  Nitric oxide-donating aspirin inhibits β-catenin/T cell factor (TCF) signaling in SW480 colon cancer cells by disrupting the nuclear β-catenin–TCF association , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[110]  Y. Vodovotz,et al.  The role of nitric oxide chemistry in cancer treatment. , 1998, Biochemistry. Biokhimiia.

[111]  R. Thampan,et al.  Membrane associated estrogen receptors and related proteins: Localization at the plasma membrane and the endoplasmic reticulum , 2003, Molecular and Cellular Biochemistry.

[112]  K. Korach,et al.  Estrogen receptors and human disease. , 2006, The Journal of clinical investigation.

[113]  P. Newcomb,et al.  POSTMENOPAUSAL HORMONE USE AND RISK OF LARGE-BOWEL CANCER , 1996 .

[114]  J. Darnell,et al.  Stat3 as an Oncogene , 1999, Cell.

[115]  R. Wolff,et al.  Associations between ERα, ERβ, and AR Genotypes and Colon and Rectal Cancer , 2005, Cancer Epidemiology Biomarkers & Prevention.

[116]  T. Morisaki,et al.  Nitric oxide synthase expression and nitric oxide production in human colon carcinoma tissue , 1999, Journal of surgical oncology.

[117]  M. Yasuno,et al.  Expression of 5-lipoxygenase in human colorectal cancer. , 2006, World journal of gastroenterology.

[118]  H. Friess,et al.  5-Lipoxygenase, a marker for early pancreatic intraepithelial neoplastic lesions. , 2003, Cancer research.

[119]  Ming Jiang,et al.  Bcl-2 constitutively suppresses p53-dependent apoptosis in colorectal cancer cells. , 2003, Genes & development.

[120]  E. Levin,et al.  Integration of the extranuclear and nuclear actions of estrogen. , 2005, Molecular endocrinology.

[121]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[122]  Rajnish A. Gupta,et al.  Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2 , 2001, Nature Reviews Cancer.

[123]  S. Narayan,et al.  Estradiol is trophic for colon cancer in mice: effect on ornithine decarboxylase and c-myc messenger RNA. , 1992, Gastroenterology.

[124]  J. Dogné,et al.  New trends in dual 5-LOX/COX inhibition. , 2002, Current medicinal chemistry.

[125]  R. DuBois,et al.  New paradigms for cancer prevention. , 2001, Carcinogenesis.

[126]  W. Birchmeier,et al.  Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. , 1998, Science.

[127]  M. Schwab,et al.  Cyclooxygenase-2 Expression in Human Colorectal Cancer Is Unrelated to Overall Patient Survival , 2005, Clinical Cancer Research.

[128]  R. Chandraratna,et al.  Enantioselective syntheses of potent retinoid X receptor ligands: differential biological activities of individual antipodes. , 2001, Journal of medicinal chemistry.

[129]  J. Soria,et al.  Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study. , 2001, Carcinogenesis.

[130]  M. Kondo,et al.  Expression of cyclooxygenase-1 and -2 in human colorectal cancer. , 1995, Cancer research.

[131]  C. Elson,et al.  Sterol‐independent regulation of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase in tumor cells , 2001, Molecular carcinogenesis.

[132]  林下 陽二 A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation , 2006 .

[133]  Marc A Pfeffer,et al.  Cardiovascular Risk Associated With Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention , 2005, The New England journal of medicine.

[134]  S. Hilsenbeck,et al.  Suppression of mammary tumorigenesis in transgenic mice by the RXR-selective retinoid, LGD1069. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[135]  J. Auwerx,et al.  Attenuation of Colon Inflammation through Activators of the Retinoid X Receptor (Rxr)/Peroxisome Proliferator–Activated Receptor γ (Pparγ) Heterodimer , 2001, The Journal of experimental medicine.

[136]  T. Hoey,et al.  G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the {beta}-catenin pathway. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[137]  B. Rigas,et al.  Nitric Oxide-Donating Aspirin Inhibits Colon Cancer Cell Growth via Mitogen-Activated Protein Kinase Activation , 2006, Journal of Pharmacology and Experimental Therapeutics.

[138]  J. Morrow,et al.  Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. , 1997, The Journal of clinical investigation.

[139]  J. Goldstein,et al.  Regulation of the mevalonate pathway , 1990, Nature.

[140]  C. Harris,et al.  Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression. , 1998, Cancer research.

[141]  M. Crisby Modulation of the inflammatory process by statins. , 2003, Drugs of today.

[142]  R. Goldbohm,et al.  Dietary folate and APC mutations in sporadic colorectal cancer. , 2006, The Journal of nutrition.

[143]  John Robbins,et al.  National cross sectional survey to determine whether the decision to delivery interval is critical in emergency caesarean section , 2004, BMJ : British Medical Journal.

[144]  J. Darnell,et al.  Stat3 Activation Is Required for Cellular Transformation by v-src , 1998, Molecular and Cellular Biology.

[145]  J. Turkson,et al.  Stat3 Activation by Src Induces Specific Gene Regulation and Is Required for Cell Transformation , 1998, Molecular and Cellular Biology.

[146]  P. Wright,et al.  Flavopiridol Sensitivity of Cancer Cells Isolated from Ascites and Pleural Fluids , 2005, Clinical Cancer Research.

[147]  A. Gotto,et al.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. , 1998, JAMA.

[148]  Kurt Zatloukal,et al.  Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. , 2005, Neoplasia.

[149]  Colleen C Nelson,et al.  Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know? , 2005, Endocrine reviews.

[150]  R. Jove,et al.  Cooperative Regulation of Mcl-1 by Janus Kinase/STAT and Phosphatidylinositol 3-Kinase Contribute to Granulocyte-Macrophage Colony-Stimulating Factor-Delayed Apoptosis in Human Neutrophils1 , 2001, The Journal of Immunology.

[151]  K. Kashfi,et al.  Nitric-oxide-donating NSAIDs as agents for cancer prevention. , 2004, Trends in molecular medicine.

[152]  Barry R. Davis,et al.  Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). , 2002, JAMA.

[153]  Michael J Thun,et al.  Cholesterol-lowering drugs and colorectal cancer incidence in a large United States cohort. , 2006, Journal of the National Cancer Institute.

[154]  M. Sporn,et al.  Treatment and Prevention of Intraepithelial Neoplasia: An Important Target for Accelerated New Agent Development: Recommendations of the American Association for Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia , 2002 .

[155]  S. Moochhala,et al.  Nitric oxide synthase activity and expression in human colorectal cancer. , 1996, Carcinogenesis.

[156]  B. Davis,et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. , 1996, The New England journal of medicine.

[157]  K. Fransén,et al.  Nitric oxide synthase 2 mRNA expression in relation to p53 and adenomatous polyposis coli mutations in primary colorectal adenocarcinomas. , 2002, Surgery.

[158]  E. Miska,et al.  How microRNAs control cell division, differentiation and death. , 2005, Current opinion in genetics & development.

[159]  Brian S. Roberts,et al.  The colorectal microRNAome. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[160]  D F Roychowdhury,et al.  Aspirin and the risk of colorectal cancer in women. , 1996, The New England journal of medicine.

[161]  Garret A FitzGerald,et al.  Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. , 2005, The Journal of clinical investigation.

[162]  C. Rao,et al.  Chemoprevention of colonic aberrant crypt foci by an inducible nitric oxide synthase-selective inhibitor. , 1999, Carcinogenesis.

[163]  Robert Riddell,et al.  Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. , 2005, The New England journal of medicine.

[164]  Christian Bogdan,et al.  Nitric oxide and the immune response , 2001, Nature Immunology.

[165]  B Getty,et al.  beta-catenin expression in primary and metastatic colorectal carcinoma. , 1999, International journal of cancer.

[166]  Eva Enmark,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1997 by The Endocrine Society Human Estrogen Receptor �-Gene Structure, Chromosomal Localization, and Expression Pattern* , 2022 .

[167]  D. Bartel,et al.  Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs , 2004, Nature Reviews Genetics.

[168]  William L. Smith,et al.  The Membrane Binding Domains of Prostaglandin Endoperoxide H Synthases 1 and 2 , 1999, The Journal of Biological Chemistry.

[169]  R. Hoover,et al.  EVIDENCE OF A HEALTHY ESTROGEN USER SURVIVOR EFFECT , 1995, Epidemiology.

[170]  C. Rao,et al.  Lamin B, caspase-3 activity, and apoptosis induction by a combination of HMG-CoA reductase inhibitor and COX-2 inhibitors: a novel approach in developing effective chemopreventive regimens. , 2002, International journal of oncology.

[171]  M. Drews,et al.  Molecular study of sex steroid receptor gene expression in human colon and in colorectal carcinomas , 1997, Journal of surgical oncology.

[172]  L. Williams,et al.  Bridging of β-catenin and glycogen synthase kinase-3β by Axin and inhibition of β-catenin-mediated transcription , 1998 .

[173]  Julian Peto,et al.  Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer , 1997, The Lancet.

[174]  A. Umezawa,et al.  Prevention of 1,2-dimethylhydrazine-induced colon tumorigenesis by HMG-CoA reductase inhibitors, pravastatin and simvastatin, in ICR mice. , 1994, Carcinogenesis.

[175]  Hans Clevers,et al.  Activation of β-Catenin-Tcf Signaling in Colon Cancer by Mutations in β-Catenin or APC , 1997, Science.

[176]  Jianjun Gao,et al.  Nitric oxide-donating aspirin induces apoptosis in human colon cancer cells through induction of oxidative stress. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[177]  I. Charles,et al.  Microencapsulated iNOS‐expressing cells cause tumor suppression in mice , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[178]  V. Speirs,et al.  Loss of expression of oestrogen receptor beta in colon cancer and its association with Dukes' staging. , 2005, Oncology reports.

[179]  S. LeVine,et al.  Experimental allergic encephalomyelitis is exacerbated in mice deficient for 12/15-lipoxygenase or 5-lipoxygenase , 2004, Brain Research.

[180]  Jie-ping Yu,et al.  Expression of estrogen receptor beta in human colorectal cancer. , 2004, World journal of gastroenterology.

[181]  M. Bertagnolli,et al.  Modulation of tumor formation and intestinal cell migration by estrogens in the Apc(Min/+) mouse model of colorectal cancer. , 2004, Carcinogenesis.

[182]  L. Marnett Aspirin and the potential role of prostaglandins in colon cancer. , 1992, Cancer research.

[183]  M. Hamberg,et al.  Transformation of arachidonic acid and homo-gamma-linolenic acid by rabbit polymorphonuclear leukocytes. Monohydroxy acids from novel lipoxygenases. , 1976, The Journal of biological chemistry.

[184]  F. Vizoso,et al.  Estrogen and Progesterone Receptors in Colorectal Cancer and Surrounding Mucosa , 2001, The International journal of biological markers.

[185]  R. Evans,et al.  Nuclear receptor that identifies a novel retinoic acid response pathway , 1990, Nature.

[186]  William K K Wu,et al.  A mechanistic study of colon cancer growth promoted by cigarette smoke extract. , 2005, European journal of pharmacology.

[187]  Leah E. Mechanic,et al.  Nitric Oxide, a Mediator of Inflammation, Suppresses Tumorigenesis , 2004, Cancer Research.

[188]  D. Moher,et al.  Nonsteroidal Anti-inflammatory Drugs and Cyclooxygenase-2 Inhibitors for Primary Prevention of Colorectal Cancer: A Systematic Review Prepared for the U.S. Preventive Services Task Force , 2007, Annals of Internal Medicine.

[189]  Y. Akao,et al.  MicroRNA-143 and -145 in colon cancer. , 2007, DNA and cell biology.

[190]  W. Wu,et al.  Nicotine Promoted Colon Cancer Growth via Epidermal Growth Factor Receptor, c-Src, and 5-Lipoxygenase-Mediated Signal Pathway , 2004, Journal of Pharmacology and Experimental Therapeutics.

[191]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[192]  X. Agirre,et al.  Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues , 2006, Molecular Cancer.

[193]  T. Narisawa,et al.  Chemopreventive efficacy of low dose of pravastatin, an HMG-CoA reductase inhibitor, on 1,2-dimethylhydrazine-induced colon carcinogenesis in ICR mice. , 1996, The Tohoku journal of experimental medicine.

[194]  R. Coffey,et al.  Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. , 1994, Gastroenterology.

[195]  S. Nozawa,et al.  Expression of estrogen receptor beta in rat bone. , 1997, Endocrinology.

[196]  Junji Kato,et al.  Aberrant Crypt Foci of the Colon as Precursors of Adenoma and Cancer , 1998 .

[197]  J. Bromberg Stat proteins and oncogenesis. , 2002, The Journal of clinical investigation.

[198]  Anton J. Enright,et al.  Human MicroRNA Targets , 2004, PLoS biology.

[199]  S. Moochhala,et al.  Aberrant expression of nitric oxide synthase in human polyps, neoplastic colonic mucosa and surrounding peritumoral normal mucosa. , 1994, Carcinogenesis.

[200]  B. Katzenellenbogen,et al.  Molecular mechanisms of estrogen action: selective ligands and receptor pharmacology , 2000, The Journal of Steroid Biochemistry and Molecular Biology.

[201]  K. Umesono,et al.  A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR , 1991, Cell.

[202]  V. Steele,et al.  Prevention of azoxymethane-induced colon cancer by combination of low doses of atorvastatin, aspirin, and celecoxib in F 344 rats. , 2006, Cancer research.

[203]  S. Hammond,et al.  MicroRNAs as oncogenes. , 2006, Current opinion in genetics & development.

[204]  C. Rao,et al.  Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac. , 1999, Gastroenterology.

[205]  M. Lipkin,et al.  Preclinical Mouse Models for Cancer Chemoprevention Studies , 1999, Annals of the New York Academy of Sciences.

[206]  Francesca Benedini,et al.  Positional Isomerism Markedly Affects the Growth Inhibition of Colon Cancer Cells by Nitric Oxide-Donating Aspirin in Vitro and in Vivo , 2005, Journal of Pharmacology and Experimental Therapeutics.

[207]  Harry K. Genant,et al.  Reduction of Vertebral Fracture Risk in Postmenopausal Women With Osteoporosis Treated With Raloxifene: Results From a 3-year Randomized Clinical Trial , 2000 .

[208]  T. Narisawa,et al.  Chemoprevention by Pravastatin, a 3‐Hydroxy‐3‐methylglutaryl‐coenzyme A Reductase Inhibitor, of N‐Methyl‐N‐nitrosourea‐induced Colon Carcinogenesis in F344 Rats , 1996, Japanese journal of cancer research : Gann.

[209]  R. Nusse,et al.  Wnt signaling: a common theme in animal development. , 1997, Genes & development.

[210]  S. Kansra,et al.  Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release , 2005, Molecular and Cellular Endocrinology.

[211]  W P Bennett,et al.  Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorectal cancer. , 1999, Journal of the National Cancer Institute.

[212]  K. Hahm,et al.  Decreased Helicobacter pylori associated gastric carcinogenesis in mice lacking inducible nitric oxide synthase , 2004, Gut.

[213]  R. Evans,et al.  The RXR heterodimers and orphan receptors , 1995, Cell.

[214]  Paul Polakis,et al.  Binding of GSK3β to the APC-β-Catenin Complex and Regulation of Complex Assembly , 1996, Science.

[215]  P. Knekt,et al.  Dietary fat, cholesterol and colorectal cancer in a prospective study , 2001, British Journal of Cancer.

[216]  B. Bapat,et al.  Cyclooxygenase-2 knockdown by RNA interference in colon cancer. , 2006, International journal of oncology.

[217]  R. DuBois,et al.  Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[218]  R. White,et al.  Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[219]  Gregor Eichele,et al.  9-cis retinoic acid is a high affinity ligand for the retinoid X receptor , 1992, Cell.

[220]  H. Harn,et al.  Expression of nuclear retinoid receptors in normal, premalignant and malignant gastric tissues determined by in situ hybridization , 1999, British Journal of Cancer.

[221]  J. Bertram,et al.  Tamoxifen inhibits colorectal cancer metastases in the liver: A study in a murine model , 1998, Journal of gastroenterology and hepatology.

[222]  N. Dean,et al.  Antisense oligonucleotide-based therapeutics for cancer , 2003, Oncogene.

[223]  P K Lala,et al.  Role of nitric oxide in carcinogenesis and tumour progression. , 2001, The Lancet. Oncology.

[224]  K. Kinzler,et al.  Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC−/− Colon Carcinoma , 1997, Science.

[225]  J. Pelletier,et al.  Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs , 2003, Annals of the rheumatic diseases.

[226]  J. Olsen,et al.  Cancer risk among statin users: A population‐based cohort study , 2005, International journal of cancer.

[227]  G. Piazza,et al.  Combinatorial chemoprevention: efficacy of lovostatin and exisulind on the formation and progression of aberrant crypt foci. , 2004, Anticancer research.

[228]  I. L. Smith,et al.  Pharmacokinetics and Pharmacodynamics of Tepoxalin after Single Oral Dose Administration to Healthy Volunteers , 1996, Journal of clinical pharmacology.

[229]  K. Seibert,et al.  Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. , 2000, Cancer research.

[230]  R Grosschedl,et al.  Functional interaction of beta-catenin with the transcription factor LEF-1. , 1996, Nature.

[231]  Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib After Cardiac Surgery , 2005 .

[232]  J. LeLorier,et al.  Do statins cause cancer? A meta-analysis of large randomized clinical trials. , 2001, The American journal of medicine.

[233]  D. Beer,et al.  Overexpression of 5-Lipoxygenase in Rat and Human Esophageal Adenocarcinoma and Inhibitory Effects of Zileuton and Celecoxib on Carcinogenesis , 2004, Clinical Cancer Research.

[234]  L. Blais,et al.  3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study. , 2000, Archives of internal medicine.

[235]  A. Jazaeri,et al.  Selective loss of estrogen receptor β in malignant human colon , 2000 .

[236]  M. Pignatelli,et al.  β-catenin - A linchpin in colorectal carcinogenesis? , 2002 .

[237]  C. Rao,et al.  Chemopreventive properties of a selective inducible nitric oxide synthase inhibitor in colon carcinogenesis, administered alone or in combination with celecoxib, a selective cyclooxygenase-2 inhibitor. , 2002, Cancer research.

[238]  F. Traganos,et al.  NO-donating nonsteroidal antiinflammatory drugs (NSAIDs) inhibit colon cancer cell growth more potently than traditional NSAIDs: a general pharmacological property? , 2004, Biochemical pharmacology.

[239]  Bert Vogelstein,et al.  APC mutations occur early during colorectal tumorigenesis , 1992, Nature.

[240]  J. Stein,et al.  HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2. , 2001, Carcinogenesis.

[241]  Richard Graham Knowles,et al.  Selective inhibition of inducible nitric oxide synthase inhibits tumor growth in vivo: studies with 1400W, a novel inhibitor. , 1997, Cancer research.

[242]  H. Ohshima,et al.  Suppression of intestinal polyposis in Apc(Min/+) mice by inhibiting nitric oxide production. , 2001, Cancer research.

[243]  C. Serhan,et al.  Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses. , 2001, The American journal of pathology.

[244]  B Vojnovic,et al.  Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability. , 2001, Cancer research.

[245]  B. Kimler,et al.  Selective estrogen-receptor modulators for primary prevention of breast cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[246]  Dahlén,et al.  Leukotrienes as targets for treatment of asthma and other diseases. Current basic and clinical research , 2000, American journal of respiratory and critical care medicine.

[247]  C C Glüer,et al.  Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. , 1999, JAMA.