PMID- 30628165 OWN - NLM STAT- MEDLINE DCOM- 20191202 LR - 20200309 IS - 1878-0261 (Electronic) IS - 1574-7891 (Print) IS - 1574-7891 (Linking) VI - 13 IP - 4 DP - 2019 Apr TI - Molecular evidence of field cancerization initiated by diabetes in colon cancer patients. PG - 857-872 LID - 10.1002/1878-0261.12438 [doi] AB - The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide-spectrum molecular studies that delve into the impact of T2DM-related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2DM. We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes-related metabolic and signaling processes. Proteomic approaches highlighted several cancer-related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD/YAP-TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high-glucose conditions. In conclusion, T2DM associates with deregulation of cancer-related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD/YAP-TAZ complex as a potential driver. CI - (c) 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. FAU - Del Puerto-Nevado, Laura AU - Del Puerto-Nevado L AD - Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. FAU - Minguez, Pablo AU - Minguez P AUID- ORCID: 0000-0003-4099-9421 AD - Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. FAU - Corton, Marta AU - Corton M AD - Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. AD - Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. FAU - Solanes-Casado, Sonia AU - Solanes-Casado S AD - Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. FAU - Prieto, Isabel AU - Prieto I AD - Radiation Oncology, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. FAU - Mas, Sebastian AU - Mas S AD - Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. FAU - Sanz, Ana Belen AU - Sanz AB AD - Nephrology and Hypertension Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. AD - REDINREN, Madrid, Spain. FAU - Gonzalez-Alonso, Paula AU - Gonzalez-Alonso P AD - Pathology Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. FAU - Villaverde, Cristina AU - Villaverde C AD - Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. AD - Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. FAU - Portal-Nunez, Sergio AU - Portal-Nunez S AD - Bone and Mineral Metabolism Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. AD - Applied Molecular Medicine Institute, School of Medicine, Universidad San Pablo CEU, CEU Universities, Madrid, Spain. FAU - Aguilera, Oscar AU - Aguilera O AD - Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. FAU - Gomez-Guerrero, Carmen AU - Gomez-Guerrero C AD - Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. FAU - Esbrit, Pedro AU - Esbrit P AD - Bone and Mineral Metabolism Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. FAU - Vivanco, Fernando AU - Vivanco F AD - Immunoallergy and Proteomics Laboratory, Immunology Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. FAU - Gonzalez, Nieves AU - Gonzalez N AD - Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. FAU - Ayuso, Carmen AU - Ayuso C AD - Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. AD - Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain. FAU - Ortiz, Alberto AU - Ortiz A AD - Nephrology and Hypertension Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. AD - REDINREN, Madrid, Spain. FAU - Rojo, Federico AU - Rojo F AD - Pathology Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. FAU - Egido, Jesus AU - Egido J AD - Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. FAU - Alvarez-Llamas, Gloria AU - Alvarez-Llamas G AD - REDINREN, Madrid, Spain. AD - Immunoallergy and Proteomics Laboratory, Immunology Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. FAU - Garcia-Foncillas, Jesus AU - Garcia-Foncillas J AD - Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. CN - DiabetesCancerConnect Consortium AD - Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain. LA - eng GR - CP16/00116/Instituto de Salud Carlos III/International GR - CPII15/00027/Instituto de Salud Carlos III/International GR - CPII17_00006/Instituto de Salud Carlos III/International GR - MS12/03262/Instituto de Salud Carlos III/International GR - MSII14/00031/Instituto de Salud Carlos III/International GR - PI13/00051/Instituto de Salud Carlos III/International GR - PI14/00386/Instituto de Salud Carlos III/International GR - PI17/01495/Instituto de Salud Carlos III/International GR - PT17/0015/0006/Instituto de Salud Carlos III/International GR - PT17/0019/Instituto de Salud Carlos III/International GR - RD016/009/Instituto de Salud Carlos III/International GR - REDINREN RD012/0021/Instituto de Salud Carlos III/International GR - RETICEF RD12/0043/008/Instituto de Salud Carlos III/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190216 PL - United States TA - Mol Oncol JT - Molecular oncology JID - 101308230 RN - IY9XDZ35W2 (Glucose) SB - IM MH - Animals MH - Carcinogenesis/genetics/pathology MH - Cohort Studies MH - Colonic Neoplasms/*etiology/*genetics MH - Diabetes Mellitus, Type 2/*complications MH - Female MH - Gene Expression Regulation, Neoplastic MH - Genomics MH - Glucose/metabolism MH - Humans MH - Hyperglycemia/complications MH - Intestinal Mucosa/pathology MH - Male MH - Mice, Nude MH - Signal Transduction/genetics MH - Transcriptome/genetics MH - Up-Regulation/genetics PMC - PMC6441931 OTO - NOTNLM OT - carcinogenesis OT - colon cancer OT - diabetes OT - field cancerization OT - omics OT - systems biology COIS- The authors have no conflicts of interest to declare. EDAT- 2019/01/11 06:00 MHDA- 2019/12/04 06:00 PMCR- 2019/04/01 CRDT- 2019/01/11 06:00 PHST- 2018/09/06 00:00 [received] PHST- 2018/12/01 00:00 [revised] PHST- 2018/12/27 00:00 [accepted] PHST- 2019/01/11 06:00 [pubmed] PHST- 2019/12/04 06:00 [medline] PHST- 2019/01/11 06:00 [entrez] PHST- 2019/04/01 00:00 [pmc-release] AID - MOL212438 [pii] AID - 10.1002/1878-0261.12438 [doi] PST - ppublish SO - Mol Oncol. 2019 Apr;13(4):857-872. doi: 10.1002/1878-0261.12438. Epub 2019 Feb 16.