title: Antagonizing pathways leading to differential dynamics in colon carcinogenesis in Shugoshin1 (Sgo1)-haploinsufficient chromosome instability model.
abstract: Colon cancer is the second most lethal cancer. It is predicted to claim 50,310 lives in 2014. Chromosome Instability (CIN) is observed in 80-90% of colon cancers, and is thought to contribute to colon cancer progression and recurrence. However, there are no animal models of CIN that have been validated for studies of colon cancer development or drug testing. In this study, we sought to validate a mitotic error-induced CIN model mouse, the Shugoshin1 (Sgo1) haploinsufficient mouse, as a colon cancer study model. Wild-type and Sgo1(-/+) mice were treated with the colonic carcinogen, azoxymethane (AOM). We tracked colon tumor development 12, 24, and 36 wk after treatment to assess progression of colon tumorigenesis. Initially, more precancerous lesions, Aberrant Crypt Foci (ACF), developed in Sgo1(-/+) mice. However, the ACF did not develop straightforwardly into larger tumors. At the 36-wk endpoint, the number of gross tumors in Sgo1(-/+) mice was no different from that in wild-type controls. However, Copy Number Variation (CNV) analysis indicated that fully developed colon tumor in Sgo1(-/+) mice carried 13.75 times more CNV. Immunohistological analyses indicated that Sgo1(-/+) mice differentially expressed IL-6, Bcl2, and p16(INK4A) . We propose that formation of ACF in Sgo1(-/+) mice is facilitated by the IL6-STAT3-SOCS3 oncogenic pathway and by the Bcl2-anti-apoptotic pathway, yet further development of the ACF to tumors is inhibited by the p16(INK4A) tumor suppressor pathway. Manipulating these pathways would be beneficial for inhibiting development of colon cancer with CIN.
authors.affiliation: Department of Medicine, Hematology/Oncology Section, Center for Cancer Prevention and Drug Development, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma.
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
authors.affiliation: College of Arts and Sciences, Baylor University, Waco, Texas.
authors.forename: Saira
authors.initials: S
authors.lastname: Sanghera
authors.affiliation: Department of Medicine, Hematology/Oncology Section, Center for Cancer Prevention and Drug Development, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Hematology/Oncology Section, Center for Cancer Prevention and Drug Development, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma.
authors.forename: Laura
authors.initials: L
authors.lastname: Biddick
authors.affiliation: Department of Medicine, Hematology/Oncology Section, Center for Cancer Prevention and Drug Development, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma.
authors.forename: Arun
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Department of Medicine, Hematology/Oncology Section, Center for Cancer Prevention and Drug Development, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma.
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.affiliation: Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, New York.
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of Medicine, Hematology/Oncology Section, Center for Cancer Prevention and Drug Development, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma.
authors.forename: Hiroshi Y
authors.initials: HY
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D057895:Haploinsufficiency; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental; D009857:Oncogenes / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018797:Cell Cycle Proteins; C527733:shugoshin protein, mouse; D001397:Azoxymethane
keywords: Azoxymethane (AOM); Chromosome Instability (CIN); Colon cancer; Sgo1 (Shugoshin 1); mice