Antagonizing pathways leading to differential dynamics in colon carcinogenesis in Shugoshin1 (Sgo1)‐haploinsufficient chromosome instability model. Issue 5 (14th March 2015)

• Record Type: Journal Article
• Authors: Rao, Chinthalapally V.; Sanghera, Saira; Zhang, Yuting; Biddick, Laura; Reddy, Arun; Lightfoot, Stan; Dai, Wei; Yamada, Hiroshi Y.
• Is Part Of: Molecular carcinogenesis. Volume 55:Issue 5(2016:May)
• Page Start: 600
• Page End: 610
• Publication Date: 2015-03-14
• Subjects: Sgo1 (Shugoshin 1) -- mice -- Colon cancer -- Azoxymethane (AOM) -- Chromosome Instability (CIN); Carcinogenesis -- Molecular aspects -- Periodicals; 616.994071
• DOI: 10.1002/mc.22306
• Languages: English
• ISSNs: 0899-1987

Abstract

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. © 2015 Wiley Periodicals, Inc.