E-poster Presentation 2014 World Cancer Congress

Haploinsufficiency of MIIP Disables APC/Ccdc20-Securin/Topoisomerase IIα Rheostat and Induces Chromosomal Instability in Colorectal Cancer (#1210)

Yan Sun 1 , Ping Ji 2 , Tao Chen 2 , Xinhui Zhou 2 , Da Yang 2 , Yuexin Liu 2 , Limei Hu 2 , Dianren Xia 2 , Asha S. Multani 2 , Ilya Shmulevich 3 , Raju Kucherlapati 4 , Scott Kopetz 2 , Anil K. Sood 2 , Stanley R. Hamilton 2 , Baocun Sun 1 , Wei Zhang 2
  1. Tianjin Medical University Cancer Hospital, Tianjin, China
  2. The University of Texas MD Anderson Cancer Center , Houston, Texas, USA
  3. Institute for Systems Biology, Seattle, WA, USA
  4. Departments of Genetics and Medicine, Harvard Medical School, Boston, MA, USA

Background: Chromosomal instability (CIN) is associated with cancer development and progression, but the driving molecular events underlying CIN remain unclear.

Aim: We report that the Migration and Invasion Inhibitory Protein (MIIP) gene on chromosome 1p36 is key in producing CIN and a tumor-suppressor gene.

Methods: We performed a genomic analysis for MIIP deletion in 188 colorectal cancer (CRC) patients in The Cancer Genome Atlas cohort and validated in an independent cohort of 518 cases in China. MIIP gene was deleted using zinc finger nuclease technology and its functions in CIN and colony formation, cell migration and invasion were examined in CRC cells. An orthotopic mouse model was used to verify the role of MIIP deletion in CRC development and progression. In addition, a series of experiments, such as ubiquitination, chromosome decatenation and segregation and co-immunoprecipitation assays, were performed to explain the mechanism of MIIP deletion inducing CIN.

Results: MIIP deletion is significantly associated with CIN and metastasis of 188 CRC patients in The Cancer Genome Atlas cohort. Attenuated MIIP protein expression is associated with CRC progression in an independent cohort of 518 patients. Deletion of a single copy of the MIIP gene by zinc finger nuclease technology resulted in CIN phenotype and liver metastasis. Mechanistically, MIIP deletion caused augmented APC/CCdc20 ubiqutination ligase activity and over-degradation of Topoisomerase IIα (TopoIIα), cyclinB1 and securin, resulting in deregulation of the decatenation checkpoint at mitosis, aberrant sister chromatid segregation, and development of CIN.

Conclusions: We identified MIIP on 1p36 as a key CIN-suppressor gene and proposed that haploinsufficiency of MIIP disables APC/Ccdc20-Securin/TopoIIα Rheostat, resulting in deregulation of the mitotic decatenation checkpoint and CIN. In addition, we demonstrated that MIIP directly regulates TopoIIα activity and further affects TopoI activity, which will help us identify colorectal cancer patients who will benefit from Topo inhibitors.