title: MIIP haploinsufficiency induces chromosomal instability and promotes tumour progression in colorectal cancer.
abstract: The gene encoding migration and invasion inhibitory protein (MIIP), located on 1p36.22, is a potential tumour suppressor gene in glioma. In this study, we aimed to explore the role and mechanism of action of MIIP in colorectal cancer (CRC). MIIP protein expression gradually decreased along the colorectal adenoma-carcinoma sequence and was negatively correlated with lymph node and distant metastasis in 526 colorectal tissue samples (p < 0.05 for all). Analysis of The Cancer Genome Atlas (TCGA) data showed that decreased MIIP expression was significantly associated with MIIP hemizygous deletion (p = 0.0005), which was detected in 27.7% (52/188) of CRC cases, and associated with lymph node and distant metastasis (p < 0.05 for both). We deleted one copy of the MIIP gene in HCT116 CRC cells using zinc finger nuclease technology and demonstrated that MIIP haploinsufficiency resulted in increased colony formation and cell migration and invasion, which was consistent with the results from siRNA-mediated MIIP knockdown in two CRC cell lines (p < 0.05 for all). Moreover, MIIP haploinsufficiency promoted CRC progression in vivo (p < 0.05). Genomic instability and spectral karyotyping assays demonstrated that MIIP haploinsufficiency induced chromosomal instability (CIN). Besides modulating the downstream proteins of APC/CCdc20, securin and cyclin B1, MIIP haploinsufficiency inhibited topoisomerase II (Topo II) activity and induced chromosomal missegregation. Therefore, we report that MIIP is a novel potential tumour suppressor gene in CRC. Moreover, we characterized the MIIP gene as a novel CIN suppressor gene, through altering the stability of mitotic checkpoint proteins and disturbing Topo II activity. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.|Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Ji
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Da
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Limei
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Dianren
authors.initials: D
authors.lastname: Xia
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Yanxue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Asha S
authors.initials: AS
authors.lastname: Multani
authors.affiliation: Institute for Systems Biology, Seattle, WA 98103, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Shmulevich
authors.affiliation: Departments of Genetics and Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hamilton
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, NC 20174, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D043171:Chromosomal Instability / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D014410:Tumor Stem Cell Assay
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C480900:MIIP protein, human; D009363:Neoplasm Proteins
keywords: MIIP; chromosomal instability; colorectal cancer; progression; topoisomerase