MIIP haploinsufficiency induces chromosomal instability and promotes tumour progression in colorectal cancer

Yan Sun, Ping Ji, Tao Chen, Xinhui Zhou, Da Yang, Yuhong Guo, Yuexin Liu, Limei Hu, Dianren Xia, Yanxue Liu, Asha S. Multani, Ilya Shmulevich, Raju Kucherlapati, Scott Kopetz, Anil K. Sood, Stanley R. Hamilton, Baocun Sun, Wei Zhang

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6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)67-79
Number of pages13
JournalJournal of Pathology
Volume241
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

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Keywords

  • chromosomal instability
  • colorectal cancer
  • MIIP
  • progression
  • topoisomerase

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Sun, Y., Ji, P., Chen, T., Zhou, X., Yang, D., Guo, Y., Liu, Y., Hu, L., Xia, D., Liu, Y., Multani, A. S., Shmulevich, I., Kucherlapati, R., Kopetz, S., Sood, A. K., Hamilton, S. R., Sun, B., & Zhang, W. (2017). MIIP haploinsufficiency induces chromosomal instability and promotes tumour progression in colorectal cancer. Journal of Pathology, 241(1), 67-79. https://doi.org/10.1002/path.4823