Research Papers:
Migration-inducing gene 7 promotes tumorigenesis and angiogenesis and independently predicts poor prognosis of epithelial ovarian cancer
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Abstract
Bihui Huang1,2,3,*, Mingzhu Yin4,5,*, Xia Li6,7, Guosheng Cao4, Jin Qi4, Ge Lou8, Shijie Sheng9,10, Junping Kou4, Kang Chen2,3,10,11,12, Boyang Yu4
1Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA
2Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan, USA
3Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Detroit, Michigan, USA
4State Key Laboratory of Natural Products and Jiangsu Key Laboratory of Traditional Chinese Medicine (TCM) Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University, Nanjing, China
5Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
6Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
7Yale Stem Cell Center, Yale University, New Haven, Connecticut, USA
8Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Harbin Medical University, Harbin, China
9Department of Pathology, Wayne State University, Detroit, Michigan, USA
10Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Center and Department of Oncology, Wayne State University, Detroit, Michigan, USA
11Department of Immunology and Microbiology, Wayne State University, Detroit, Michigan, USA
12Mucosal Immunology Studies Team, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
*B.H. and M.Y. are interchangeable co-first authors and contributed equally to this study
Correspondence to:
Junping Kou, e-mail: [email protected]
Kang Chen, e-mail: [email protected]
Keywords: epithelial ovarian cancer, biomarker, prognosis, Migration-Inducting Gene 7, angiogenesis
Received: November 30, 2015 Accepted: March 18, 2016 Published: March 30, 2016
ABSTRACT
Epithelial ovarian carcinomas (EOC) cause more mortality than any other cancer of the female reproductive system. New therapeutic approaches to reduce EOC mortality have been largely unsuccessful due to the poor understanding of the mechanisms underlying EOC proliferation and metastasis. Progress in EOC treatment is further hampered by a lack of reliable prognostic biomarkers for early risk assessment. In this study, we identify that Migration-Inducting Gene 7 (MIG-7) is specifically induced in human EOC tissues but not normal ovaries or ovarian cyst. Ovarian MIG-7 expression strongly correlated with EOC progression. Elevated MIG-7 level at the time of primary cytoreductive surgery was a strong and independent predictor of poor survival of EOC patients. Cell and murine xenograft models showed that MIG-7 was required for EOC proliferation and invasion, and MIG-7 enhanced EOC-associated angiogenesis by promoting the expression of vascular endothelial growth factor. Inhibiting MIG-7 by RNA interference in grafted EOC cells retarded tumor growth, angiogenesis and improved host survival, and suppressing MIG-7 expression with a small molecule inhibitor D-39 identified from the medicinal plant Liriope muscari mitigated EOC growth and invasion and specifically abrogated the expression of vascular endothelial growth factor. Our data not only reveal a critical function of MIG-7 in EOC growth and metastasis and support MIG-7 as an independent prognostic biomarker for EOC, but also demonstrate that therapeutic targeting of MIG-7 is likely beneficial in the treatment of EOC.
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