Migration-inducing gene 7 promotes tumorigenesis and angiogenesis and independently predicts poor prognosis of epithelial ovarian cancer.

Bihui Huang,Xia Li,Ge Lou,Kang Chen,Junping Kou,Jin Qi,Shijie Sheng,Boyang Yu,Mingzhu Yin,Guosheng Cao

doi:10.18632/oncotarget.8487

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.

Highlights

ACTB FGF2 HGF IGF1 MIG2 MIG6 MIG7 MIG14 PDGFA PDGFB PGF PTGS2 TGFB1 TNF VEGFA VEGFB VEGFC
Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense Sense Anti-sense
Sequence 5′-CATGTACGTTGCTATCCAGGC-3′ 5′-CTCCTTAATGTCACGCACGAT-3′ 5′-AGTGTGTGCTAACCGTTACCT-3′ 5′-ACTGCCCAGTTCGTTTCAGTG-3′ 5′-GCTATCGGGGTAAAGACCTACA-3′ 5′-CGTAGCGTACCTCTGGATTGC-3′ 5′-GCTCTTCAGTTCGTGTGTGGA-3′ 5′-GCCTCCTTAGATCACAGCTCC-3′ 5′-TGTGGAGCAGATCAATCGCAA-3′ 5′-GTTGGGCAACCGAAGGATGA-3′ 5′-CTGGAGCAGTCGCAGTGAG-3′ 5′-GCCATTCATCGGAGCAGATTTG-3′ 5′-CACCTGCCTCTGGTCGTTAGG-3′ 5′-TACTGGATTCCTCTAGCTTTGGTGTT-3′ 5′-ATGAGGGCCGTTACTATGAATGT-3′ 5′-CCTTGGTGAAGCCTCCATTTTG-3′ 5′-GCAAGACCAGGACGGTCATTT-3′ 5′-GGCACTTGACACTGCTCGT-3′ 5′-CTCGATCCGCTCCTTTGATGA-3′ 5′-CGTTGGTGCGGTCTATGAG-3′ 5′-GAACGGCTCGTCAGAGGTG-3′ 5′-ACAGTGCAGATTCTCATCGCC-3′ 5′-CTGGCGCTCAGCCATACAG-3′ 5′-CGCACTTATACTGGTCAAATCCC-3′ 5′-CTAATGGTGGAAACCCACAACG-3′ 5′-TATCGCCAGGAATTGTTGCTG-3′ 5′-CCTCTCTCTAATCAGCCCTCTG-3′ 5′-GAGGACCTGGGAGTAGATGAG-3′ 5′-AGGGCAGAATCATCACGAAGT-3′ 5′-AGGGTCTCGATTGGATGGCA-3′ 5′-GAGATGTCCCTGGAAGAACACA-3′ 5′-GAGTGGGATGGGTGATGTCAG-3′ 5′-GGCTGGCAACATAACAGAGAA-3′ 5′-CCCCACATCTATACACACCTCC-3′