Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines
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  • 作者：Natascia Marino ; Joshua W. Collins ; Changyu Shen…
  • 关键词：Metastasis suppressor genes ; Metastasis ; Gene expression profiling ; Bioinformatics ; PDE5A ; Breast cancer
  • 刊名：Clinical & Experimental Metastasis
  • 出版年：2014
  • 出版时间：October 2014
  • 年：2014
  • 卷：31
  • 期：7
  • 页码：771-786
  • 全文大小：1,160 KB
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  • 作者单位：Natascia Marino (1)
    Joshua W. Collins (1)
    Changyu Shen (2)
    Natasha J. Caplen (3)
    Anand S. Merchant (4)
    Yesim G?kmen-Polar (5)
    Chirayu P. Goswami (6)
    Takashi Hoshino (7)
    Yongzhen Qian (8)
    George W. Sledge Jr (10) (9)
    Patricia S. Steeg (1)

    1. Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Building 37/Room 1126, 37 Convent Drive, Bethesda, MD, 20892, USA
    2. Department of Biostatistics, Indiana University School of?Medicine, Indianapolis, IN, USA
    3. Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
    4. CCRIFX Bioinformatics Core, Advanced Biomedical Computing Center, Leidos Biomed, Frederick, MD, USA
    5. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    6. Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA
    7. Takeda Pharmaceutical Company Ltd, Tsukuba, Japan
    8. Laboratory Animal Sciences Program, SAIC-Frederick, National Cancer Institute, Frederick, MD, USA
    10. Stanford University School of Medicine, Palo Alto, CA, USA
    9. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
  • ISSN：1573-7276
文摘
Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A),?an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66?% compared to the empty vector-expressing cells (p?=?0.01 and p?=?0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-2?% fewer lung metastases than shRNA-scramble expressing cells (p?=?0.045 and p?=?0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.

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