title: Expression array analysis of the hepatocyte growth factor invasive program.
abstract: Signaling by human hepatocyte growth factor (hHGF) via its cell surface receptor (MET) drives mitogenesis, motogenesis and morphogenesis in a wide spectrum of target cell types and embryologic, developmental and homeostatic contexts. Oncogenic pathway activation also contributes to tumorigenesis and cancer progression, including tumor angiogenesis and metastasis, in several prevalent malignancies. The HGF gene encodes full-length hHGF and two truncated isoforms known as NK1 and NK2. NK1 induces all three HGF activities at modestly reduced potency, whereas NK2 stimulates only motogenesis and enhances HGF-driven tumor metastasis in transgenic mice. Prior studies have shown that mouse HGF (mHGF) also binds with high affinity to human MET. Here we show that, like NK2, mHGF stimulates cell motility, invasion and spontaneous metastasis of PC3M human prostate adenocarcinoma cells in mice through human MET. To identify target genes and signaling pathways associated with motogenic and metastatic HGF signaling, i.e., the HGF invasive program, gene expression profiling was performed using PC3M cells treated with hHGF, NK2 or mHGF. Results obtained using Ingenuity Pathway Analysis software showed significant overlap with networks and pathways involved in cell movement and metastasis. Interrogating The Cancer Genome Atlas project also identified a subset of 23 gene expression changes in PC3M with a strong tendency for co-occurrence in prostate cancer patients that were associated with significantly decreased disease-free survival.
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892-1501, USA.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Cecchi
authors.affiliation: Molecular Characterization and Clinical Assay Development Laboratory, Leidos Biomedical Research, Inc. and Frederick National Laboratory for Cancer Research, Frederick, MD, 21702-1201, USA.
authors.forename: Chih-Jian
authors.initials: CJ
authors.lastname: Lih
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892-1501, USA.
authors.forename: Young H
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Molecular Characterization and Clinical Assay Development Laboratory, Leidos Biomedical Research, Inc. and Frederick National Laboratory for Cancer Research, Frederick, MD, 21702-1201, USA.
authors.forename: William
authors.initials: W
authors.lastname: Walsh
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892-1501, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Rabe
authors.affiliation: Molecular Characterization and Clinical Assay Development Laboratory, Leidos Biomedical Research, Inc. and Frederick National Laboratory for Cancer Research, Frederick, MD, 21702-1201, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Williams
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892-1501, USA. don.bottaro@nih.gov.|Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bldg 10 CRC Rm 2-3952, 10 Center Drive MSC 1107, Bethesda, MD, 20892-1107, USA. don.bottaro@nih.gov.
authors.forename: Donald P
authors.identifier: http://orcid.org/0000-0002-5057-5334
authors.initials: DP
authors.lastname: Bottaro
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D020033:Protein Isoforms / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
keywords: Cell migration; Hepatocyte growth factor; MET receptor tyrosine kinase; Prostate cancer; Signal transduction; Tumor metastasis