title: MET-dependent cancer invasion may be preprogrammed by early alterations of p53-regulated feedforward loop and triggered by stromal cell-derived HGF.
abstract: MET, a receptor protein tyrosine kinase activated by hepatocyte growth factor (HGF), is a crucial determinant of metastatic progression. Recently, we have identified p53 as an important regulator of MET-dependent cell motility and invasion. This regulation occurs via feedforward loop suppressing MET expression by miR-34-dependent and -independent mechanisms. Here, by using Dicer conditional knockout, we provide further evidence for microRNA-independent MET regulation by p53. Furthermore, we show that while MET levels increase immediately after p53 inactivation, mutant cells do not contain active phosphorylated MET and remain non-invasive for a long latency period at contrary to cell culture observations. Evaluation of mouse models of ovarian and prostate carcinogenesis indicates that formation of desmoplastic stroma, associated production of HGF by stromal cells and coinciding MET phosphorylation precede cancer invasion. Thus, initiation mutation of p53 is sufficient for preprogramming motile and invasive properties of epithelial cells, but the stromal reaction may represent a critical step for their manifestation during cancer progression.
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.
authors.forename: Chang-Il
authors.initials: CI
authors.lastname: Hwang
authors.forename: Jinhyang
authors.initials: J
authors.lastname: Choi
authors.forename: Zongxiang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Andrea
authors.initials: A
authors.lastname: Flesken-Nikitin
authors.forename: Alexander
authors.initials: A
authors.lastname: Tarakhovsky
authors.forename: Alexander Yu
authors.initials: AY
authors.lastname: Nikitin
mesh_terms: D000818:Animals; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C553307:HGF protein, mouse; D035683:MicroRNAs; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
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