title: Phosphatase PRL-3 is a direct regulatory target of TGFbeta in colon cancer metastasis.
abstract: Metastasis causes most deaths from cancer yet mechanistic understanding and therapeutic options remain limited. Overexpression of the phosphatase PRL-3 (phosphatase of regenerating liver) is associated with metastasis of colon cancer. Here, we show that PRL-3 is a direct target of signaling by TGFβ, which is broadly implicated in progression and metastasis. We found that suppression of PRL-3 expression by TGFβ was mediated by Smad-dependent inhibition of PRL-3 transcription at the level of promoter activity. PRL-3 activation stimulated PI3K/AKT signaling that caused resistance to stress-induced apoptosis. PRL-3 overexpression promoted metastatic colonization in an orthotopic mouse model of colon cancer, whereas PRL-3 knockdown reduced metastatic potential. Altered metastatic phenotypes were not derivative of primary tumor development or local invasion but could be attributed to PRL-3-mediated cell survival. Our findings suggest that inhibiting PRL-3 expression might be an important mechanism through which TGFβ suppresses metastasis in colon cancer. In addition, our findings suggest that loss of TGFβ signaling, which occurs commonly during colon cancer progression, is sufficient to activate a PRL-3-mediated cell survival pathway that can selectively promote metastasis. Therefore, a major implication of our findings is that PRL-3 antagonists may offer significant value for antimetastatic therapy in patients with colon cancer.
authors.affiliation: University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska 68198, USA.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Xiao-Qiong
authors.initials: XQ
authors.lastname: Liu
authors.forename: Ashwani
authors.initials: A
authors.lastname: Rajput
authors.forename: Liying
authors.initials: L
authors.lastname: Geng
authors.forename: Melanie
authors.initials: M
authors.lastname: Ongchin
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Taylor
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*
chemical_list: D009363:Neoplasm Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases