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CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE
    • Publication Information:
      Publication: <2002->: Basingstoke : Nature Publishing Group
      Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-
    • Subject Terms:
      Membrane Glycoproteins/*metabolism ; Receptors, G-Protein-Coupled/*metabolism ; Receptors, Lysophosphatidic Acid/*metabolism ; Thyroid Neoplasms/*metabolism; Animals ; Cell Differentiation ; Cell Line, Tumor ; Disease Models, Animal ; Disease Progression ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Ki-67 Antigen ; Lung Neoplasms/secondary ; Mice ; Mice, Transgenic ; Neoplasm Invasiveness ; Phosphorylation ; Proto-Oncogene Proteins c-akt ; Signal Transduction ; rhoA GTP-Binding Protein/genetics ; rhoA GTP-Binding Protein/metabolism
    • Abstract:
      CD97, a member of the adhesion family of G-protein-coupled receptors (GPCRs), complexes with and potentiates lysophosphatidic acid (LPA) receptor signaling to the downstream effector RHOA. We show here that CD97 was expressed in a majority of thyroid cancers but not normal thyroid epithelium and that the level of CD97 expression was further elevated with progression to poorly differentiated and undifferentiated carcinoma. Intratumoral progression also showed that CD97 expression correlates with invasiveness and dedifferentiation. To determine the functional role of CD97, we produced a transgenic model of thyroglobulin promoter-driven CD97 expression. Transgenic CD97 in combination with Thrb(PV), an established mouse model of thyroid follicular cell carcinogenesis, significantly increased the occurrence of vascular invasion and lung metastasis. Expression of transgenic CD97 in thyroid epithelium led to elevated ERK phosphorylation and increased numbers of Ki67+ cells in developing tumors. In addition, tumor cell cultures derived from CD97 transgenic as compared with non-transgenic mice demonstrated enhanced, constitutive and LPA-stimulated ERK activation. In human thyroid cancer cell lines, CD97 depletion reduced RHO-GTP and decreased LPA-stimulated invasion but not EGF-stimulated invasion, further suggesting that CD97 influences an LPA-associated mechanism of progression. Consistent with the above, CD97 expression in human thyroid cancers correlated with LPA receptor and markers of aggressiveness including Ki67 and pAKT. This study shows an autonomous effect of CD97 on thyroid cancer progression and supports the investigation of this GPCR as a therapeutic target for these cancers.
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    • Grant Information:
      ZIA BC010802 United States Intramural NIH HHS
    • Accession Number:
      0 (Adgre5 protein, mouse)
      0 (Ki-67 Antigen)
      0 (Membrane Glycoproteins)
      0 (Receptors, G-Protein-Coupled)
      0 (Receptors, Lysophosphatidic Acid)
      EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
      EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
      EC 3.6.5.2 (rhoA GTP-Binding Protein)
    • Publication Date:
      Date Created: 20120717 Date Completed: 20130729 Latest Revision: 20211021
    • Publication Date:
      20250114
    • Accession Number:
      PMC7561260
    • Accession Number:
      10.1038/onc.2012.301
    • Accession Number:
      22797060