Podocalyxin influences malignant potential by controlling epithelial–mesenchymal transition in lung adenocarcinoma

  • Hidenori Kusumoto
    Department of General Thoracic Surgery Osaka University Graduate School of Medicine Osaka Japan
  • Yasushi Shintani
    Department of General Thoracic Surgery Osaka University Graduate School of Medicine Osaka Japan
  • Ryu Kanzaki
    Department of General Thoracic Surgery Osaka University Graduate School of Medicine Osaka Japan
  • Tomohiro Kawamura
    Department of General Thoracic Surgery Osaka University Graduate School of Medicine Osaka Japan
  • Soichiro Funaki
    Department of General Thoracic Surgery Osaka University Graduate School of Medicine Osaka Japan
  • Masato Minami
    Department of General Thoracic Surgery Osaka University Graduate School of Medicine Osaka Japan
  • Izumi Nagatomo
    Department of Respiratory Medicine, Allergy and Rheumatic Disease Osaka University Graduate School of Medicine Osaka Japan
  • Eiichi Morii
    Department of Pathology Osaka University Graduate School of Medicine Osaka Japan
  • Meinoshin Okumura
    Department of General Thoracic Surgery Osaka University Graduate School of Medicine Osaka Japan

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説明

<jats:p>Epithelial–mesenchymal transition (<jats:styled-content style="fixed-case">EMT</jats:styled-content>) plays an important role in the progression of lung carcinoma. Podocalyxin (<jats:styled-content style="fixed-case">PODXL</jats:styled-content>), which belongs to the <jats:styled-content style="fixed-case">CD</jats:styled-content>34 family and regulates cell morphology, has been linked to <jats:styled-content style="fixed-case">EMT</jats:styled-content> in lung cancer, and <jats:styled-content style="fixed-case">PODXL</jats:styled-content> overexpression is associated with poor prognosis in several different classes of cancers. The aim of this study was to clarify the role of <jats:styled-content style="fixed-case">PODXL</jats:styled-content> overexpression in <jats:styled-content style="fixed-case">EMT</jats:styled-content> in lung cancer, and to determine the prognostic value of <jats:styled-content style="fixed-case">PODXL</jats:styled-content> overexpression in tumors from lung cancer patients. The morphology, <jats:styled-content style="fixed-case">EMT</jats:styled-content> marker expression, and migration and invasion abilities of engineered A549 <jats:styled-content style="fixed-case">PODXL</jats:styled-content>‐knockdown (<jats:styled-content style="fixed-case">KD</jats:styled-content>) or <jats:styled-content style="fixed-case">PODXL</jats:styled-content>‐overexpression (<jats:styled-content style="fixed-case">OE</jats:styled-content>) lung adenocarcinoma cells were examined. <jats:styled-content style="fixed-case">PODXL</jats:styled-content> expression levels were assessed by immunohistochemistry in 114 human clinical lung adenocarcinoma specimens and correlated with clinical outcomes. <jats:styled-content style="fixed-case">PODXL</jats:styled-content>‐<jats:styled-content style="fixed-case">KD</jats:styled-content> cells were epithelial in shape, whereas <jats:styled-content style="fixed-case">PODXL</jats:styled-content>‐<jats:styled-content style="fixed-case">OE</jats:styled-content> cells displayed mesenchymal morphology. Epithelial markers were upregulated in <jats:styled-content style="fixed-case">PODXL</jats:styled-content>‐<jats:styled-content style="fixed-case">KD</jats:styled-content> cells and downregulated in <jats:styled-content style="fixed-case">PODXL</jats:styled-content>‐<jats:styled-content style="fixed-case">OE</jats:styled-content> cells, whereas mesenchymal markers were downregulated in the former and upregulated in the latter. A highly selective inhibitor of phosphatidylinositol 3‐kinase‐Akt signaling attenuated <jats:styled-content style="fixed-case">EMT</jats:styled-content> of <jats:styled-content style="fixed-case">PODXL</jats:styled-content>‐<jats:styled-content style="fixed-case">OE</jats:styled-content> cells, while a transforming growth factor inhibitor did not, suggesting that <jats:styled-content style="fixed-case">PODXL</jats:styled-content> induces <jats:styled-content style="fixed-case">EMT</jats:styled-content> of lung adenocarcinoma cells via the phosphatidylinositol 3‐kinase pathway. In lung adenocarcinoma clinical specimens, <jats:styled-content style="fixed-case">PODXL</jats:styled-content> expression was detected in minimally invasive and invasive adenocarcinoma, but not in non‐invasive adenocarcinoma. Disease free survival and cancer‐specific survival were significantly worse for patients whose tumors overexpressed <jats:styled-content style="fixed-case">PODXL</jats:styled-content>. <jats:styled-content style="fixed-case">PODXL</jats:styled-content> overexpression induces <jats:styled-content style="fixed-case">EMT</jats:styled-content> in lung adenocarcinoma and contributes to tumor progression.</jats:p>

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