Stress Chaperone Mortalin Contributes to Epithelial-to-Mesenchymal Transition and Cancer Metastasis

  • Youjin Na
    1Drug Discovery & Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan.
  • Sunil C. Kaul
    1Drug Discovery & Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan.
  • Jihoon Ryu
    1Drug Discovery & Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan.
  • Jung-Sun Lee
    2Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea.
  • Hyo Min Ahn
    1Drug Discovery & Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan.
  • Zeenia Kaul
    3Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio.
  • Rajkumar S. Kalra
    1Drug Discovery & Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan.
  • Ling Li
    1Drug Discovery & Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan.
  • Nashi Widodo
    4Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Malang, Indonesia.
  • Chae-Ok Yun
    2Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea.
  • Renu Wadhwa
    1Drug Discovery & Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan.

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<jats:title>Abstract</jats:title> <jats:p>Mortalin/mthsp70 (HSPA9) is a stress chaperone enriched in many cancers that has been implicated in carcinogenesis by promoting cell proliferation and survival. In this study, we examined the clinical relevance of mortalin upregulation in carcinogenesis. Consistent with high mortalin expression in various human tumors and cell lines, we found that mortalin overexpression increased the migration and invasiveness of breast cancer cells. Expression analyses revealed that proteins involved in focal adhesion, PI3K–Akt, and JAK–STAT signaling, all known to play key roles in cell migration and epithelial-to-mesenchymal transition (EMT), were upregulated in mortalin-expressing cancer cells. We further determined that expression levels of the mesenchymal markers vimentin (VIM), fibronectin (FN1), β-catenin (CTNNB1), CK14 (KRT14), and hnRNP-K were also increased upon mortalin overexpression, whereas the epithelial markers E-cadherin (CDH1), CK8 (KRT8), and CK18 (KRT18) were downregulated. Furthermore, shRNA-mediated and pharmacologic inhibition of mortalin suppressed the migration and invasive capacity of cancer cells and was associated with a diminished EMT gene signature. Taken together, these findings support a role for mortalin in the induction of EMT, prompting further investigation of its therapeutic value in metastatic disease models. Cancer Res; 76(9); 2754–65. ©2016 AACR.</jats:p>

収録刊行物

  • Cancer Research

    Cancer Research 76 (9), 2754-2765, 2016-05-01

    American Association for Cancer Research (AACR)

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