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miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC

Author

Listed:
  • Young-Jun Jeon

    (The Ohio State University
    Stanford University School of Medicine)

  • Taewan Kim

    (The Ohio State University)

  • Dongju Park

    (The Ohio State University)

  • Gerard J. Nuovo

    (The Ohio State University)

  • Siyeon Rhee

    (Stanford University)

  • Pooja Joshi

    (The Ohio State University)

  • Bum-Kyu Lee

    (The University of Texas at Austin)

  • Johan Jeong

    (Stanford University)

  • Sung-suk Suh

    (Mokpo National University)

  • Jeff E. Grotzke

    (Yale University School of Medicine)

  • Sung-Hak Kim

    (Chonnam National University
    Korea Basic Science Institute)

  • Jieun Song

    (The Ohio State University)

  • Hosung Sim

    (The Ohio State University)

  • Yonghwan Kim

    (Sookmyung Woman’s University)

  • Yong Peng

    (The Ohio State University
    Sichuan University, and Collaborative Innovation Center for Biotherapy)

  • Youngtae Jeong

    (Stanford University School of Medicine)

  • Michela Garofalo

    (The Ohio State University
    University of Manchester)

  • Nicola Zanesi

    (The Ohio State University)

  • Jonghwan Kim

    (The University of Texas at Austin)

  • Guang Liang

    (Wenzhou Medical University, Wenzhou)

  • Ichiro Nakano

    (University of Alabama at Birmingham)

  • Peter Cresswell

    (Yale University School of Medicine)

  • Patrick Nana-Sinkam

    (The Ohio State University)

  • Ri Cui

    (The Ohio State University
    Wenzhou Medical University, Wenzhou)

  • Carlo M. Croce

    (The Ohio State University
    The Ohio State University)

Abstract

Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.

Suggested Citation

  • Young-Jun Jeon & Taewan Kim & Dongju Park & Gerard J. Nuovo & Siyeon Rhee & Pooja Joshi & Bum-Kyu Lee & Johan Jeong & Sung-suk Suh & Jeff E. Grotzke & Sung-Hak Kim & Jieun Song & Hosung Sim & Yonghwan, 2018. "miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07561-8
    DOI: 10.1038/s41467-018-07561-8
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