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Cellular prion protein transcriptionally regulated by NFIL3 enhances lung cancer cell lamellipodium formation and migration through JNK signaling

Oncogene volume 39, pages 385–398 (2020)Cite this article

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Abstract

Tumor invasion and metastasis are the major causes of treatment failure and mortality in lung cancer patients. In this study, we identified a group of genes with differential expression in in situ and invasive lung adenocarcinoma tissues by expression profiling; among these genes we further characterized the association of the upregulation of PRNP, the gene encoding cellular Prion protein (PrPc), with lung adenocarcinoma invasiveness. Immunohistochemistry on clinical specimens showed an association of PrPc expression with invasive but not in situ lung adenocarcinoma. Consistently, the expression of PrPc was higher in the highly invasive than in the lowly invasive lung adenocarcinoma cell lines. Knockdown of PrPc expression in cultured lung adenocarcinoma cells decreased their lamellipodium formation, in vitro migration and invasion, and in vivo experimental lung metastasis. Phosphorylation of JNKs was found to correlate with PrPc expression and the inhibition of JNKs suppressed the PrPc-induced up-regulation of lamellipodium formation, cell migration, and invasion. Moreover, we identified the nuclear factor, interleukin 3 regulated (NFIL3) protein as a transcriptional activator of the PRNP promoter. Accordingly, NFIL3 promoted lung cancer cell migration and invasion in a PrPc-dependent manner. High NFIL3 expression in clinical specimens of lung adenocarcinoma was also associated with tumor invasiveness. Overall, our observations suggest that the NFIL3/PrPc axis, through regulating lamellipodium formation and cell mobility via JNK signaling, plays a critical role in lung cancer invasiveness and metastasis.

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Acknowledgements

The authors thank Dr. Pan-Chyr Yang for providing lung adenocarcinoma cell lines CL1-5F4, CL1-1 and CL1-5, Dr. Sin-Lian Doong for providing expressing vector pSuper-Hygromycin B and Dr. Ann-Ping Tsou for providing luciferase reporter plasmids.

Funding:

This work was supported by grant 102-2320-B-010-005-MY3 from the Ministry of Science and Technology and grants VGH94-286, V98C1-102, V99C1-187, V100C-082 and V101C-009 from Taipei Veterans General Hospital, Taiwan.

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  1. These authors contributed equally: Shin-Chih Lin, Chia-Hung Lin

Authors and Affiliations

  1. Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, 11221, Taiwan

    Shin-Chih Lin, Mei-Yu Chen & Teh-Ying Chou

  2. Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, 11221, Taiwan

    Shin-Chih Lin, Hsin-Ling Liu, Kun-Yang Lin, Mei-Yu Chen & Teh-Ying Chou

  3. Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, 11221, Taiwan

    Chia-Hung Lin, Yi-Cheng Lin, Yi-Chen Yeh & Teh-Ying Chou

  4. Institute of Clinical Medicine, National Yang-Ming University, Taipei, 11221, Taiwan

    Nien-Chu Shih, Wen-Chao Wang, Zih-Yu Liu, Yu-Jhen Tseng, Hsueh-Kai Chang & Teh-Ying Chou

  5. Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan

    Hiroshi Minato

  6. Department of Pathology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Takeshi Fujii

  7. Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, 11221, Taiwan

    Yu-Chung Wu

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Lin, SC., Lin, CH., Shih, NC. et al. Cellular prion protein transcriptionally regulated by NFIL3 enhances lung cancer cell lamellipodium formation and migration through JNK signaling. Oncogene 39, 385–398 (2020). https://doi.org/10.1038/s41388-019-0994-0

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