LY6E: a conductor of malignant tumor growth through modulation of the PTEN/PI3K/Akt/HIF-1 axis.

// Chan Joo Yeom 1, 2 , Lihua Zeng 1, 2, 3 , Yoko Goto 1, 2 , Akiyo Morinibu 1, 2 , Yuxi Zhu 1, 2, 4 , Kazumi Shinomiya 1, 2 , Minoru Kobayashi 1, 2 , Satoshi Itasaka 1 , Michio Yoshimura 1 , Cheol-Goo Hur 5 , Hideaki Kakeya 6 , Ester M. Hammond 7 , Masahiro Hiraoka 1 , Hiroshi Harada 1, 2, 8, 9, 10 1 Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan 2 Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan 3 Department of Radiation Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, China 4 Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Yuanjiagang, Yuzhong District, Chongqing 400016, China 5 Cancer Genomics Branch, Division of Convergence Technology, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Korea 6 Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan 7 CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom 8 Hakubi Center, Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto 606-8501, Japan 9 Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan 10 Laboratory of Cancer Cell Biology, Radiation Biology Center, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan Correspondence to: Hiroshi Harada, email: harada.hiroshi.5e@kyoto-u.ac.jp , hharada@kuhp.kyoto-u.ac.jp Keywords: tumor hypoxia, hypoxia-inducible factor 1 (HIF-1), lymphocyte antigen 6 complex, locus E (LY6E), PTEN/PI3K/Akt/HIF-1 axis Received: August 31, 2015     Accepted: August 21, 2016     Published: August 29, 2016 ABSTRACT Lymphocyte antigen 6 complex, locus E (LY6E) has been implicated in the malignant progression of various types of cancers; however, the underlying mechanism remains unclear. Here, we identified LY6E as an activator of HIF-1 and revealed their mechanistic and functional links in malignant tumor growth. The aberrant overexpression of LY6E increased HIF-1α gene expression principally at the transcription level. This, in turn, led to the expression of the pro-angiogenic factors, VEGFA and PDGFB , through decreases in the expression levels of PTEN mRNA and subsequent activation of the PI3K/Akt pathway. The LY6E-HIF-1 axis functioned to increase tumor blood vessel density and promoted tumor growth in immunodeficient mice. LY6E expression levels were significantly higher in human breast cancers than in normal breast tissues, and were strongly associated with the poor prognoses of various cancer patients. Our results characterized LY6E as a novel conductor of tumor growth through its modulation of the PTEN/PI3K/Akt/HIF-1 axis and demonstrated the validity of targeting this pathway for cancer therapy.