title: LY6E: a conductor of malignant tumor growth through modulation of the PTEN/PI3K/Akt/HIF-1 axis.
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.
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.|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.
authors: Chan Joo
authors: CJ
authors: Yeom
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.|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.|Department of Radiation Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors: Lihua
authors: L
authors: Zeng
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.|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.
authors: Yoko
authors: Y
authors: Goto
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.|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.
authors: Akiyo
authors: A
authors: Morinibu
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.|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.|Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Yuanjiagang, Yuzhong District, Chongqing 400016, China.
authors: Yuxi
authors: Y
authors: Zhu
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.|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.
authors: Kazumi
authors: K
authors: Shinomiya
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.|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.
authors: Minoru
authors: M
authors: Kobayashi
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Satoshi
authors: S
authors: Itasaka
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Michio
authors: M
authors: Yoshimura
authors: Cancer Genomics Branch, Division of Convergence Technology, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Korea.
authors: Cheol-Goo
authors: CG
authors: Hur
authors: Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Hideaki
authors: H
authors: Kakeya
authors: CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors: Ester M
authors: EM
authors: Hammond
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Masahiro
authors: M
authors: Hiraoka
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.|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.|Hakubi Center, Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto 606-8501, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.|Laboratory of Cancer Cell Biology, Radiation Biology Center, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Hiroshi
authors: H
authors: Harada
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000954:Antigens, Surface; D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C439870:LY6E protein, human; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PTEN/PI3K/Akt/HIF-1 axis; hypoxia-inducible factor 1 (HIF-1); locus E (LY6E); lymphocyte antigen 6 complex; tumor hypoxia