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

Chan Joo Yeom,Yuxi Zhu,Ester M Hammond,Michio Yoshimura,Satoshi Itasaka,Hiroshi Harada,Hideaki Kakeya,Kazumi Shinomiya,Masahiro Hiraoka,Cheol-Goo Hur,Minoru Kobayashi,Lihua Zeng,Akiyo Morinibu,Yoko Goto

doi:10.18632/oncotarget.11670

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.

Highlights

Lymphocyte antigen 6 complex, locus E (LY6E), designated as stem cell antigen 2 (SCA2) and thymic shared antigen-1 (TSA-1), is a member of the lymphostromal cell membrane Ly6 superfamily [1,2,3]
We identified mouse lymphocyte antigen 6 complex, locus E (Ly6e) as a novel candidate activator of hypoxiainducible factor-1 (HIF-1)
Our in vitro studies revealed that the aberrant overexpression of LY6E upregulated the transcription of the HIF-1α gene by reducing PTEN expression at the mRNA level and subsequently activating the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway

Summary

Introduction

Lymphocyte antigen 6 complex, locus E (LY6E), designated as stem cell antigen 2 (SCA2) and thymic shared antigen-1 (TSA-1), is a member of the lymphostromal cell membrane Ly6 superfamily [1,2,3]. In the field of cancer biology associations with tumorigenicity [10,11,12], cancer stem cell properties [13], and cancer metastases [12, 14] have been described It currently remains unclear how LY6E promotes malignant phenotypes and accelerates tumor growth. The proline residues, P402 and P564, in the oxygen-dependent degradation (ODD) domain of HIF-1α are hydroxylated by prolyl-4hydroxylases (PHDs) [18, 19]. This hydroxylation triggers the ubiquitination of HIF-1α by a von Hippel-Lindau (VHL)-containing E3 ubiquitin ligase, leading to the rapid degradation of HIF-1α [18, 19]. Whereas the oxygen-dependent regulation of HIF-1 activity has been characterized, the upstream signaling pathways that stimulate HIF-1 activity have not yet been fully elucidated, which makes it difficult to develop strategies that efficiently inhibit HIF-1 activity

Methods

Results

Conclusion