title: Huntingtin-Interacting Protein-1 Is an Early-Stage Prognostic Biomarker of Lung Adenocarcinoma and Suppresses Metastasis via Akt-mediated Epithelial-Mesenchymal Transition.
abstract: BACKGROUND
  Non-small cell lung cancer (NSCLC) carries a poor survival rate mainly because of metastasis. However, the molecular mechanisms that govern NSCLC metastasis have not been described. Because huntingtin-interacting protein-1 (HIP1) is known to play a role in tumorigenesis, we tested the involvement of HIP1 in NSCLC progression and metastasis.
  
  
  OBJECTIVE
  HIP1 expression was measured in human NSCLC tumors, and correlation with survival outcome was evaluated. Furthermore, we investigated the ability of HIP1 to suppress metastasis. The molecular mechanism by which HIP1 contributes to suppress metastasis was investigated.
  
  
  METHODS
  We used tissue arrays containing samples from 121 patients with NSCLC to analyze HIP1 expression by immunohistochemistry. To investigate the role of HIP1 expression on metastasis, we evaluated cellular mobility, migration, and invasion using lung adenocarcinoma (AdCA) cells with modified HIP1 expression levels. The human disease mouse models with the same cells were applied to evaluate the HIP1 suppressing metastasis and its mechanism in vivo.
  
  
  RESULTS
  HIP1 expression in AdCA progression was found to be an early-stage prognostic biomarker, with low expression correlated to poor prognosis. We also found HIP1 to be a metastatic suppressor in AdCA. HIP1 significantly repressed the mobility of lung cancer cells in vitro and in vivo and regulated the epithelial-mesenchymal transition by repressing AKT/glycogen synthase kinase-3β/β-catenin signaling.
  
  
  CONCLUSIONS
  HIP1 serves as an early-stage prognostic biomarker and a metastatic suppressor. Reduced expression during AdCA progression can relieve HIP1 suppression of Akt-mediated epithelial-mesenchymal transition and thereby lead to development of late metastases and poor prognosis.
authors.affiliation: 1 Institute of Basic Medical Sciences, College of Medicine.
authors.forename: Che-Yu
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: 2 Institute of Clinical Medicine, College of Medicine, and.|3 Genomics Research Center, Academia Sinica, Taipei, Taiwan; and.
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lin
authors.affiliation: 3 Genomics Research Center, Academia Sinica, Taipei, Taiwan; and.
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Jan
authors.affiliation: 3 Genomics Research Center, Academia Sinica, Taipei, Taiwan; and.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Su
authors.affiliation: 4 Clinical Medicine Research Center, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yun-Chin
authors.initials: YC
authors.lastname: Yao
authors.affiliation: 2 Institute of Clinical Medicine, College of Medicine, and.
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Cheng
authors.affiliation: 1 Institute of Basic Medical Sciences, College of Medicine.
authors.forename: Tai-I
authors.initials: TI
authors.lastname: Hsu
authors.affiliation: 2 Institute of Clinical Medicine, College of Medicine, and.
authors.forename: Po-Shun
authors.initials: PS
authors.lastname: Wang
authors.affiliation: 2 Institute of Clinical Medicine, College of Medicine, and.
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Su
authors.affiliation: 5 Department of Internal Medicine, Kaohsiung Medical University Hospital and School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: 5 Department of Internal Medicine, Kaohsiung Medical University Hospital and School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Shyan
authors.initials: MS
authors.lastname: Huang
authors.affiliation: 2 Institute of Clinical Medicine, College of Medicine, and.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Calkins
authors.affiliation: 3 Genomics Research Center, Academia Sinica, Taipei, Taiwan; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: 1 Institute of Basic Medical Sciences, College of Medicine.|2 Institute of Clinical Medicine, College of Medicine, and.
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D016019:Survival Analysis; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C489537:HIP1R protein, human; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins
keywords: Huntingtin-interacting protein-1; adenocarcinoma; epithelial–mesenchymal transition; metastasis; prognosis