title: SLC39A6: a potential target for diagnosis and therapy of esophageal carcinoma.
abstract: BACKGROUND
  Esophageal squamous cell carcinoma (ESCC) is a highly lethal cancer, and its underlying molecular mechanisms are poorly understood. Recent large-scale genome-wide association studies in Chinese Han populations have identified an ESCC susceptibility locus within the SLC39A6 gene. Here, we sought to explore the expression and biological function of SLC39A6 in ESCC.
  
  
  METHODS
  Multiethnic validation of SLC39A6 protein expression was performed in different cohorts of patients from Chinese Han and Kazakh populations in the Xinjiang region by immunohistochemistry. The associations among SLC39A6 expression, clinicopathological parameters, and prognosis outcomes of ESCC were analyzed. And the effects of SLC39A6 silencing by siRNA on cell proliferation, apoptosis, and invasiveness, as well as the proteins involved in epithelial-to-mesenchymal transition (EMT) of esophageal cancer cells, were studied.
  
  
  RESULTS
  SLC39A6 protein expression increased progressively from normal esophageal epithelium (NEE) to low-grade intraepithelial neoplasia to ESCC, and finally reached the highest in high-grade intraepithelial neoplasia from Han ethnic. Similarly, SLC39A6 protein was significantly overexpressed in Kazakh ethnic ESCC compared with that in NEE. Increased expression of SLC39A6 was found to be closely correlated with histological grade and early Tumor-Node-Metastasis stage I/II. High tumorous SLC39A6 expression was significantly correlated with shorter overall survival (OS). Cox regression analysis confirmed that SLC39A6 expression was an independent prognostic factor for poor OS in ESCC. Experimentally, the suppression of SLC39A6 expression promoted ESCC cell apoptosis but abrogated proliferation and invasion, and induced an EMT phenotype that included enhanced expression of E-cadherin, loss of vimentin, and morphological changes in ESCC cells in vitro.
  
  
  CONCLUSIONS
  Combined, our findings highlight a tumor-promoting role for SLC39A6 in ESCC, suggesting that SLC39A6 could serve as an early detector of high-risk subjects and prognostic biomarker. The targeting of SLC39A6 might be a potential therapeutic strategy for blocking ESCC.
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. cuixiaobin4363@foxmail.com.|Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, 430030, Wuhan, China. cuixiaobin4363@foxmail.com.
authors.forename: Xiao-Bin
authors.initials: XB
authors.lastname: Cui
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 491437260@qq.com.|Department of Pathology, People Hospital of Xinjiang Uygur Autonomous Region, Ürümqi, China. 491437260@qq.com.
authors.forename: Yao-Yuan
authors.initials: YY
authors.lastname: Shen
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 474621590@qq.com.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Jin
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 944873356@qq.com.
authors.forename: Su
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 824989630@qq.com.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Li
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 617936327@qq.com.
authors.forename: Shu-Mao
authors.initials: SM
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 334672404@qq.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 342682442@qq.com.
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Liu
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 251068648@qq.com.
authors.forename: Shu-Gang
authors.initials: SG
authors.lastname: Li
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. yl-branda@163.com.
authors.forename: Lan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Oncology, The First Affiliated Hospital, Shihezi University School of Medicine, 832002, Shihezi, China. 1500921245@qq.com.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 39189926@qq.com.|Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, 430030, Wuhan, China. 39189926@qq.com.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Hu
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 2106538234@qq.com.
authors.forename: Jin-Fang
authors.initials: JF
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 243083166@qq.com.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. 34742913@qq.com.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Liang
authors.affiliation: Department of CT and MRI, The First Affiliated Hospital, Shihezi University School of Medicine, 832002, Shihezi, China. 24363941@qq.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital, Shihezi University School of Medicine, 832002, Shihezi, China. 53447780@qq.com.
authors.forename: Yu-Tao
authors.initials: YT
authors.lastname: Wei
authors.affiliation: Department of Pathology, People Hospital of Xinjiang Uygur Autonomous Region, Ürümqi, China. sunzhenzhu@medmail.com.cn.
authors.forename: Zhen-Zhu
authors.initials: ZZ
authors.lastname: Sun
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. carywu@pitt.edu.|Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15261, USA. carywu@pitt.edu.
authors.forename: Chuan-Yue
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. cyz0515@sina.com.
authors.forename: Yun-Zhao
authors.initials: YZ
authors.lastname: Chen
authors.affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. lifeng7855@126.com.|Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, 430030, Wuhan, China. lifeng7855@126.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D002277:Carcinoma / Q000175:diagnosis / Q000208:ethnology / Q000378:metabolism / Q000628:therapy; D027682:Cation Transport Proteins / Q000235:genetics*; D049109:Cell Proliferation; D002681:China; D015331:Cohort Studies; D058750:Epithelial-Mesenchymal Transition; D004938:Esophageal Neoplasms / Q000175:diagnosis* / Q000208:ethnology / Q000628:therapy*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D034741:RNA, Small Interfering / Q000378:metabolism; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D027682:Cation Transport Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C418627:SLC39A6 protein, human