title: Elevated HOXA1 expression correlates with accelerated tumor cell proliferation and poor prognosis in gastric cancer partly via cyclin D1.
abstract: BACKGROUND
  HOXA1 is a member of the Homeobox gene family, which encodes a group of highly conserved transcription factors that are important in embryonic development. However, it has been reported that HOXA1 exhibits oncogenic properties in many malignancies. This study focused on the expression and clinical significance of HOXA1 in gastric cancer (GC).
  
  
  METHODS
  To assess the mRNA and protein expression of HOXA1 and cyclin D1 in GC tissues, we utilized qRT-PCR and western blotting, respectively. The effects of HOXA1 on GC cell proliferation, migration, and invasion, as well as xenograft tumor formation and the cell cycle were investigated in our established stable HOXA1 knockdown GC cell lines. The protein expression of HOXA1 and cyclin D1 was examined by immunohistochemistry using GC tissue microarrays (TMA) to analyze their relationship on a histological level. The Kaplan-Meier method and cox proportional hazards model were used to analyze the relationship of HOXA1 and cyclin D1 expression with GC clinical outcomes.
  
  
  RESULTS
  HOXA1 mRNA and protein expression were upregulated in GC tissues. Knockdown of HOXA1 in GC cells not only inhibited cell proliferation, migration, and invasion in vitro but also suppressed xenograft tumor formation in vivo. Moreover, HOXA1 knockdown induced changes in the cell cycle, and HOXA1 knockdown cells were arrested at the G1 phase, the number of cells in S phase was reduced, and the expression of cyclin D1 was decreased. In GC tissues, high cyclin D1 mRNA and protein expression were detected, and a significant correlation was found between the expression of HOXA1 and cyclin D1. Survival analysis indicated that HOXA1 and cyclin D1 expression were significantly associated with disease-free survival (DFS) and overall survival (OS). Interestingly, patients with tumors that were positive for HOXA1 and cyclin D1 expression showed worse prognosis. Multivariate analysis confirmed that the combination of HOXA1 and cyclin D1 was an independent prognostic indicator for OS and DFS.
  
  
  CONCLUSIONS
  Our data show that HOXA1 plays a crucial role in GC development and clinical prognosis. HOXA1, alone or combination with cyclin D1, may serve as a novel prognostic biomarker for GC.
authors.affiliation: Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, P. R. China. chenwei_yuan@126.com.
authors.forename: Chenwei
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, P. R. China. zhuxingwu2015@126.com.
authors.forename: Xingwu
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, P. R. China. hyhanyang85@126.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, P. R. China. songchenlong1992@sina.com.
authors.forename: Chenlong
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, P. R. China. lccliu_chenchen@sina.com.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pathology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, P. R. China. lu_su1987@sina.com.
authors.forename: Su
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Pathology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, P. R. China. meng_zhang1988@sina.com.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, P. R. China. fudong_yu@sina.com.
authors.forename: Fudong
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, P. R. China. peng_zhihai@tom.com.
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, P. R. China. chongzhi_zhou@163.com.|Department of General Surgery, Kashgar Prefecture Second People's Hospital, Kashgar, Xinjiang Uyghur Autonomous Region, 844000, P. R. China. chongzhi_zhou@163.com.
authors.forename: Chongzhi
authors.initials: C
authors.lastname: Zhou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011379:Prognosis; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000099261:Homeobox A1 Protein
chemical_list: D019938:Cyclin D1; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C530104:CCND1 protein, human