Combined over-expression of the hypoxia-inducible factor 2α gene and its long non-coding RNA predicts unfavorable prognosis of patients with osteosarcoma

Pathol Res Pract. 2016 Oct;212(10):861-866. doi: 10.1016/j.prp.2016.06.013. Epub 2016 Jun 27.

Abstract

Background: LncRNA hypoxia-inducible factor-2α (HIF-2α) promoter upstream transcript (HIF2PUT) functions as a novel regulatory factor of osteosarcoma stem cells partly by controlling HIF-2α expression. The aim of this study was to investigate the clinical significance of HIF-2α and HIF2PUT in human osteosarcoma.

Materials and methods: Quantitative real-time PCR was performed to detect the expression levels of HIF-2α mRNA and HIF2PUT in 82 surgical specimens of primary osteosarcoma and matched non-cancerous bone tissues. Then, the associations of HIF-2α and/or HIF2PUT expression with various clinicopathological features of osteosarcoma patients were statistically analyzed. Moreover, their prognostic value was further evaluated.

Results: Compared with non-cancerous bone tissues, HIF-2α mRNA and HIF2PUT expression were both significantly upregulated in osteosarcoma tissues (all P<0.001). Interestingly, the expression levels of HIF-2α mRNA in osteosarcoma tissues were positively correlated with those of HIF2PUT (r=0.28, P=0.009). Additionally, osteosarcoma patients with HIF-2α mRNA and/or HIF2PUT over-expression more frequently had large tumor size (all P<0.05), advanced clinical stage (all P<0.01) and positive distant metastasis (all P<0.01). Moreover, osteosarcoma patients with HIF-2α mRNA and/or HIF2PUT over-expression had a significantly shorter overall and disease-free survival (all P<0.05). Furthermore, Cox multivariate analysis identified that HIF-2α mRNA and/or HIF2PUT expression, clinical stage and distant metastasis were all independent and significant prognostic factors for both overall and disease-free survival (all P<0.05).

Conclusions: HIF-2α and HIF2PUT upregulation may be a common feature in human osteosarcomas with aggressive potency. The over-expression of the two molecules, alone or combined, may predict poor prognosis in osteosarcoma patients.

Keywords: Clinicopathologic features; Hypoxia-inducible factor 2α; Hypoxia-inducible factor-2α; Long non-coding RNA; Osteosarcoma; Prognosis; Promoter upstream transcript.

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / mortality
  • Bone Neoplasms / pathology
  • Disease-Free Survival
  • Female
  • Humans
  • Male
  • Middle Aged
  • Osteosarcoma / genetics*
  • Osteosarcoma / metabolism
  • Osteosarcoma / mortality
  • Osteosarcoma / pathology
  • Prognosis
  • Promoter Regions, Genetic*
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Survival Rate
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • RNA, Long Noncoding
  • endothelial PAS domain-containing protein 1