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BNIP3 expression in endometrial cancer relates to active hypoxia inducible factor 1α pathway and prognosis
  1. A Giatromanolaki1,
  2. M I Koukourakis1,
  3. K C Gatter2,
  4. A L Harris3,
  5. E Sivridis1
  1. 1
    Departments of Pathology, and Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece
  2. 2
    Department of Pathology, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DS, UK
  3. 3
    Cancer Research UK, Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 7LJ, UK
  1. Alexandra Giatromanolaki, MD, Department of Pathology, Democritus University of Thrace, PO Box 12, Alexandroupolis 68100, Greece; targ{at}her.forthnet.gr

Abstract

Aims: BNIP3 is a pro-apoptotic mitochondrial protein induced under hypoxic stress, with the BNIP3 gene being under direct regulation of the hypoxia-inducible HIF-1α transcription factor. Induction of BNIP3 leads to caspase-independent necrosis-like cell death and an aggressive tumour phenotype. The role of BNIP3 in endometrial cancer was examined.

Methods: The immunohistochemical patterns of BNIP3 expression in 72 early endometrial adenocarcinomas of the endometrioid cell type were studied. Correlation of BNIP3 with the hypoxia-inducible factor HIF-1α pathway and with prognosis was also examined.

Results: BNIP3 was strongly and extensively expressed in the cytoplasm of cancer cells in 23/72 (31.9%) cases. This high BNIP3 reactivity was not related to histological grade, depth of myometrial invasion or steroid hormone receptor expression. There was, however, a significant association of BNIP3 reactivity with HIF-1α (p = 0.04), VEGF (p = 0.04) and, particularly, LDH-5 expression (p = 0.0001). Furthermore, high BNIP3 was associated with poor survival in both univariate (p = 0.05) and multivariate (p = 0.03) models.

Conclusion: BNIP3 seems to be an important hypoxia-regulated molecule involved in endometrial cancer pathology. Given that high BNIP3 reactivity, being linked with poor post-operative outcome, has been linked with a favourable response to cytotoxic therapy (as previously indicated in experimental studies), high BNIP3 expression may be an indicator for adjuvant chemoradiotherapy in stage I endometrial carcinomas.

  • endometrial cancer
  • BNIP3
  • HIF1α
  • LDH-5
  • prognosis

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Footnotes

  • Funding: The study was financially supported by the Tumour and Angiogenesis Research Group, and Cancer Research UK.

  • Competing interests: None.

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