BNIP3 expression in endometrial cancer relates to active hypoxia inducible factor 1alpha pathway and prognosis.
OBJECTIVE
BNIP3 is a pro-apoptotic mitochondrial protein induced under hypoxic stress, with the BNIP3 gene being under direct regulation of the hypoxia-inducible HIF-1alpha 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-1alpha 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-1alpha (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.


CONCLUSIONS
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.
Giatromanolaki
A
A
Department of Pathology, Democritus University of Thrace, Alexandroupolis 68100, Greece. targ@her.forthnet.gr
Koukourakis
M I
MI
Gatter
K C
KC
Harris
A L
AL
Sivridis
E
E
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis
C090121:BNIP3 protein, human; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins