BNIP3 Expression Is Linked with Hypoxia-Regulated Protein Expression and with Poor Prognosis in Non–Small Cell Lung Cancer

Abstract

BNIP3 is a proapoptotic protein regulated by hypoxiainducible factor 1. We analyzed BNIP3 expression in 105 tumor samples from early operable, non-small lung cancer and the relationship of expression to hypoxia-inducible factor 1␣, other hypoxia-regulated pathways, and prognosis. There was strong cytoplasmic expression in >10% of cells in 40 of 105 cases. BNIP3 expression was associated significantly with high hypoxia-inducible factor 1␣ (P ‫؍‬ 0.003), carbonic anhydrase 9 (P ‫؍‬ 0.04), and was inversely associated with bcl-2 expression (P ‫؍‬ 0.009). High BNIP3 expression was a major independent factor for overall survival. Thus, high expression of a hypoxia regulated proapoptotic pathway was associated with a selection of an aggressive phenotype in vivo.

Selective silencing of the hypoxia-inducible factor 1 target gene BNIP3 by histone deacetylation and methylation in colorectal cancer

“…In 10 of the matched pairs, BNIP3 was higher in the tumour sample than in the normal (Figure 2a and b) as shown in other tumour types (Sowter et al, 2003;Giatromanolaki et al, 2004). However, in 54 cases, BNIP3 expression was reduced in the tumour samples relative to the normal, indicating that there had been a loss of BNIP3 expression during cancer development (Figure 2c and d).…”

“…Other mechanisms to by-pass the effects of BNIP3 have been shown, for example, growth factor signalling can protect against BNIP3-mediated cell death in breast cancer cell lines (Kothari et al, 2003). There is also evidence that nuclear sequestration may act as a mechanism of BNIP3 silencing in non-small-cell lung cancer (Giatromanolaki et al, 2004). Taken together, the data presented here along with recent studies support a model whereby hypoxic upregulation of BNIP3 in tumour development can cause significant hypoxia-induced cell death, but that this negative function provides pressure for the selection of cells that evade this phenotype.…”

“…Indeed, clinical studies have shown that BNIP3 expression is predictive of poor outcome and aggressive tumour growth (Giatromanolaki et al, 2004). With relation to the paradox of HIF signalling, it may thus be envisaged that under hypoxia, upregulation of HIF results in the expression of genes that positively contribute to tumour growth and also those whose negative function exerts selection pressure to drive the cancer towards a more aggressive phenotype.…”

“…BNIP3 mRNA and protein have been demonstrated to accumulate in response to hypoxia in a wide range of cell lines (Bruick, 2000;Sowter et al, 2001). Upregulation of BNIP3 is also detected in human breast and lung tumours, where BNIP3 mRNA or protein is expressed at higher levels compared to normal tissue (Sowter et al, 2001;Giatromanolaki et al, 2004). That BNIP3 functions as an effector of cell death has been demonstrated by overexpression of the protein in a number of cell types, including mouse embryonic fibroblasts and cardiac myocytes (Chen et al, 1997;Vande Velde et al, 2000;Kubasiak et al, 2002).…”

Hypoxia and cancer

“…These markers were shown to correlate for both primary breast tumours and lymph node metastases [53], and further studies have demonstrated reduced survival correlated with CA IX expression in breast cancer [54]. In breast cancer, high BNIP3 expression was associated with good survival outcome in invasive carcinoma but with an increased risk of recurrence and shorter disease-free survival in ductal carcinoma in situ [55], while in non-small lung cancer, high expression was an independent factor for overall survival [56]. Further investigation is required to obtain a better appreciation of the value of HIF or HIF-related marker immunohistochemistry for prognosis.…”