Hypoxia induced high expression of thioredoxin interacting protein (TXNIP) in non-small cell lung cancer and its prognostic effect.

Yan Li,Min Yu,Yong-Long Xiao,Li-Yun Miao,Kui Meng,Hou-Rong Cai,Mei Huang

doi:10.7314/apjcp.2015.16.7.2953

Abstract

Although associations between thioredoxin interacting protein (TXNIP) and cancers have been recognized, the effects of TXNIP on non-small cell lung cancer (NSCLC) prognosis remained to be determined in detail. In addition, while hypoxia is a key characteristic of tumor cell growth microenvironment, the effect of hypoxia on TXNIP expression is controversial. In this study, formaldehyde fixed and paraffin embedded (FFPE) samples of 70 NSCLC patients who underwent resection between January 2010 and December 2011 were obtained. Evaluation of TXNIP and hypoxia inducible factor-1α (HIF-1α) protein expression in FFPE samples was made by immunohistochemistry. By Kaplan-Meier method, patients with high TXNIP expression demonstrated a significantly shorter progression free survival (PFS) compared with those with low TXNIP expression (18.0 months, 95%CI: 11.7, 24.3 versus 23.0 months, 95%CI: 17.6, 28.4, P=0.02). High TXNIP expression level was also identified as an independent prognostic factor by Cox regression analysis (adjusted hazard ratio: 2.46; 95%CI: 1.08, 5.56; P=0.03). Furthermore, TXNIP expression was found to be significantly correlated with HIF- 1α expression (Spearman correlation=0.67, P=0.000). To further confirm correlations, we established a tumor cell hypoxic culture model. Expression of TXNIP was up-regulated in all three NSCLC cell lines (A549, SPC-A1, and H1299) under hypoxic conditions. This study suggests that hypoxia induces increased TXNIP expression in NSCLC and high TXNIP expression could be a poor prognostic marker.

Highlights

Thioredoxin interacting protein (TXNIP), known as vitamin D3 upregulated protein (VDUP-1) or thioredoxin binding protein-2 (TBP-2), was originally reported as a gene of unknown function in HL-60 cells induced by 1α, 25-dihydroxyvitamin D3 (Chen and DeLuca, 1994)
Invasion, energy metabolism and incompletion of the local blood vessels lead to a hypoxic state in local tissue
thioredoxin interacting protein (TXNIP) expression was up-regulated in non-small cell lung cancer (NSCLC) cell lines under hypoxic condition

Summary

Introduction

Thioredoxin interacting protein (TXNIP), known as vitamin D3 upregulated protein (VDUP-1) or thioredoxin binding protein-2 (TBP-2), was originally reported as a gene of unknown function in HL-60 cells induced by 1α, 25-dihydroxyvitamin D3 (Chen and DeLuca, 1994). The human TXNIP gene is located on chromosome 1q21.1, contains 8 exons and is 4174 bp in length. TXNIP plays an important role in a wide variety of biological functions, such as the regulation of cell death, growth, differentiation, and energy metabolism (Aitken et al, 2004; Lee et al, 2005; Ahsan et al, 2006; Corbett, 2008; Oka et al, 2009). TXNIP is an important gene that is known to be transcriptionally regulated in response to hypoxia (Wong and Hagen, 2013). The effect of hypoxia on TXNIP expression in Non-small cell lung cancer (NSCLC) remained undefined

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