Expression of the Stress Response Oncoprotein LEDGF/p75 in Human Cancer: A Study of 21 Tumor Types

Anamika Basu,Hiya Banerjee,Kayla Y Perez,Heather Rojas,Irena B Cabrera,Carlos A Casiano,Marino De León,John R Battista

doi:10.1371/journal.pone.0030132

Anamika Basu, Hiya Banerjee + Show 6 more

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https://doi.org/10.1371/journal.pone.0030132

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Abstract

Oxidative stress-modulated signaling pathways have been implicated in carcinogenesis and therapy resistance. The lens epithelium derived growth factor p75 (LEDGF/p75) is a transcription co-activator that promotes resistance to stress-induced cell death. This protein has been implicated in inflammatory and autoimmune conditions, HIV-AIDS, and cancer. Although LEDGF/p75 is emerging as a stress survival oncoprotein, there is scarce information on its expression in human tumors. The present study was performed to evaluate its expression in a comprehensive panel of human cancers. Transcript expression was examined in the Oncomine cancer gene microarray database and in a TissueScan Cancer Survey Panel quantitative polymerase chain reaction (Q-PCR) array. Protein expression was assessed by immunohistochemistry (IHC) in cancer tissue microarrays (TMAs) containing 1735 tissues representing single or replicate cores from 1220 individual cases (985 tumor and 235 normal tissues). A total of 21 major cancer types were analyzed. Analysis of LEDGF/p75 transcript expression in Oncomine datasets revealed significant upregulation (tumor vs. normal) in 15 out of 17 tumor types. The TissueScan Cancer Q-PCR array revealed significantly elevated LEDGF/p75 transcript expression in prostate, colon, thyroid, and breast cancers. IHC analysis of TMAs revealed significant increased levels of LEDGF/p75 protein in prostate, colon, thyroid, liver and uterine tumors, relative to corresponding normal tissues. Elevated transcript or protein expression of LEDGF/p75 was observed in several tumor types. These results further establish LEDGF/p75 as a cancer-related protein, and provide a rationale for ongoing studies aimed at understanding the clinical significance of its expression in specific human cancers.

Highlights

A growing body of evidence supports the central hypothesis that an augmented state of cellular oxidative stress (ASCOS) is a major contributing factor to carcinogenesis [1,2]
In silico analysis of LEDGF/PSIP1 mRNA expression in cancer tissues was carried out using cancer gene microarray datasets from the Oncomine database that compared cancer tissues to normal tissues
Our results indicated significant upregulation of both LEDGF/p75 transcript and protein in prostate, colon, and thyroid tumors, inferred by the analysis of transcript expression in the Oncomine cancer gene microarray database and the TissueScan Cancer QPCR array, and analysis of protein expression by IHC in tissue microarrays (TMAs)

Summary

Introduction

A growing body of evidence supports the central hypothesis that an augmented state of cellular oxidative stress (ASCOS) is a major contributing factor to carcinogenesis [1,2]. ASCOS causes damage to DNA, protein, and lipids, as well as activation of stress transcription factors, leading to the activation of stress, antioxidant, inflammatory, and pro-survival pathways that contribute to malignant transformation, cell cycle deregulation, resistance to cell death and therapy, invasion, angiogenesis, and metastasis [1,2]. LEDGF/p75 is known as transcription coactivator p75 [8], PC4 and SFRS1 interacting protein (PSIP1) [9], and dense fine speckled autoantigen of 70 kD (DFS70) [10]. It has been implicated in inflammation, autoimmunity, HIV-1 replication, and cancer [10,11,12,13,14,15,16,17]. Our group reported previously that LEDGF/p75 is upregulated in cancer cells compared to normal cells, and that LEDGF/p52 is expressed at relatively low levels in cancer cells, induces apoptosis when ectopically expressed, and antagonizes the pro-survival functions of LEDGF/p75 [7,16,25]

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