Oxidized LDL Receptor 1 (OLR1) as a Possible Link between Obesity, Dyslipidemia and Cancer

Magomed Khaidakov,Jawahar L Mehta,Weleetka C Carter,Vinay Raj,Susan Kadlubar,Giuseppe Novelli,Xianwei Wang,Sona Mitra,Maria Winters,Bum-Yong Kang,Carlo Gaetano

doi:10.1371/journal.pone.0020277

Magomed Khaidakov, Jawahar L Mehta + Show 9 more

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https://doi.org/10.1371/journal.pone.0020277

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Abstract

Recent studies have linked expression of lectin-like ox-LDL receptor 1 (OLR1) to tumorigenesis. We analyzed microarray data from Olr1 knockout (KO) and wild type (WT) mice for genes involved in cellular transformation and evaluated effects of OLR1 over-expression in normal mammary epithelial cells (MCF10A) and breast cancer cells (HCC1143) in terms of gene expression, migration, adhesion and transendothelial migration. Twenty-six out of 238 genes were inhibited in tissues of OLR1 KO mice; the vast majority of OLR1 sensitive genes contained NF-κB binding sites in their promoters. Further studies revealed broad inhibition of NF-kB target genes outside of the transformation-associated gene pool, with enrichment themes of defense response, immune response, apoptosis, proliferation, and wound healing. Transcriptome of Olr1 KO mice also revealed inhibition of de novo lipogenesis, rate-limiting enzymes fatty acid synthase (Fasn), stearoyl-CoA desaturase (Scd1) and ELOVL family member 6 (Elovl6), as well as lipolytic phospholipase A2 group IVB (Pla2g4b). In studies comparing MCF10A and HCC1143, the latter displayed 60% higher OLR1 expression. Forced over-expression of OLR1 resulted in upregulation of NF-κB (p65) and its target pro-oncogenes involved in inhibition of apoptosis (BCL2, BCL2A1, TNFAIP3) and regulation of cell cycle (CCND2) in both cell lines. Basal expression of FASN, SCD1 and PLA2G4B, as well as lipogenesis transcription factors PPARA, SREBF2 and CREM, was higher in HCC1143 cells. Over-expression of OLR1 in HCC1143 cells also enhanced cell migration, without affecting their adherence to TNFα-activated endothelium or transendothelial migration. On the other hand, OLR1 neutralizing antibody inhibited both adhesion and transmigration of untreated HCC1143 cells. We conclude that OLR1 may act as an oncogene by activation of NF-kB target genes responsible for proliferation, migration and inhibition of apoptosis and de novo lipogenesis genes.

Highlights

ox-LDL receptor 1 (OLR1), a lectin-like scavenger receptor, is highly conserved in mammals [1] and it is capable of recognizing several ligands including the protein moiety of oxidized-LDL, advanced glycation end-products, gram-positive and gram-negative bacteria and apoptotic cells [2]
This study suggests multiple potential links between OLR1 and susceptibility to cancer
The microarray database in the mice with Olr1 abrogation exhibited a marked reduction in expression of NF-kB target genes involved in cellular transformation [14], as well as genes related to lipogenesis

Summary

Introduction

OLR1, a lectin-like scavenger receptor, is highly conserved in mammals [1] and it is capable of recognizing several ligands including the protein moiety of oxidized-LDL (ox-LDL), advanced glycation end-products, gram-positive and gram-negative bacteria and apoptotic cells [2]. OLR1 is primarily expressed in vascular cells and vasculature-rich organs [3], and its activation by a wide range of stimuli indicative of dyslipidemia, inflammation and damage initiates several signaling cascades including MAPKs, other protein kinases as well as transcription factors NF-kB and AP-1 [4,5]. Overexpression of OLR1 has been shown in cellular components of atherosclerotic lesions [6]. Deletion of Olr in Ldlr knockout (KO) mice results in much smaller atherosclerotic lesions associated with a drastic reduction of inflammation in the aortic wall [7]. Abrogation of Olr reduces the extent of ischemia/reperfusion injury [9]

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