Oxidized LDL receptor 1 (OLR1) as a possible link between obesity, dyslipidemia and cancer.
Oxidized LDL receptor 1 (OLR1) as a possible link between obesity, dyslipidemia and cancer.
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DOI：
10.1371/journal.pone.0020277
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Mehta JL
中科院分区：
文献类型：
--
作者：
Khaidakov M;Mitra S;Kang BY;Wang X;Kadlubar S;Novelli G;Raj V;Winters M;Carter WC;Mehta JL
最近的研究表明，凝集素样氧化低密度脂蛋白受体1（OLR 1）的表达与肿瘤发生有关。我们分析了来自Olr 1基因敲除（KO）和野生型（WT）小鼠的微阵列数据，以寻找参与细胞转化的基因，并评估了OLR 1在正常乳腺上皮细胞（MCF 10A）和乳腺癌细胞（HCC 1143）中过表达对基因表达、迁移、粘附和跨内皮迁移的影响。OLR 1 KO小鼠组织中238个基因中有26个受到抑制;绝大多数OLR 1敏感基因的启动子中含有NF-κB结合位点。进一步的研究表明，广泛抑制NF-kB靶基因以外的转化相关的基因库，与防御反应，免疫反应，细胞凋亡，增殖和伤口愈合的富集主题。Olr 1 KO小鼠的转录组还显示了对新生脂肪生成、限速酶脂肪酸合成酶（Fasn）、硬脂酰-CoA去饱和酶（Scd 1）和NH 4VL家族成员6（Elov 16）以及脂解磷脂酶A2组IVB（Pla 2g 4 b）的抑制。在比较MCF 10A和HCC 1143的研究中，后者显示OLR 1表达高出60%。OLR 1的强制过表达导致NF-κB（p65）及其靶向原癌基因（BCL 2、BCL 2A 1、TNFAIP 3）在两种细胞系中的上调，所述靶向原癌基因参与抑制凋亡和调节细胞周期（CCND 2）。HCC 1143细胞中FXR、SCD 1和PLA 2G 4 B以及脂肪生成转录因子PPARA、SREBF 2和CREM的基础表达较高。OLR 1在HCC 1143细胞中的过表达也增强了细胞迁移，而不影响它们对TNFα激活的内皮的粘附或跨内皮迁移。另一方面，OLR 1中和抗体抑制未处理的HCC 1143细胞的粘附和迁移。我们的结论是，OLR 1可能作为一个致癌基因的NF-κ B的靶基因负责增殖，迁移和抑制凋亡和从头脂肪生成基因的激活。
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.
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