众所周知，肿瘤的入侵是癌症扩散的一个关键性步骤。最近，美国肯塔基大学的Rolf J. Craven等人研究发现中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的表达依赖于肿瘤有关的受体S2RPgrmc1。因此，S2RPgrmc1可能会成为一个潜在的抑制肿瘤浸润的靶点。相关论文发表在3月14日的美国《生化周刊》（JBC）上。
研究表明：S2RPgrmc1是一个与细胞色素b5有关的σ2受体，并且该受体对于肿瘤的形成和扩散是必须的。在整个过程中，分泌型蛋白起到了推进作用，所以Rolf J. Craven等人尝试用抗体阵列来筛选S2RPgrmc1依赖的分泌蛋白。
NGAL/LCN2是一种偶联MMP-9的分泌型糖蛋白，实验发现：S2RPgrmc1明显的调节了NGAL/LCN2的表达。因为敲除S2RPgrmc1后NGAL/LCN2在蛋白及RNA水平的表达会受到阻遏，同时MMP9 的活性也会相应下调。而MMP-9的活性以及肿瘤的形成都需要NGAL的表达。S2RPgrmc1与EGFR作用后会提高细胞膜上EGFR的水平。EGFR的抑制剂埃罗替尼和AG1478以及Akt及ERK的抑制剂降低了NGAL/LCN2 的RNA及蛋白表达水平。NGAL的转录受到了NFκB的调节，在敲除S2RPgrmc1后下调了NFκB 的亚单位p65/RelA的乙酰化、磷酸化，结果降低了它的活性。在S2RPgrmc1敲除的细胞中，p65的乙酰化作用被组蛋白去乙酰化酶1的抑制剂所逆转，而这种抑制剂可以部分修复NGAL回到正常水平。
与建立的模型一致，实验结果表明S2RPgrmc1确实经由EGFR来激活NFκB，并以此来提升NGAL/LCN2的水平。（生物谷Bioon.com）
doi: 10.1074/jbc.M111.324921
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PMID:
Neutrophil gelatinase-associated lipocalin (NGAL) expression dependent on the tumor-associated sigma-2 receptor S2RPgrmc1
Shakeel U. R. Mir, Ling Jin and Rolf J. Craven.
Tumor invasion is a critical step in the spread of cancer. S2R (sigma-2 receptor)/Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome b5-related drug-binding orphan receptor essential for tumor formation and invasion. Secretory proteins drive these processes, so we screened for S2RPgrmc1-dependent secreted proteins using antibody arrays.S2RPgrmc1 markedly regulated the expression of NGAL/LCN2 (neutrophil gelatinase-associated lipocalin/lipocalin 2), a secreted glycoprotein that binds to MMP-9 (matrix metalloproteinase 9) and protects it from degradation. S2RPgrmc1 knock-down blocked NGAL/LCN2 expression at the protein and RNA levels and decreased MMP9 activity.NGAL expression was required for MMP-9 activity and tumor formation. S2RPgrmc1 associates with EGFR and increases EGFR levels at the plasma membrane, and the EGFR inhibitors erlotinib and AG1478, as well as Akt and ERK inhibitors, suppressed the NGAL/LCN2 RNA and protein levels. NGAL is transcriptionally regulated by NFκB, and S2RPgrmc1 knock-down decreased the NFκB sub-unit p65/RelA acetylation, phosphorylation and activation.In S2RPgrmc1 knock-down cells, p65 acetylation was reversed by inhibitors of histone deacetylase 1, and the inhibitors partially restored NGAL levels. Our results are consistent with a model in which S2RPgrmc1 increases NGAL/LCN2 levels by activating NFκB via EGFR..
