眾所周知,，腫瘤的入侵是癌癥擴(kuò)散的一個關(guān)鍵性步驟。最近,，美國肯塔基大學(xué)的Rolf J. Craven等人研究發(fā)現(xiàn)中性粒細(xì)胞明膠酶相關(guān)脂質(zhì)運載蛋白（NGAL）的表達(dá)依賴于腫瘤有關(guān)的受體S2RPgrmc1,。因此，S2RPgrmc1可能會成為一個潛在的抑制腫瘤浸潤的靶點,。相關(guān)論文發(fā)表在3月14日的美國《生化周刊》（JBC）上,。
研究表明：S2RPgrmc1是一個與細(xì)胞色素b5有關(guān)的σ2受體，并且該受體對于腫瘤的形成和擴(kuò)散是必須的,。在整個過程中,，分泌型蛋白起到了推進(jìn)作用，所以Rolf J. Craven等人嘗試用抗體陣列來篩選S2RPgrmc1依賴的分泌蛋白,。
NGAL/LCN2是一種偶聯(lián)MMP-9的分泌型糖蛋白，實驗發(fā)現(xiàn)：S2RPgrmc1明顯的調(diào)節(jié)了NGAL/LCN2的表達(dá),。因為敲除S2RPgrmc1后NGAL/LCN2在蛋白及RNA水平的表達(dá)會受到阻遏,，同時MMP9 的活性也會相應(yīng)下調(diào)。而MMP-9的活性以及腫瘤的形成都需要NGAL的表達(dá),。S2RPgrmc1與EGFR作用后會提高細(xì)胞膜上EGFR的水平,。EGFR的抑制劑埃羅替尼和AG1478以及Akt及ERK的抑制劑降低了NGAL/LCN2 的RNA及蛋白表達(dá)水平,。NGAL的轉(zhuǎn)錄受到了NFκB的調(diào)節(jié)，在敲除S2RPgrmc1后下調(diào)了NFκB 的亞單位p65/RelA的乙?；?、磷酸化，結(jié)果降低了它的活性,。在S2RPgrmc1敲除的細(xì)胞中,，p65的乙酰化作用被組蛋白去乙?；?的抑制劑所逆轉(zhuǎn),，而這種抑制劑可以部分修復(fù)NGAL回到正常水平。
與建立的模型一致,，實驗結(jié)果表明S2RPgrmc1確實經(jīng)由EGFR來激活NFκB,，并以此來提升NGAL/LCN2的水平。（生物谷Bioon.com）
doi: 10.1074/jbc.M111.324921
PMC:
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..
