PO.TB03.06 · 肿瘤生物学
S-亚硝基化 COX-2 是一种受微环境调控的间充质表型乳腺癌生物标志物
S-Nitrosylated COX-2 is a microenvironment-regulated breast cancer biomarker of mesenchymal phenotypes
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
COX-2 是一种诱导型酶，是产生炎性前列腺素的关键。COX-2 在乳腺癌小鼠模型中还具有肿瘤内在的致癌活性。此前，我们报道了 Cys-526 亚硝基化 COX-2（SNO-COX-2）表达增加——而非非亚硝基化 COX-2——与人早期乳腺癌向浸润性导管癌进展相关。在此，我们使用早期人乳腺癌的三维培养模型（MCF10DCIS 细胞）来研究 SNO-COX-2 表达与间充质/侵袭性肿瘤细胞形态之间的关系。我们发现 SNO-COX-2——而非非亚硝基化 COX-2——与由纤维状 I 型胶原诱导的间充质表型密切相关。有趣的是，侵袭性表型与经典上皮-间充质转化（EMT）标志物（包括 SNAIL、CDH2（N-cadherin）和 VIM（vimentin））的诱导无关。相比之下，TGFbeta-1 强烈诱导 EMT 相关转录本，但不诱导 SNO-COX-2 蛋白表达，也不诱导间充质表型。这些观察结果表明，在 MCF10DCIS 细胞中，SNO-COX-2 与间充质表型的关联比非亚硝基化 COX-2 蛋白或经典 EMT 转录本的表达更强。在体内支持这些观察结果的是，一个异质性小鼠乳腺肿瘤模型（D2A1 细胞注射）证明，与上皮性肿瘤区域相比，侵袭性间充质肿瘤区域的 SNO-COX-2 表达也增加。此外，使用微环境微阵列在 300 种不同的肿瘤微环境条件下检测 MCF10DCIS.com 细胞，我们发现 SNO-COX-2 蛋白表达由炎症、创伤修复和癌症相关因子驱动。突出者包括 TNC、SPP1、核心蛋白聚糖（decorin）、纤维状 I 型和 III 型胶原、INF-gamma 以及 IL-4/13，并有证据表明特定的细胞外基质-配体相互作用驱动 SNO-COX-2 的高表达和低表达。总之，在 MCF10DCIS 细胞中，SNO-COX-2 的表达高度依赖微环境，并与侵袭性/间充质生长强烈相关，表明 SNO-COX-2 有潜力作为评估早期乳腺癌进展风险的生物标志物。
查看英文原文 English abstract
COX-2 is an inducible enzyme key to the production of inflammatory prostaglandins. COX-2 also has tumor intrinsic oncogenic activity in mouse models of breast cancer. Previously, we reported that increased expression of Cys-526-nitrosylated COX-2 (SNO-COX-2), but not non-nitrosylated COX-2, associated with progression of early-stage human breast cancer to invasive ductal carcinoma. Here, we used a 3D culture model of early-stage human breast cancer (MCF10DCIS cells) to investigate the relationship between SNO-COX-2 expression and mesenchymal/invasive tumor cell morphology. We find that SNO-COX-2, but not non-nitrosylated COX-2, closely associated with mesenchymal phenotypes induced by fibrillar type I collagen. Interestingly, invasive phenotypes did not associate with induction of classic epithelial-to-mesenchymal transition (EMT) markers including SNAIL , CDH2 (N-cadherin), and VIM (vimentin). By contrast TGFbeta-1 strongly induced EMT-related transcripts, but not SNO-COX-2 protein expression nor mesenchymal phenotypes. These observations suggest that in MCF10DCIS cells, SNO-COX-2 associates with mesenchymal phenotypes more strongly than non-nitrosylated COX-2 protein or expression of classic EMT transcripts. Supporting these observations in vivo , a heterogeneous mouse breast tumor model (D2A1 cell injection) demonstrates that invasive mesenchymal tumor regions also have increased SNO-COX-2 expression compared to epithelial tumor regions. Further, using a microenvironment microarray to test MCF10DCIS.com cells 300 distinct tumor microenvironment conditions we find SNO-COX-2 protein expression is driven by inflammation, wound resolution, and cancer-associated factors. Standouts include TNC, SPP1, decorin, fibrillar type I and III collagens, INF-gamma, and IL-4/13, with evidence for specific extracellular matrix-ligand interactions driving both high and low SNO-COX-2 expression. In sum, in MCF10DCIS cells, expression of SNO-COX-2 is highly microenvironment-dependent and strongly associated with invasive/mesenchymal growth, indicating potential for SNO-COX-2 as a biomarker to assess risk of early-stage breast cancer progression.
利益披露 Disclosure
R. J. Hoffmann, None..
A. Bensen, None..
M. Dane, None..
J. Arterberry, None..
R. Smith, None..
J. Korkola, None..
P. Schedin, None.