Suppression of integrin alpha3beta1 in breast cancer cells reduces cyclooxygenase-2 gene expression and inhibits tumorigenesis, invasion, and cross-talk to endothelial cells.
Suppression of integrin alpha3beta1 in breast cancer cells reduces cyclooxygenase-2 gene expression and inhibits tumorigenesis, invasion, and cross-talk to endothelial cells.
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DOI：
10.1158/0008-5472.can-09-4283
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发表时间：
2010-08-01
期刊：
影响因子：
11.2
通讯作者：
Dipersio CM
中科院分区：
文献类型：
--
作者：
Mitchell K;Svenson KB;Longmate WM;Gkirtzimanaki K;Sadej R;Wang X;Zhao J;Eliopoulos AG;Berditchevski F;Dipersio CM
细胞粘附细胞外基质的整合素受体在促进肿瘤生长和进展中具有重要作用。整合素α3β1在乳腺癌细胞中高表达，被认为可促进侵袭和转移；然而，其在调节恶性肿瘤细胞行为中的作用仍不清楚。在当前的研究中，我们使用短发夹 RNA (shRNA) 证明，抑制人乳腺癌细胞系 MDA-MB-231 中的 α3β1 会导致致瘤性降低、侵袭性降低以及刺激内皮细胞迁移的因子产生减少。实时 PCR 显示，抑制 α3β1 会导致环氧合酶-2 (COX-2) 基因的表达急剧减少，该基因在乳腺癌中经常过度表达，并已被用作治疗靶点。 COX-2 的减少伴随着前列腺素 E2 (PGE2) 的减少，前列腺素 E2 是 COX-2 下游产生的主要前列腺素，也是 COX-2 信号传导的重要效应物。 shRNA 介导的 COX-2 抑制表明它在肿瘤细胞侵袭和与内皮细胞的串扰中发挥作用。此外，PGE2 治疗可恢复 α3β1 缺陷的 MDA-MB-231 细胞的这些功能。这些发现确定了 α3β1 在调节肿瘤细胞促进癌症进展的两种特性中的作用：侵袭性和刺激内皮细胞的能力。他们还揭示了 COX-2 作为肿瘤细胞中 α3β1 下游效应子的新作用，从而确定 α3β1 作为抑制乳腺癌的潜在治疗靶点。
Integrin receptors for cell adhesion to extracellular matrix have important roles in promoting tumor growth and progression. Integrin α3β1 is highly expressed in breast cancer cells where it is thought to promote invasion and metastasis; however, its roles in regulating malignant tumor cell behavior remain unclear. In the current study, we used short-hairpin RNA (shRNA) to show that suppression of α3β1 in a human breast cancer cell line, MDA-MB-231, leads to decreased tumorigenicity, reduced invasiveness, and decreased production of factors that stimulate endothelial cell migration. Real-time PCR revealed that suppression of α3β1 caused a dramatic reduction in expression of the cyclooxygenase-2 (COX-2) gene, which is frequently over-expressed in breast cancers and has been exploited as a therapeutic target. Decreased COX-2 was accompanied by reduced prostaglandin E2 (PGE2), a major prostanoid produced downstream of COX-2 and an important effector of COX-2 signaling. shRNA-mediated suppression of COX-2 showed that it has a role in tumor cell invasion and crosstalk to endothelial cells. Furthermore, treatment with PGE2 restored these functions in α3β1-deficient MDA-MB-231 cells. These findings identify a role for α3β1 in regulating two properties of tumor cells that facilitate cancer progression: invasiveness and ability to stimulate endothelial cells. They also reveal a novel role for COX-2 as a downstream effector of α3β1 in tumor cells, thereby identifying α3β1 as a potential therapeutic target to inhibit breast cancer.