Gasca J, Flores M L, Jiménez-Guerrero R, Sáez M E, Barragán I, Ruíz-Borrego M, Tortolero M, Romero F, Sáez C, Japón M A
Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain.
Centro Andaluz de Estudios Bioinformáticos (CAEBi), 41013 Seville, Spain.
Cell Death Discov. 2020 Sep 16;6:86. doi: 10.1038/s41420-020-00322-x. eCollection 2020.
Epithelial-mesenchymal transition (EMT) has recently been associated with tumor progression, metastasis, and chemotherapy resistance in several tumor types. We performed a differential gene expression analysis comparing paclitaxel-resistant vs. paclitaxel-sensitive breast cancer cells that showed the upregulation of (EGF Like Repeats and Discoidin I Like Domains Protein 3). This gene codifies an extracellular matrix protein that has been identified as a novel regulator of EMT, so we studied its role in tumor progression and paclitaxel response. Our results demonstrated that EDIL3 expression levels were increased in paclitaxel-resistant breast and prostate cancer cells, and in subsets of high-grade breast and prostate tumors. Moreover, we observed that EDIL3 modulated the expression of EMT markers and this was impaired by cilengitide, which blocks the EDIL3-integrin αβ interaction. EDIL3 knockdown reverted EMT and sensitized cells to paclitaxel. In contrast, EDIL3 overexpression or the culture of cells in the presence of EDIL3-enriched medium induced EMT and paclitaxel resistance. Adding cilengitide resensitized these cells to paclitaxel treatment. In summary, EDIL3 may contribute to EMT and paclitaxel resistance through autocrine or paracrine signaling in cancer cells. Blockade of EDIL3-integrin αβ interaction by cilengitide restores sensitivity to paclitaxel and reverts EMT in paclitaxel-resistant cancer cells. Combinations of cilengitide and taxanes could be beneficial in the treatment of subsets of breast and prostate cancers.
上皮-间质转化（EMT）最近被认为与多种肿瘤类型的肿瘤进展、转移及化疗耐药相关。我们进行了一项差异基因表达分析，比较了耐紫杉醇与紫杉醇敏感的乳腺癌细胞，结果显示（表皮生长因子样重复序列和盘状结构域蛋白1样蛋白3）表达上调。该基因编码一种细胞外基质蛋白，已被确定为EMT的新型调节因子，因此我们研究了其在肿瘤进展和紫杉醇反应中的作用。我们的结果表明，EDIL3在耐紫杉醇的乳腺癌和前列腺癌细胞以及高级别乳腺癌和前列腺肿瘤亚组中的表达水平升高。此外，我们观察到EDIL3调节EMT标志物的表达，而西仑吉肽可阻断EDIL3与整合素αβ的相互作用，从而削弱这种调节作用。敲低EDIL3可逆转EMT并使细胞对紫杉醇敏感。相反，过表达EDIL3或在富含EDIL3的培养基中培养细胞会诱导EMT和紫杉醇耐药。添加西仑吉肽可使这些细胞对紫杉醇治疗重新敏感。总之，EDIL3可能通过癌细胞中的自分泌或旁分泌信号传导促进EMT和紫杉醇耐药。西仑吉肽阻断EDIL3与整合素αβ的相互作用可恢复对紫杉醇的敏感性，并逆转耐紫杉醇癌细胞中的EMT。西仑吉肽与紫杉烷类药物联合使用可能对治疗部分乳腺癌和前列腺癌有益。
