Ercolano Giuseppe, De Cicco Paola, Rubino Valentina, Terrazzano Giuseppe, Ruggiero Giuseppina, Carriero Roberta, Kunderfranco Paolo, Ianaro Angela
Department of Oncology UNIL CHUV and Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Lausanne, Switzerland.
Department of Pharmacy, University of Naples Federico II, Naples, Italy.
Front Pharmacol. 2019 Dec 5;10:1456. doi: 10.3389/fphar.2019.01456. eCollection 2019.
CRISPR/Cas9 has become a powerful method to engineer genomes and to activate or to repress genes expression. As such, in cancer research CRISPR/Cas9 technology represents an efficient tool to dissect mechanisms of tumorigenesis and to discover novel targets for drug development. Here, we employed the CRISPR/Cas9 technology for studying the role of prostaglandin-endoperoxide synthase 2 (PTGS2) in melanoma development and progression. Melanoma is the most aggressive form of skin cancer with a median survival of less than 1 year. Although oncogene-targeted drugs and immune checkpoint inhibitors have demonstrated a significant success in improving overall survival in patients, related toxicity and emerging resistance are ongoing challenges. Gene therapy appears to be an appealing option to enhance the efficacy of currently available melanoma therapeutics leading to better patient prognosis. Several gene therapy targets have been identified and have proven to be effective against melanoma cells. Particularly, PTGS2 is frequently expressed in malignant melanomas and its expression significantly correlates with poor survival in patients. In this study we investigated on the effect of knockdown in B16F10 murine melanoma cells. Our results show that reduced expression of in melanoma cells: ) inhibits cell proliferation, migration, and invasiveness; ) modulates immune response by impairing myeloid derived suppressor cell differentiation; ) reduces tumor development and metastasis . Collectively, these findings indicate that could represent an ideal gene to be targeted to improve success rates in the development of new and highly selective drugs for melanoma treatment.
CRISPR/Cas9已成为一种用于改造基因组以及激活或抑制基因表达的强大方法。因此，在癌症研究中，CRISPR/Cas9技术是剖析肿瘤发生机制和发现药物开发新靶点的有效工具。在此，我们运用CRISPR/Cas9技术研究前列腺素内过氧化物合酶2（PTGS2）在黑色素瘤发生和发展中的作用。黑色素瘤是最具侵袭性的皮肤癌形式，中位生存期不到1年。尽管针对癌基因的药物和免疫检查点抑制剂在提高患者总体生存率方面已取得显著成功，但相关毒性和新出现的耐药性仍是持续存在的挑战。基因治疗似乎是增强现有黑色素瘤治疗药物疗效以改善患者预后的一个有吸引力的选择。已经确定了几个基因治疗靶点，并且已证明它们对黑色素瘤细胞有效。特别是，PTGS2在恶性黑色素瘤中经常表达，其表达与患者的不良生存显著相关。在本研究中，我们研究了在B16F10小鼠黑色素瘤细胞中敲低PTGS2的效果。我们的结果表明，黑色素瘤细胞中PTGS2表达降低：（1）抑制细胞增殖、迁移和侵袭；（2）通过损害髓源性抑制细胞分化来调节免疫反应；（3）减少肿瘤发生和转移。总体而言，这些发现表明，PTGS2可能是一个理想的靶点基因，有助于提高开发用于黑色素瘤治疗的新型高选择性药物的成功率。
