Shi Shuo, Li Fei, Wu Liangcai, Zhang Liwei, Liu Lei
Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
Hum Gene Ther. 2021 Aug;32(15-16):828-838. doi: 10.1089/hum.2020.214. Epub 2021 Feb 22.
Ovarian cancer is the most lethal gynecological cancer, most patients relapse within 12-24 months, and eventually die, especially platinum-resistant patients. Gene therapy has been one of the most potential methods for tumor treatment. Bone marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. Sodium iodide symporter (NIS) is an intrinsic membrane glycoprotein and can concentrate I, which is important for radionuclide therapy and nuclear medicine imaging in recent years. However, the rapid iodine efflux has become a bottleneck for NIS-mediated radionuclide gene therapy. Our previous studies found that the early growth response-1 (Egr1) promoter containing CC(A/T)6GG (CArG) elements had an I radiation-positive feedback effect on the NIS gene. Other research showed the synthesized Egr1 promoter containing four CArG elements, E4, was nearly three times as sensitive as the Egr1 promoter. In our study, BMSC-E4-NIS was engineered to express NIS under the control of E4 promoter using lentivirial vectors. After BMSC-E4-NIS implantation, no tumors were seen in BALB/c nude mice and BMSC-E4-NIS did not promote the growth of SKOV3 tumor. BMSCs migrated toward ovarian cancer samples in chemotaxis assays and to ovarian tumors in mice. Using micro-single-photon emission computed tomography/computed tomography (SPECT/CT) imaging, we found that E4 promoter produced a notable increase in I uptake after I irradiation, the radionuclide uptake is almost three and six times more than Egr1 and cytomegalovirus (CMV) promoters. These studies confirmed the feasibility of using BMSCs as carriers for lentivirus-mediated E4-NIS gene therapy for ovarian cancer. Further research on BMSC-E4-NIS gene therapy for ovarian cancer will also be carried on, and if successful, this might provide a new adjuvant therapeutical option for platinum-resistant ovarian cancer patients and provide a new method for dynamic evaluation of curative effect.
卵巢癌是最致命的妇科癌症，大多数患者在12 - 24个月内复发并最终死亡，尤其是铂耐药患者。基因治疗一直是肿瘤治疗最具潜力的方法之一。骨髓间充质干细胞（BMSCs）已被用于将治疗性基因全身递送至实体瘤。碘化钠同向转运体（NIS）是一种内在膜糖蛋白，可浓聚碘，这对近年来的放射性核素治疗和核医学成像很重要。然而，碘的快速外流已成为NIS介导的放射性核素基因治疗的瓶颈。我们之前的研究发现，含有CC(A/T)6GG（CArG）元件的早期生长反应-1（Egr1）启动子对NIS基因有碘辐射正反馈作用。其他研究表明，合成的含有四个CArG元件的Egr1启动子E4，其敏感性几乎是Egr1启动子的三倍。在我们的研究中，使用慢病毒载体构建了BMSC-E4-NIS，使其在E4启动子的控制下表达NIS。BMSC-E4-NIS植入后，BALB/c裸鼠未出现肿瘤，且BMSC-E4-NIS未促进SKOV3肿瘤生长。在趋化实验中，BMSCs向卵巢癌样本迁移，在小鼠体内向卵巢肿瘤迁移。使用微单光子发射计算机断层扫描/计算机断层扫描（SPECT/CT）成像，我们发现E4启动子在碘辐射后碘摄取显著增加，放射性核素摄取几乎是Egr1和巨细胞病毒（CMV）启动子的三倍和六倍。这些研究证实了使用BMSCs作为慢病毒介导的E4-NIS基因治疗卵巢癌载体的可行性。还将对BMSC-E4-NIS基因治疗卵巢癌进行进一步研究，如果成功，这可能为铂耐药卵巢癌患者提供一种新的辅助治疗选择，并为疗效的动态评估提供一种新方法。
