外源干扰性LncRNA同时抑制多种致癌性miRNAs功能及其针对胆囊癌的治疗策略

Many overexpressed OncomiRs participate in the origin, proliferation, invasion and metastasis of cancer cells, which are the useful targets for cancer therapy. But the efficacy of intervention targeting single miRNA is limited, cancer cells are easily reactivated to acquire proliferative activity through the bypass signaling pathways. We previously designed an interfering artificial long non-coding RNA (LncRNAi), which is expressed by oncolytic adenovirus and competitively inhibits the function of multiple OncomiRs simultaneously to protect many corresponding tumor-suppressor target genes, then exerts more effective antitumor effect. The strategy was certified on xenograft models of hepatocellular carcinoma (HCC) and diffused large B-cell lymphoma (DLBCL). Due to the reason of no effective treatment approach for gallbladder cancer, we will further improve this strategy by means of optimization of best OncomiRs combination, optimization of LncRNAi expression vectors, configuration of several xenograft tumor models with different types of cell transplantation, and set up three kinds of security mechanisms. The verification of inhibiting cell malignant biological behaviors of gallbladder cancer and influencing gene expression profile and signaling pathways of cancer cells is carried out to further establish new effective strategy through different injection modes, including the intratumoral, interventional, intravenous injection, which simulations the situations of planting patterns of transplantation tumor model, the tumor recurrence within the original site or liver metastases, and the positive circulating tumor cells. Finally, this project may establish a reliable curative effective strategy for adjuvant treatment of gallbladder cancer.

细胞内大量高表达OncomiRs广泛参与癌细胞起源、增殖、侵袭及转移，是肿瘤治疗的有用靶标。但针对单一miRNA干预疗效有限，癌细胞容易通过旁路信号途径重新获得增殖活力。我们前期人工设计了一条干扰性LncRNA（LncRNAi），通过溶瘤腺病毒介导表达，能同时竞争性抑制多种OncomiRs功能，保护抑癌性靶基因，发挥有效抗癌作用。该策略在肝癌和DLBCL模型上得到验证。由于目前胆囊癌缺少有效治疗手段，我们拟进一步优选最佳OncomiRs组合、优化LncRNAi表达载体、优配多种移植瘤模型、设置3种安全机制的基础上，对该策略进行改良，验证其对胆囊癌细胞恶性生物学行为的抑制以及对癌细胞基因表达谱和信号传导通路的影响，再通过不同种植模式的移植瘤模型、模拟肿瘤原发灶、肝内复发转移灶、循环肿瘤细胞阳性等情况下的瘤内、介入、静脉注射方式，确立该策略的有效性，为胆囊癌治疗建立一种疗效可靠的辅助治疗策略。

细胞内大量高表达OncomiRs广泛参与癌细胞起源、增殖、侵袭及转移，是肿瘤治疗的有用靶标。但针对单一miRNA干预疗效有限，癌细胞容易通过旁路信号途径重新获得增殖活力。我们通过人工设计了一条干扰性LncRNA（LncRNAi），以溶瘤腺病毒为载体介导表达，能同时竞争性抑制多种OncomiRs功能，保护抑癌性靶基因，发挥有效抗癌作用。该策略在胆囊癌模型上得到验证。由于目前胆囊癌缺少有效治疗手段，我们进一步优选最佳OncomiRs组合、优化LncRNAi表达载体、优配多种移植瘤模型、设置3种安全机制的基础上，对该策略进行改良，验证其对胆囊癌细胞恶性生物学行为的抑制以及对癌细胞基因表达谱和信号传导通路的影响，再通过不同种植模式的移植瘤模型、模拟肿瘤原发灶、肝内复发转移灶、循环肿瘤细胞阳性等情况下的瘤内、介入、静脉注射方式，确立该策略的有效性，为胆囊癌治疗建立一种疗效可靠的辅助治疗策略。