Department of Biochemistry and Biology, University of Houston, Houston, Texas.
Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas.
Cancer. 2019 Jul 15;125(14):2409-2422. doi: 10.1002/cncr.32053. Epub 2019 Apr 23.
Over 96% of high-grade ovarian carcinomas and 50% of all cancers are characterized by alterations in the p53 gene. Therapeutic strategies to restore and/or reactivate the p53 pathway have been challenging. By contrast, p63, which shares many of the downstream targets and functions of p53, is rarely mutated in cancer.
A novel strategy is presented for circumventing alterations in p53 by inducing the tumor-suppressor isoform TAp63 (transactivation domain of tumor protein p63) through its direct downstream target, microRNA-130b (miR-130b), which is epigenetically silenced and/or downregulated in chemoresistant ovarian cancer.
Treatment with miR-130b resulted in: 1) decreased migration/invasion in HEYA8 cells (p53 wild-type) and disruption of multicellular spheroids in OVCAR8 cells (p53-mutant) in vitro, 2) sensitization of HEYA8 and OVCAR8 cells to cisplatin (CDDP) in vitro and in vivo, and 3) transcriptional activation of TAp63 and the B-cell lymphoma (Bcl)-inhibitor B-cell lymphoma 2-like protein 11 (BIM). Overexpression of TAp63 was sufficient to decrease cell viability, suggesting that it is a critical downstream effector of miR-130b. In vivo, combined miR-130b plus CDDP exhibited greater therapeutic efficacy than miR-130b or CDDP alone. Mice that carried OVCAR8 xenograft tumors and were injected with miR-130b in 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) liposomes had a significant decrease in tumor burden at rates similar to those observed in CDDP-treated mice, and 20% of DOPC-miR-130b plus CDDP-treated mice were living tumor free. Systemic injections of scL-miR-130b plus CDDP in a clinically tested, tumor-targeted nanocomplex (scL) improved survival in 60% and complete remissions in 40% of mice that carried HEYA8 xenografts.
The miR-130b/TAp63 axis is proposed as a new druggable pathway that has the potential to uncover broad-spectrum therapeutic options for the majority of p53-altered cancers.
超过 96%的高级卵巢癌和 50%的所有癌症都表现出 p53 基因的改变。恢复和/或重新激活 p53 途径的治疗策略具有挑战性。相比之下，p63 很少在癌症中发生突变，但其下游靶标和功能与 p53 有许多相似之处。
提出了一种新的策略，通过其直接下游靶标 microRNA-130b（miR-130b）诱导肿瘤抑制因子 TAp63（肿瘤蛋白 p63 的转录激活结构域），从而绕过 p53 的改变，miR-130b 在化疗耐药性卵巢癌中被表观遗传沉默和/或下调。
miR-130b 处理导致：1）HEYA8 细胞（p53 野生型）迁移/侵袭减少和 OVCAR8 细胞（p53 突变型）多细胞球体破坏，2）HEYA8 和 OVCAR8 细胞对顺铂（CDDP）的体外和体内敏感性增加，以及 3）TAp63 和 B 细胞淋巴瘤（Bcl）抑制剂 B 细胞淋巴瘤 2 样蛋白 11（BIM）的转录激活。TAp63 的过表达足以降低细胞活力，表明它是 miR-130b 的关键下游效应物。在体内，miR-130b 联合 CDDP 比单独使用 miR-130b 或 CDDP 具有更好的治疗效果。携带 OVCAR8 异种移植肿瘤的小鼠，并用 miR-130b 在 1,2-二油酰基-sn-甘油-3-磷酸胆碱（DOPC）脂质体中注射，肿瘤负担显著减少，与接受 CDDP 治疗的小鼠相似，并且 20%的 DOPC-miR-130b 加 CDDP 治疗的小鼠无肿瘤存活。在临床测试的肿瘤靶向纳米复合物（scL）中全身注射 scL-miR-130b 加 CDDP，可使携带 HEYA8 异种移植肿瘤的小鼠的存活率提高 60%，完全缓解率提高 40%。
提出了 miR-130b/TAp63 轴作为一种新的可药物治疗途径，有可能为大多数 p53 改变的癌症提供广谱治疗选择。
