MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways
MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways
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DOI：
10.1038/s41388-019-0860-0
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发表时间：
2019-08-08
期刊：
影响因子：
8
通讯作者：
Santamaria, Anna
中科院分区：
文献类型：
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作者：
Majem, Blanca;Parrilla, Alfonso;Santamaria, Anna
卵巢癌是妇科恶性肿瘤中死亡率最高的一种，其发病早、隐匿性好、耐药快。组织学上的异质性，它包括几个亚型与不同的突变景观，阻碍了有效的靶向治疗的发展。非编码RNA正在成为癌症治疗的潜在新靶点。为了寻找与卵巢癌相关的microRNA特征并研究其作为有效靶向治疗的潜力，我们检测了大量肿瘤样本中768种miRNA的表达，发现miR-654- 5 p在卵巢浆液性癌中表达不足，卵巢浆液性癌是最常见和最具侵袭性的类型。miR 654 - 5 p水平的恢复降低了体外和体内肿瘤细胞的活力，并损害了离体卵巢癌患者来源的腹水细胞的球体形成能力和活力。发现CDCP 1和PLAGL 2癌基因是最相关的直接miR-654- 5 p靶标，并且这两种基因在与卵巢肿瘤发生相关的关键癌症途径（例如MYC、WNT和AKT途径）相关的分子特征中传递。总之，我们揭示了miR-654- 5 p的肿瘤抑制功能，这表明其对CDCP 1和PLAGL 2的恢复或共靶向可能是卵巢癌的有效治疗方法。
Ovarian cancer is the most lethal gynecological malignancy due to the silent nature on its early onset and the rapid acquisition of drug resistance. Histologically heterogeneous, it includes several subtypes with different mutational landscapes, hampering the development of effective targeted therapies. Non-coding RNAs are emerging as potential new therapeutic targets in cancer. To search for a microRNA signature related to ovarian carcinomas and study its potential as effective targeted therapy, we examined the expression of 768 miRNA in a large collection of tumor samples and found miR-654-5p to be infraexpressed in ovarian serous carcinomas, the most common and aggressive type. Restoration of miR654-5p levels reduced tumor cell viability in vitro and in vivo and impaired sphere formation capacity and viability of ovarian cancer patient-derived ascitic cells ex vivo. CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AKT pathways. Together, we unveiled the tumor suppressor function of miR-654-5p, suggesting that its restoration or co-targeting of CDCP1 and PLAGL2 may be an effective therapeutic approach for ovarian cancer.