Torres Anna, Kozak Joanna, Korolczuk Agnieszka, Wdowiak Paulina, Domańska-Glonek Ewa, Maciejewski Ryszard, Torres Kamil
Laboratory of Biostructure, Chair of Human Anatomy, Medical University of Lublin, Jaczewskiego 4, Lublin, 20-090, Poland.
Department of Clinical Pathomorphology, Medical University of Lublin, Jaczewskiego 8a, Lublin, 20-090, Poland.
BMC Cancer. 2016 Oct 26;16(1):822. doi: 10.1186/s12885-016-2867-z.
Endometrial cancer is the most common cancer of the female reproductive tract. Based on our previous studies we speculated that miR-92a exhibited pro-oncogenic properties in endometrial cancer, and therefore its inhibition could be used as a therapeutic measure in this disease. Therefore in the present study we aimed to investigate both in vitro and in vivo if inhibition of miR-92a in endometrial cancer would limit cancer cells proliferation.
miR-92a expression was evaluated in four endometrial cancer cell lines using qPCR. Inhibition of miR-92a activity was obtained in endometrial cancer cell lines by a transient transfection of a custom designed Locked Nucleic Acid (LNA)-Inhibitor, developed to work both in vitro and in vivo. In vitro proliferation studies were performed using xCELLigence RTCA DP system. In vivo experiment was performed in Cby.Cg-Foxn1 < nu>/cmdb mice bearing endometrial cancer xenografts, which were intraperitoneally injected with nine dosages of 25 mg/kg of miR-205-LNA-inhibitor.
qPCR revealed increased expression of miR-92a in HEC-1-B, Ishikawa and AN3CA cells. LNA-i-miR-92a inhibited endometrial cancer growth in vitro. It was also demonstrated that systemic administration of LNA-i-miR-92a was feasible and exerted inhibitory effect on endometrial cancer xenograft growth in vivo with only mild toxic effects in treated animals, however the effect was observed until 12 experimental day and the last three dosages did not maintain the attenuating effect with the acceleration of tumor growth observed at the end and after cessation of the intraperitoneal therapy.
Taken together, these results indicate that intraperitoneal delivery of miR-92a-LNA-modified-inhibitor is feasible, devoid of significant toxicity and moderately inhibits endometrial cancer growth in vivo, and therefore warrants further studies investigating other routes of inhibitor delivery possibly in other animal models.
子宫内膜癌是女性生殖道最常见的癌症。基于我们之前的研究，我们推测miR-92a在子宫内膜癌中具有促癌特性，因此抑制它可作为这种疾病的一种治疗措施。因此，在本研究中，我们旨在研究在体外和体内抑制子宫内膜癌中的miR-92a是否会限制癌细胞增殖。
使用qPCR评估四种子宫内膜癌细胞系中miR-92a的表达。通过瞬时转染定制设计的锁核酸（LNA）抑制剂来抑制子宫内膜癌细胞系中miR-92a的活性，该抑制剂在体外和体内均有效。使用xCELLigence RTCA DP系统进行体外增殖研究。在携带子宫内膜癌异种移植瘤的Cby.Cg-Foxn1
qPCR显示HEC-1-B、Ishikawa和AN3CA细胞中miR-92a表达增加。LNA-i-miR-92a在体外抑制子宫内膜癌生长。还证明全身给予LNA-i-miR-92a是可行的，并且对体内子宫内膜癌异种移植瘤生长具有抑制作用，对治疗的动物只有轻微毒性作用，然而该作用在实验第12天之前观察到，并且最后三剂在腹腔治疗结束和停止后随着肿瘤生长加速未维持减弱作用。
综上所述，这些结果表明腹腔递送miR-92a-LNA修饰的抑制剂是可行的，没有明显毒性，并且在体内适度抑制子宫内膜癌生长，因此有必要进一步研究在其他动物模型中可能的其他抑制剂递送途径。
