Liu Shikai, Song Lili, Zhang Liang, Zeng Saitian, Gao Fangyuan
Cangzhou Central Hospital, Hebei 061001, China.
Cangzhou Central Hospital, Hebei 061001, China.
Biochem Biophys Res Commun. 2015 Apr 17;459(4):679-85. doi: 10.1016/j.bbrc.2015.03.004. Epub 2015 Mar 11.
Although multiple miRNAs are found involved in radioresistance development in HR-HPV positive (+) cervical cancer, only limited studies explored the regulative mechanism of the miRNAs. miR-21 is one of the miRNAs significantly upregulated in HR-HPV (+) cervical cancer is also significantly associated with radioresistance. However, the detailed regulative network of miR-21 in radioresistance is still not clear. In this study, we confirmed that miR-21 overexpression was associated with higher level of radioresistance in HR-HPV (+) cervical cancer patients and thus decided to further explore its role. Findings of this study found miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells and decrease radiation induced G2/M block and increase S phase accumulation. By using dual luciferase assay, we verified a binding site between miR-21 and 3'-UTR of large tumor suppressor kinase 1 (LATS1). Through direct binding, miR-21 can regulate LATS1 expression in cervical cancer cells. LATS1 overexpression can reverse miR-21 induced higher colony formation rate and also reduced miR-21 induced S phase accumulation and G2/M phase block reduction under radiation treatment. These results suggested that miR-21-LATS1 axis plays an important role in regulating radiosensitivity.
虽然发现多种miRNA参与HR-HPV阳性（+）宫颈癌的放射抗性发展，但仅有有限的研究探索了这些miRNA的调控机制。miR-21是在HR-HPV（+）宫颈癌中显著上调的miRNA之一，也与放射抗性显著相关。然而，miR-21在放射抗性中的详细调控网络仍不清楚。在本研究中，我们证实miR-21过表达与HR-HPV（+）宫颈癌患者较高水平的放射抗性相关，因此决定进一步探索其作用。本研究结果发现，miR-21可对HR-HPV（+）宫颈癌细胞的放射敏感性产生负面影响，并减少辐射诱导的G2/M期阻滞，增加S期积累。通过双荧光素酶测定，我们验证了miR-21与大肿瘤抑制激酶1（LATS1）的3'-UTR之间的结合位点。通过直接结合，miR-21可调节宫颈癌细胞中LATS1的表达。LATS1过表达可逆转miR-21诱导的较高集落形成率，也可减少miR-21诱导的辐射处理下S期积累和G2/M期阻滞的减少。这些结果表明，miR-21-LATS1轴在调节放射敏感性中起重要作用。
