miR-2861 acts as a tumor suppressor via targeting EGFR/AKT2/CCND1 pathway in cervical cancer induced by human papillomavirus virus 16 E6.
miR-2861 acts as a tumor suppressor via targeting EGFR/AKT2/CCND1 pathway in cervical cancer induced by human papillomavirus virus 16 E6.
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miR-2861通过靶向EGFR/AKT2/CCND1通路在人乳头瘤病毒16 E6诱导的宫颈癌中发挥肿瘤抑制作用
DOI：
10.1038/srep28968
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发表时间：
2016-07-01
影响因子：
4.6
通讯作者：
Lu W
中科院分区：
文献类型：
--
作者：
Xu J;Wan X;Chen X;Fang Y;Cheng X;Xie X;Lu W
致癌性人乳头瘤病毒（HPV）的持续感染是宫颈癌及其前体的重要因素，HPV E6蛋白的异常表达是宫颈癌恶变过程中的关键事件。在此，我们使用miRNA微阵列来鉴定HEK 293 T细胞中HPV 16 E6异位过表达后miRNA的变化，发现与载体对照相比，miR-2861在表达HPV 16 E6的HEK 293 T和HaCaT细胞中均大大减少。此外，我们证明了宫颈癌细胞中HPV 16 E6、miR-2861、EGFR、AKT 2和CCND 1之间的生物学联系。我们发现miR-2861在宫颈癌组织中表达下调，并与晚期肿瘤分期和淋巴结转移呈负相关。miR-2861过表达可抑制宫颈癌细胞增殖和侵袭，并促进细胞凋亡。随后的研究发现EGFR、AKT 2和CCND 1都是miR-2861的直接靶点。重要的是，沉默EGFR、AKT 2和/或CCND 1重现了在miR-2861过表达时观察到的细胞效应。EGFR、AKT 2和/或CCND 1的恢复抵消了miR-2861表达的作用。因此，我们确定了一个新的途径，使用miR-2861，EGFR，AKT 2和CCND 1，可能介导HPV 16 E6诱导的宫颈癌的发生和发展。
Persistent infection with oncogenic human papillomavirus viruses (HPVs) is a casual factor for cervical cancer and its precursors and the abnormal constitutive expression of viral oncoprotein E6 is a key event during the malignant transformation. Here, we performed miRNA microarray to identify changes of miRNAs following ectopic HPV16 E6 overexpression in HEK293T cells and found miR-2861 was greatly decreased in both HEK293T and HaCaT cells expressing HPV16 E6 compared to vector control. Further, we demonstrated a biological link among HPV16 E6, miR-2861, EGFR, AKT2 and CCND1 in cervical cancer cells. We showed that miR-2861 was downregulated in cervical cancer tissues and negatively correlated with advanced tumor stage and lymph node metastasis. Overexpression of miR-2861 suppressed cervical cancer cell proliferation and invasion and enhanced apoptosis. Subsequent investigation revealed that EGFR, AKT2 and CCND1 were all the direct targets of miR-2861. Importantly, silencing EGFR, AKT2, and/or CCND1 recapitulated the cellular effects seen upon miR-2861 overexpression. Restoration of EGFR, AKT2, and/or CCND1 counteracted the effects of miR-2861 expression. Thus, we identified a new pathway employing miR-2861, EGFR, AKT2 and CCND1 that may mediate HPV16 E6 induced initiation and progression of cervical cancer.