Downregulated miR-506 expression facilitates pancreatic cancer progression and chemoresistance via SPHK1/Akt/NF-κB signaling.
Downregulated miR-506 expression facilitates pancreatic cancer progression and chemoresistance via SPHK1/Akt/NF-κB signaling.
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下调 miR-506 表达通过 SPHK1/Akt/NF-kappa B 信号传导促进胰腺癌进展和化疗耐药
DOI：
10.1038/onc.2016.90
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发表时间：
2016-10-20
期刊：
影响因子：
8
通讯作者：
Wang, H.
中科院分区：
文献类型：
--
作者：
Li, J.;Wu, H.;Li, W.;Yin, L.;Guo, S.;Xu, X.;Ouyang, Y.;Zhao, Z.;Liu, S.;Tian, Y.;Tian, Z.;Ju, J.;Ni, B.;Wang, H.
microRNA（miRNAs）的异常表达已成为癌症的重要标志。然而，miRNA表达变化的分子机制仍不清楚。在这项研究中，我们发现了一种新的miR-506调控的表观遗传机制，并研究了其在胰腺癌中的功能意义。测序分析显示，与非癌组织相比，miR-506启动子在胰腺癌组织中高度甲基化。miR-506表达降低与胰腺癌患者的临床分期、病理肿瘤状态、远处转移和生存率降低显著相关。miR-506可抑制胰腺癌细胞的增殖，诱导细胞周期停滞于G1/S期，增强胰腺癌细胞的凋亡和化疗敏感性。此外，我们确定鞘氨醇激酶1（SPHK 1）作为miR-506的新靶点，其表达抑制SPHK 1/Akt/NF-κB信号通路，该通路在胰腺癌中被激活。SPHK 1高表达与一个大的胰腺癌样本队列的生存率低显著相关。我们的数据表明，miR-506作为一种肿瘤抑制miRNA，在胰腺癌中表观遗传沉默。新发现的miR-506/SPHK 1轴代表了未来胰腺癌治疗的新治疗策略。
The aberrant expression of microRNAs (miRNAs) has emerged as an important hallmark of cancer. However, the molecular mechanisms underlying the changes in miRNA expression remain unclear. In this study, we discovered a novel epigenetic mechanism of miR-506 regulation and investigated its functional significance in pancreatic cancer. Sequencing analysis revealed that the miR-506 promoter is highly methylated in pancreatic cancer tissues compared with non-cancerous tissues. Reduced miR-506 expression was significantly associated with clinical stage, pathologic tumor status, distant metastasis and decreased survival of pancreatic cancer patients. miR-506 inhibited cell proliferation, induced cell cycle arrest at the G1/S transition and enhanced apoptosis and chemosensitivity of pancreatic cancer cells. Furthermore, we identified sphingosine kinase 1 (SPHK1) as a novel target of miR-506, the expression of which inhibited the SPHK1/Akt/NF-κB signaling pathway, which is activated in pancreatic cancer. High SPHK1 expression was significantly associated with poor survival in a large cohort of pancreatic cancer specimens. Our data suggest that miR-506 acts as a tumor suppressor miRNA and is epigenetically silenced in pancreatic cancer. The newly identified miR-506/SPHK1 axis represents a novel therapeutic strategy for future pancreatic cancer treatment.
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影响因子：
30.8
作者：
Bentwich, I;Avniel, A;Bentwich, Z
通讯作者：
Bentwich, Z
影响因子：
5.7
作者：
Guillermet-Guibert, Julie;Davenne, Lise;Bousquet, Corinne
通讯作者：
Bousquet, Corinne
影响因子：
4.8
作者：
Kawamori, Toshihiko;Kaneshiro, Tatsuya;Obeid, Lina M.
通讯作者：
Obeid, Lina M.
影响因子：
29.4
作者：
Frampton, Adam E.;Castellano, Leandro;Jiao, Long R.
通讯作者：
Jiao, Long R.
影响因子：
8.8
作者：
Lai, N-s;Wu, D-g;Fang, X-g;Lin, Y-c;Chen, S-s;Li, Z-b;Xu, S-s
通讯作者：
Xu, S-s