The miR-491-3p/mTORC2/FOXO1 regulatory loop modulates chemo-sensitivity in human tongue cancer.
The miR-491-3p/mTORC2/FOXO1 regulatory loop modulates chemo-sensitivity in human tongue cancer.
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miR-491-3p/mTORC2/FOXO1 调节环调节人舌癌的化疗敏感性
DOI：
10.18632/oncotarget.3165
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发表时间：
2015-03-30
期刊：
影响因子：
--
通讯作者：
He Z
中科院分区：
文献类型：
--
作者：
Zheng G;Jia X;Peng C;Deng Y;Yin J;Zhang Z;Li N;Deng M;Liu X;Liu H;Lu M;Wang C;Gu Y;He Z
我们发现miR-491- 3 p的水平在多药耐药的舌癌（TC）细胞中降低。诱导miR-491- 3 p表达使TC细胞对化疗敏感。与此一致，miR-491- 3 p的功能抑制增强了TC细胞对化疗的抗性。我们发现miR-491- 3 p直接靶向mTORC 2组分Rictor并抑制mTORC 2活性，其在具有高p-Akt（Ser 473）、p-SGK 1（Ser 422）和p-FOXO 1（Thr 24）水平的耐药TC细胞中增加。通过Rictor敲低或mTOR抑制剂抑制mTORC 2活性反过来使TC细胞对化疗敏感。与此一致，Rictor的过表达增加了mTORC 2的活性，并诱导TC细胞对化疗的耐药性。作为反馈环，mTORC 2通过灭活FOXO 1下调miR-491- 3 p表达，否则FOXO 1将转录诱导miR-491- 3 p表达。TC组织中miR-491-3水平与Rictor或mTORC 2活性呈负相关。最后，低水平的miR-491- 3 p和高表达的Rictor与舌癌患者的不良预后相关。这些数据为靶向干预miR-491- 3 p/mTORC 2轴以增强舌癌化疗疗效提供了理论基础。
We found that levels of miR-491-3p were decreased in multidrug-resistant tongue cancer (TC) cells. Induction of miR-491-3p expression sensitized TC cells to chemotherapy. In agreement, functional inhibition of miR-491-3p enhanced resistance of TC cells to chemotherapy. We found that miR-491-3p directly targeted mTORC2 component Rictor and inhibited mTORC2 activity, which was increased in resistant TC cells with high p-Akt(Ser473), p-SGK1(Ser422) and p-FOXO1(Thr24) levels. Inhibition of mTORC2 activity via either Rictor knockdown or mTOR inhibitor in turn sensitized TC cells to chemotherapy. In agreement, overexpression of Rictor increased the mTORC2 activity and induced resistance of TC cells to chemotherapy. As a feedback loop, mTORC2 downregulated miR-491-3p expression by inactivating FOXO1, which otherwise would transcriptionally induce miR-491-3p expression. Levels of miR-491–3 and Rictor or mTORC2 activity negatively correlated in TC tissues. Finally, low levels of miR-491-3p and highly expressed Rictor were associated with poor prognosis in tongue cancer patients. These data provide a rationale for targeted intervention on miR-491-3p/mTORC2 axis to enhance the efficacy of chemotherapy against tongue cancer.
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影响因子：
3.7
作者：
Oneyama C;Kito Y;Asai R;Ikeda J;Yoshida T;Okuzaki D;Kokuda R;Kakumoto K;Takayama K;Inoue S;Morii E;Okada M
通讯作者：
Okada M
影响因子：
5.3
作者：
Rui W;Bing F;Hai-Zhu S;Wei D;Long-Bang C
通讯作者：
Long-Bang C
影响因子：
37.3
作者：
Roulin D;Cerantola Y;Dormond-Meuwly A;Demartines N;Dormond O
通讯作者：
Dormond O
FOXO1 下调有助于原发性纵隔 B 细胞淋巴瘤的致癌过程。
影响因子：
--
作者：
Xie L;Ritz O;Leithäuser F;Guan H;Färbinger J;Weitzer CD;Gehringer F;Bruederlein S;Holzmann K;Vogel MJ;Möller P;Wirth T;Ushmorov A
通讯作者：
Ushmorov A
基于微阵列的分析：鉴定视网膜母细胞瘤细胞中缺氧调节的 microRNA
影响因子：
5.2
作者：
Xu, Xiaofang;Jia, Renbing;Fan, Xianqun
通讯作者：
Fan, Xianqun