MYC-binding lncRNA EPIC1 promotes AKT-mTORC1 signaling and rapamycin resistance in breast and ovarian cancer.
MYC-binding lncRNA EPIC1 promotes AKT-mTORC1 signaling and rapamycin resistance in breast and ovarian cancer.
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DOI：
10.1002/mc.23248
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发表时间：
2020-10
影响因子：
4.6
通讯作者：
Yang D
中科院分区：
文献类型：
--
作者：
Wang Y;Zhang M;Wang Z;Guo W;Yang D
AKT-mTORC1(雷帕霉素复合体1的哺乳动物靶点)信号通路在肿瘤发生中起关键作用，并可作为雷帕霉素的靶点。然而，LncRNAs(长非编码RNA)如何调控AKT-mTORC1途径的潜在机制尚不清楚。EPIC1是一种Myc结合的lncRNA，已被证明在多种癌症类型中过表达。在对4962例癌症患者进行的通路分析中，我们观察到在包括乳腺癌和卵巢癌在内的10多种癌症类型中，lncRNA EPIC1的表达与AKT-mTORC1信号通路呈正相关。对乳腺和卵巢癌细胞的RNA-SEQ分析表明，EPIC1基因敲除导致AKT-mTORC1信号通路中的基因下调。在MCF-7、OVCAR4和A2780cis细胞中，EPIC1基因敲除和过表达分别抑制和激活了磷酸化的AKT和下游的4EBP1和S6K的磷酸化水平。Myc的进一步下调取消了EPIC1对AKT-mTORC1信号的S调节，提示EPIC1对AKT、ERK、4EBP1和S6K的磷酸化水平的调节依赖于Myc的表达。此外，EPIC1过表达的MCF-7、A2780cis和OVCAR4细胞经雷帕霉素处理后，对p-S6K和p-S6的抑制作用明显低于对照组。集落形成实验和四甲基偶氮唑盐比色法表明EPIC1过表达导致乳腺癌细胞和卵巢癌细胞对雷帕霉素耐药。我们的结果表明，在乳腺癌和卵巢癌中，lncRNA EPIC1的表达通过Myc激活了AKT-mTORC1信号通路，并导致了雷帕霉素耐药。
AKT-mTORC1(mammalian target of rapamycin complex 1) signaling pathway plays a critical role in tumorigenesis and can be targeted by rapamycin. However, the underlying mechanism of how lncRNAs (long noncoding RNA) regulate the AKT-mTORC1 pathway remains unclear. EPIC1 is a Myc-binding lncRNA, which has been previously demonstrated to be overexpressed in multiple cancer types. In a pathway analysis including 4962 cancer patients, we observed that lncRNA EPIC1 expression was positively correlated with the AKT-mTORC1 signaling pathway in more than 10 cancer types, including breast and ovarian cancers. RNA-seq analysis of breast and ovarian cancer cells demonstrated that EPIC1-knockdown led to the downregulation of genes in the AKT-mTORC1 signaling pathway. In MCF-7, OVCAR4 and A2780cis cell lines, EPIC1 knockdown and overexpression respectively inhibited and activated phosphorylated AKT and the downstream phosphorylation levels of 4EBP1 and S6K. Further knockdown of Myc abolished the EPIC1’s regulation of AKT-mTORC1 signaling; suggested that the regulation of phosphorylation level of AKT, ERK, 4EBP1 and S6K by EPIC1 depended on the expression of Myc. Moreover, EPIC1 overexpressed MCF-7, A2780cis, and OVCAR4 cells treated with rapamycin showed significant decreasing in rapamycin mediated inhibition of p-S6K and p-S6 comparing with the control group. In addition, Colony Formation assay and MTT assay indicated that EPIC1 overexpression led to rapamycin resistance in breast and ovarian cancer cell lines. Our results demonstrated the lncRNA EPIC1 expression activated the AKT-mTORC1 signaling pathway through Myc and led to rapamycin resistance in breast and ovarian cancer.
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DOI：
10.1186/s13058-016-0697-1
发表时间：
2016-04-05
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Leroy C;Ramos P;Cornille K;Bonenfant D;Fritsch C;Voshol H;Bentires-Alj M
通讯作者：
Bentires-Alj M
影响因子：
5.2
作者：
Fu Z;Wen D
通讯作者：
Wen D
影响因子：
45.3
作者：
Chan, S;Scheulen, ME;Moore, L
通讯作者：
Moore, L
影响因子：
4.8
作者：
Gera, JF;Mellinghoff, IK;Lichtenstein, AK
通讯作者：
Lichtenstein, AK
影响因子：
3.9
作者：
Morlando M;Ballarino M;Fatica A
通讯作者：
Fatica A