miR-372 and miR-373 enhance the stemness of colorectal cancer cells by repressing differentiation signaling pathways.
miR-372 and miR-373 enhance the stemness of colorectal cancer cells by repressing differentiation signaling pathways.
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miR-372和miR-373通过抑制分化信号通路增强结直肠癌细胞的干性
DOI：
10.1002/1878-0261.12376
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发表时间：
2018-11
影响因子：
6.6
通讯作者：
Qu LH
中科院分区：
文献类型：
--
作者：
Wang LQ;Yu P;Li B;Guo YH;Liang ZR;Zheng LL;Yang JH;Xu H;Liu S;Zheng LS;Zhou H;Qu LH
miR - 372/373是一组被Wnt通路反激活的干细胞特异性microrna，据报道在各种癌症，特别是结直肠癌（CRC）中失调；然而，这些微小rna在癌症中的独特作用仍有待发现。在本研究中，我们从癌症基因组图谱数据中描述了miR‐372/373在结直肠癌组织中的表达上调，然后表明miR‐372/373的过表达通过丰富CD26/CD24阳性细胞群，促进结直肠癌细胞的自我更新、化疗耐药性和侵袭潜力，增强了结直肠癌细胞的干性。为了阐明microRNA诱导干性的机制，我们分析了过表达miR - 372/373的CRC细胞中的45条细胞信号通路，发现干性相关通路（如Nanog和Hedgehog）上调。相反，分化相关通路，如NFκB、MAPK/Erk和VDR，被miR‐372/373显著抑制。miR‐372/373的许多新靶点被发现，包括SPOP、VDR和SETD7，它们都是细胞分化的重要因子。此外，与miR‐372/373在结直肠癌组织中的表达增加相反，SPOP和VDR mRNA的表达水平在这些组织中显著下调，表明结直肠癌的分化状态较差。综上所述，我们的研究结果表明miR‐372/373通过抑制分化基因的表达来增强CRC细胞的干细胞性。这些结果为理解干细胞特异性microrna在结直肠癌转移和耐药发展中的功能和机制提供了新的见解。
miR‐372/373, a cluster of stem cell‐specific microRNAs transactivated by the Wnt pathway, has been reported to be dysregulated in various cancers, particularly colorectal cancer (CRC); however, the unique role of these microRNAs in cancer remains to be discovered. In the present study, we characterized the upregulation in expression of miR‐372/373 in CRC tissues from The Cancer Genome Atlas data, and then showed that overexpression of miR‐372/373 enhanced the stemness of CRC cells by enriching the CD26/CD24‐positive cell population and promoting self‐renewal, chemotherapy resistance and the invasive potential of CRC cells. To clarify the mechanism underlying microRNA‐induced stemness, we profiled 45 cell signaling pathways in CRC cells overexpressing miR‐372/373 and found that stemness‐related pathways, such as Nanog and Hedgehog, were upregulated. Instead, differentiation‐related pathways, such as NFκB, MAPK/Erk and VDR, were markedly repressed by miR‐372/373. Numerous new targets of miR‐372/373 were identified, including SPOP, VDR and SETD7, all of which are factors important for cell differentiation. Furthermore, in contrast to the increase in miR‐372/373 expression in CRC tissues, the expression levels of SPOP and VDR mRNA were significantly downregulated in these tissues, indicative of the poor differentiation status of CRC. Taken together, our findings suggest that miR‐372/373 enhance CRC cell stemness by repressing the expression of differentiation genes. These results provide new insights for understanding the function and mechanisms of stem cell‐specific microRNAs in the development of metastasis and drug resistance in CRC.
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影响因子：
3.7
作者：
Castaño J;Morera C;Sesé B;Boue S;Bonet-Costa C;Martí M;Roque A;Jordan A;Barrero MJ
通讯作者：
Barrero MJ
影响因子：
4.2
作者：
Jia, Yongsheng;Liu, Honglin;Zhang, Wenjian
通讯作者：
Zhang, Wenjian
影响因子：
6.6
作者：
Ding X;Zhang N;Cai Y;Li S;Zheng C;Jin Y;Yu T;Wang A;Zhou X
通讯作者：
Zhou X
影响因子：
3.7
作者：
An Y;Kang Q;Zhao Y;Hu X;Li N
通讯作者：
Li N
影响因子：
14.9
作者：
Haraguchi T;Ozaki Y;Iba H
通讯作者：
Iba H