Upregulation of BMI1-suppressor miRNAs (miR-200c, miR-203) during terminal differentiation of colon epithelial cells.
Upregulation of BMI1-suppressor miRNAs (miR-200c, miR-203) during terminal differentiation of colon epithelial cells.
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DOI：
10.1007/s00535-022-01865-9
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发表时间：
2022-06
影响因子：
6.3
通讯作者：
Shimono, Yohei
中科院分区：
文献类型：
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作者：
Hisamori, Shigeo;Mukohyama, Junko;Koul, Sanjay;Hayashi, Takanori;Rothenberg, Michael Evan;Maeda, Masao;Isobe, Taichi;Valencia Salazar, Luis Enrique;Qian, Xin;Johnston, Darius Michael;Qian, Dalong;Lao, Kaiqin;Asai, Naoya;Kakeji, Yoshihiro;Gennarino, Vincenzo Alessandro;Sahoo, Debashis;Dalerba, Piero;Shimono, Yohei
MicroRNAs(MiRNAs)是干细胞功能的关键调节因子，包括自我更新和分化。在这项研究中，我们的目的是确定在人类结肠上皮细胞终末分化过程中上调的miRNAs，并阐明它们在干细胞特性的机制控制中的作用。用流式细胞仪对8例原代结肠标本(人6例，小鼠2例)的“隐窝底部”(EpCAM+/CD44+/CD66alow)和“隐窝顶部”(EpCAM+/CD44neg/CD66aHigh)上皮细胞进行纯化，分析335个miRNAs的差异表达。在结肠癌RNA-seq数据库(n=439名患者)中，对在“隐窝顶端”(终末分化)上皮细胞中显示最高上调的miRNAs进行了正相关和与生存结果的相关性测试。评估了两个具有最强“隐窝顶部”表达谱的miRNAs下调自我更新效应器和抑制结肠癌细胞体外增殖的能力、体外正常结肠上皮细胞的有机类化合物形成和患者来源的异种移植(PDX)的体内致瘤性。6个miRNAs(miR-200a、miR-200b、miR-200c、miR-203、miR-210、miR-345)在“隐窝顶端”细胞中表达上调，且在结肠癌中的表达呈正相关。相关系数最高的三个miRNAs(miR-200a、miR-200b、miR-200C)的过度表达与生存率的提高有关。前两个过表达的miRNAs(miR-200C，miR-203)在抑制BMI1的表达方面协同作用，BMI1是干细胞群体自我更新的关键调节因子，并抑制结肠上皮细胞的增殖、器官形成和致瘤性。在结肠上皮中，终末分化与miR-200C和miR-203的协同上调有关，它们协同抑制BMI1，使上皮细胞的扩张能力丧失。
MicroRNAs (miRNAs) are key regulators of stem cell functions, including self-renewal and differentiation. In this study, we aimed to identify miRNAs that are up-regulated during terminal differentiation in the human colon epithelium, and elucidate their role in the mechanistic control of stem cell properties. “Bottom-of-the-crypt” (EPCAM+/CD44+/CD66alow) and “top-of-the-crypt” (EPCAM+/CD44neg/CD66ahigh) epithelial cells from 8 primary colon specimens (6 human, 2 murine) were purified by flow cytometry and analyzed for differential expression of 335 miRNAs. The miRNAs displaying the highest up-regulation in “top-of-the-crypt” (terminally differentiated) epithelial cells were tested for positive correlation and association with survival outcomes in a colon cancer RNA-seq database (n=439 patients). The two miRNAs with the strongest “top-of-the-crypt” expression profile were evaluated for capacity to down-regulate self-renewal effectors and inhibit in vitro proliferation of colon cancer cells, in vitro organoid formation by normal colon epithelial cells and in vivo tumorigenicity by patient-derived xenografts (PDX). Six miRNAs (miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-345) were upregulated in “top-of-the-crypt” cells and positively correlated in expression among colon carcinomas. Overexpression of the three miRNAs with the highest inter-correlation coefficients (miR-200a, miR-200b, miR-200c) associated with improved survival. The top two overexpressed miRNAs (miR-200c, miR-203) cooperated synergistically in suppressing expression of BMI1, a key regulator of self-renewal in stem cell populations, and in inhibiting proliferation, organoid-formation and tumorigenicity of colon epithelial cells. In the colon epithelium, terminal differentiation associates with the coordinated up-regulation of miR-200c and miR-203, which cooperate to suppress BMI1 and disable the expansion capacity of epithelial cells.
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影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
16.6
作者：
Cantini L;Isella C;Petti C;Picco G;Chiola S;Ficarra E;Caselle M;Medico E
通讯作者：
Medico E
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
11.2
作者：
Bracken, Cameron P.;Gregory, Philip A.;Goodall, Gregory J.
通讯作者：
Goodall, Gregory J.