miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN.
miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN.
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miR-125b通过双靶点CFTR和CGN促进结直肠癌迁移和侵袭
DOI：
10.3390/cancers13225710
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发表时间：
2021-11-15
期刊：
影响因子：
5.2
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Zhang X;Li T;Han YN;Ge M;Wang P;Sun L;Liu H;Cao T;Nie Y;Fan D;Guo H;Wu K;Zhao X;Lu Y
结直肠癌(CRC)是导致癌症相关死亡的第三大原因，而转移在其中起着关键作用。因此，我们的目标是找出大肠癌转移的可能机制。研究发现，miR-125b在正常、原发和远处转移组织中的表达水平依次升高，且高水平与淋巴结转移和肿瘤分化程度呈正相关。体外和体内实验表明miR-125b显著促进了结直肠癌的迁移和侵袭。为了阐明其可能的作用机制，我们将囊性纤维化跨膜电导调节器(CFTR)和cinglin(CGN)定义为miR-125b的两个靶基因。MiR-125b一方面通过抑制CFTR促进上皮-间充质转化(EMT)和尿激酶型纤溶酶原激活物(UPA)的产生和分泌；另一方面，miR-125b通过抑制CGN而激活Ras Homolog Family Members A(RhoA)/Rho Kinase(ROCK)信号。因此，我们为今后结直肠癌的防治提供了一个潜在的生物标志物。转移是结直肠癌预后差的原因之一，其原因尚不完全清楚。此前，我们发现miR-125b(登录号：MIMAT0000423)与结直肠癌(CRC)的西妥昔单抗耐药有关。在这项研究中，我们发现了一种新的机制，miR-125b通过靶向囊性纤维化跨膜电导调节因子(CFTR)和紧密连接相关适配器cinglin(CGN)来促进结直肠癌的转移。我们发现miR-125b在原发灶和转移灶中的表达较癌旁正常组织上调。在大肠癌细胞中过表达miR-125b可增强细胞的迁移能力，而敲除miR-125b可降低细胞的迁移和侵袭能力。RNA测序(RNA-seq)和双荧光素酶报告分析证实cftr和cgn是miR-125b的靶基因，体内外进一步验证了cftr和cgn对肿瘤转移的抑制作用。此外，我们还发现miR-125b通过靶向CFTR促进上皮-间充质转化(EMT)过程以及尿激酶型纤溶酶原激活物(UPA)的表达和分泌，并通过靶向CGN增强Ras Homolog Family Members A(RhoA)/Rho Kinase(ROCK)通路的活性。总之，这些发现表明miR-125b在结直肠癌中是一个关键的功能分子，并有望成为诊断和治疗结直肠癌的生物标志物。
Colorectal cancer (CRC) is the third leading cause for cancer related death, in which metastasis exerts a pivotal role. Therefore, we aim to find out the possible mechanism underlying CRC metastasis. We found that the level of miR-125b was elevated in normal, primary CRC, and distant metastasis tissues stepwise, and high level miR-125b was positively correlated with lymph node metastasis and tumor differentiation. In vitro and in vivo assays showed miR-125b significantly promoted CRC migration and invasion. To elucidate the potential mechanism, cystic fibrosis transmembrane conductance regulator (CFTR) and cingulin (CGN) were defined as two target genes of miR-125b. On the one hand, miR-125b promoted epithelial-mesenchymal transition (EMT) and the production and secretion of urokinase plasminogen activator (uPA) by inhibiting CFTR; on the other hand, miR-125b activated Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) signaling by repressing CGN. Therefore, we provided a potential biomarker for CRC prevention and treatment in the future. Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.
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影响因子：
5.7
作者：
Liu HN;Liu TT;Wu H;Chen YJ;Tseng YJ;Yao C;Weng SQ;Dong L;Shen XZ
通讯作者：
Shen XZ
cingulin包含球形和盘绕螺旋域，并与ZO-1，ZO-2，ZO-3和肌球蛋白相互作用。
影响因子：
7.8
作者：
Cordenonsi, M;D'Atri, F;Hammar, E;Parry, D A;Kendrick-Jones, J;Shore, D;Citi, S
通讯作者：
Citi, S
解析结直肠癌进展和转移中的 miRNA 特征
影响因子：
9.7
作者：
Huang, Xiangjie;Zhu, Xinping;Cui, Ri
通讯作者：
Cui, Ri
影响因子：
4.2
作者：
Lin, Maosong;Chen, Weichang;Shen, Xaoying
通讯作者：
Shen, Xaoying
影响因子：
14.8
作者：
de Planell-Saguer, Mariangels;Celina Rodicio, Maria;Mourelatos, Zissimos
通讯作者：
Mourelatos, Zissimos