microRNA-375 inhibits colorectal cancer cells proliferation by downregulating JAK2/STAT3 and MAP3K8/ERK signaling pathways.
microRNA-375 inhibits colorectal cancer cells proliferation by downregulating JAK2/STAT3 and MAP3K8/ERK signaling pathways.
复制标题
microRNA-375通过下调JAK2/STAT3和MAP3K8/ERK信号通路抑制结直肠癌细胞增殖
DOI：
10.18632/oncotarget.15114
复制
发表时间：
2017-03-07
期刊：
影响因子：
--
通讯作者：
Cui Q
中科院分区：
文献类型：
--
作者：
Wei R;Yang Q;Han B;Li Y;Yao K;Yang X;Chen Z;Yang S;Zhou J;Li M;Yu H;Yu M;Cui Q
MicroRNA-375与多种类型的消化系统癌症有关。我们前期研究发现，microRNA-375在癌组织中较癌旁组织显著下调，强烈提示microRNA-375可能抑制结直肠癌的发生发展。然而，microRNA-375在结直肠癌中的调控机制尚不清楚。在本研究中，我们首先从多个数据库中筛选出jak2、map3k8和atg7作为microRNA-375靶向基因，发现jak2、map3k8及其下游基因stat3和erk在癌组织中上调。其次，我们在结直肠癌细胞系（HCT116、Caco2和HT29）中过表达microRNA-375。结果表明，在过表达microRNA-375的细胞中，JAK2/STAT3和MAP3K8/ERK蛋白下调，细胞增殖受到抑制，细胞迁移速率未发生变化。过表达HT29/Caco2细胞的microRNA-375与对照组的ATG7表达无显著差异，而在HCT116细胞中，microRNA-375特异性下调ATG7表达。最后，我们证明了表达microRNA-375可以抑制裸鼠的肿瘤形成。综上所述，microRNA-375可能作为肿瘤抑制基因抑制结直肠癌细胞增殖，主要通过靶向JAK2/STAT3和MAP3K8/ERK信号通路。这些发现表明miR-375是一种有前景的诊断标记物和结直肠癌治疗药物。
MicroRNA-375 is involved in many types of alimentary system cancers. Our previous studies showed that microRNA-375 was significantly down-regulated in carcinoma tissues compared with para-carcinoma tissues, which strongly indicates that microRNA-375 might suppress the occurrence and development of colorectal cancer. However, the mechanism underlying the microRNA-375 regulation in colorectal cancer remains unclear. In this study, we first sorted out jak2, map3k8 and atg7 as microRNA-375 targeted genes from multiple databases, and found that jak2, map3k8 and their downstream genes stat3 and erk were up-regulated in carcinoma tissues. Secondly, we over-expressed microRNA-375 in colorectal cancer cell lines (HCT116, Caco2 and HT29). Our results showed that in microRNA-375 over-expressing cells, JAK2/STAT3 and MAP3K8/ERK proteins were down-regulated, cell proliferation was inhibited, cell migration rate did not change. There was no significant difference on ATG7 expression between the control group and microRNA-375 over-expressing HT29/Caco2 cells, whereas microRNA-375 down-regulated ATG7 specifically in HCT116 cells. Finally, we demonstrated that expressing microRNA-375 suppressed tumor formation in nude mice. In conclusion, microRNA-375 might function as a tumor-repressive gene to inhibit cell proliferation, mainly through targeting both JAK2/STAT3 and MAP3K8/ERK signaling pathways in colorectal cancer. These findings suggest miR-375 as a promising diagnostic marker and a therapeutic drug for colorectal cancer.