CXCL12/CXCR4 axis induced miR-125b promotes invasion and confers 5-fluorouracil resistance through enhancing autophagy in colorectal cancer.
CXCL12/CXCR4 axis induced miR-125b promotes invasion and confers 5-fluorouracil resistance through enhancing autophagy in colorectal cancer.
复制标题
CXCL12/CXCR4轴诱导的miR-125b通过增强结直肠癌的自噬促进侵袭并赋予5-氟尿嘧啶耐药性
DOI：
10.1038/srep42226
复制
发表时间：
2017-02-08
影响因子：
4.6
通讯作者：
Qu X
中科院分区：
文献类型：
--
作者：
Yu X;Shi W;Zhang Y;Wang X;Sun S;Song Z;Liu M;Zeng Q;Cui S;Qu X
CXCL 12/CXCR 4轴的激活与肿瘤的侵袭、转移和化疗耐药等潜在进展相关。然而，CXCL 12/CXCR 4轴和癌症进展的潜在机制尚未得到充分探索。我们推测miRNA可能是CXCL 12/CXCR 4轴的关键下游介质，参与了CRC的肿瘤侵袭和化疗耐药性。在人CRC细胞中，我们发现CXCL 12/CXCR 4轴的激活促进上皮-间质转化（EMT）和miR-125 b的同时上调。miR-125 b的过表达强烈地触发EMT和癌症侵袭，这反过来又增强了CXCR 4的表达。更重要的是，CXCR 4和miR-125 b之间的正反馈环通过靶向大肠腺瘤性息肉病（APC）基因进一步激活了Wnt/β-catenin信号通路。配对结直肠组织标本中miR-125 b的表达与APC mRNA的表达呈负相关。进一步的实验表明，miR-125 b可能通过增加体外和体内的自噬而在CRC中赋予5-氟尿嘧啶（5-FU）抗性。miR-125 b是CXCL 12/CXCR 4轴活化的重要下游调节因子，参与大肠癌的EMT、侵袭和5-FU耐药。这些发现为miR-125 b的作用提供了新的见解，并为CRC提供了潜在的治疗靶点。
The activation of CXCL12/CXCR4 axis is associated with potential progression of cancer, such as invasion, metastasis and chemoresistance. However, the underlying mechanisms of CXCL12/CXCR4 axis and cancer progression have been poorly explored. We hypothesized that miRNAs might be critical downstream mediators of CXCL12/CXCR4 axis involved in cancer invasion and chemoresistance in CRC. In human CRC cells, we found that the activation of CXCL12/CXCR4 axis promoted epithelial-mesenchymal transition (EMT) and concurrent upregulation of miR-125b. Overexpression of miR-125b robustly triggered EMT and cancer invasion, which in turn enhanced the expression of CXCR4. Importantly, the reciprocal positive feedback loop between CXCR4 and miR-125b further activated the Wnt/β-catenin signaling by targetingAdenomatous polyposis coli(APC) gene. There was a negative correlation of the expression of miR-125b withAPCmRNA in paired human colorectal tissue specimens. Further experiments indicated a role of miR-125b in conferring 5-fluorouracil (5-FU) resistance in CRC probably through increasing autophagy bothin vitroandin vivo. MiR-125b functions as an important downstream mediator upon the activation of CXCL12/CXCR4 axis that involved in EMT, invasion and 5-FU resistance of CRC. These findings shed a new insight into the role of miR-125b and provide a potential therapeutic target in CRC.