CXCL12/CXCR4 axis induced miR-125b promotes invasion and confers 5-fluorouracil resistance through enhancing autophagy in colorectal cancer.
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 targeting Adenomatous polyposis coli (APC) gene. There was a negative correlation of the expression of miR-125b with APC mRNA 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 both in vitro and in 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.
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Xinfeng
X
Yu
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Wenna
W
Shi
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Yuhang
Y
Zhang
Department of General Surgery, Xuan Wu Hospital, Capital Medical University, Beijing, China.
Xiaohui
X
Wang
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Shiyue
S
Sun
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Zhiyu
Z
Song
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Man
M
Liu
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Qiao
Q
Zeng
Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China.
Shuxiang
S
Cui
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Xianjun
X
Qu
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D025601:Adenomatous Polyposis Coli Protein; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D019718:Receptors, CXCR4; D005472:Fluorouracil