CXCL12/CXCR4 axis induced miR-125b promotes invasion and confers 5-fluorouracil resistance through enhancing autophagy in colorectal cancer

Abstract

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.

Development of a Non‐Coding‐RNA‐based EMT/CSC Inhibitory Nanomedicine for In Vivo Treatment and Monitoring of HCC

“…For example, miR-125b-5p inhibits breast cancer by targeting KIAA1522, [16] suppresses esophageal squamous cell carcinoma by regulating HMGA2, [26] enhances the chemotherapy sensitivity of gallbladder cancer by downregulating Bcl2, [33] and selectively targets IRF4 in multiple myeloma cells. [35] However, in this study, we did not notice the coexpression of miR-125b with CXCL12/CXCR4 axis in HCC. [35] However, in this study, we did not notice the coexpression of miR-125b with CXCL12/CXCR4 axis in HCC.…”

Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells

“…Autophagy may exert an inhibitory effect in early stage tumors, reducing invasion, and metastasis. During later stages, autophagy promotes metastasis by supporting cell survival following ECM detachment and preventing cell dormancy upon ECM reattachment . Autophagy is already known to play an important role in CRC progression .…”

Mesenchymal stem cells promote cell invasion and migration and autophagy‐induced epithelial‐mesenchymal transition in A549 lung adenocarcinoma cells

“…Cellular ROS levels closely associated with the regulation of autophagy, which plays an important role in cancer metastasis by enhancing EMT . Thus, we next examined whether MSC coculture promotes autophagy activation in A549 cells.…”

“…Eventually, a series of autophagy‐related (Atg) protein, such Beclin‐1 (mammalian homologue of Atg6) are elevated and contributed to the maturation of autophagosomes and formation of autolysosomes. Whereas some studies have shown that autophagy could inhibit cancer cell migration and invasion, particularly during the early stages of tumour initiation, as well as suppress EMT by degrading EMT‐associated transcription factors, other studies have shown that autophagy can enhance cancer metastasis via EMT . In colorectal cancer cells, enhancing autophagy is able to increase cell invasion, EMT, and chemotherapy resistance .…”