The SOX17/miR-371-5p/SOX2 axis inhibits EMT, stem cell properties and metastasis in colorectal cancer

Abstract

Cancer stem cells (CSCs) and EMT-type cells, which share molecular characteristics with CSCs, have been believed to play critical roles in tumor metastasis. Although much progress has been garnered in elucidating the molecular pathways that trigger EMT, stemness and metastasis, a number of key mechanistic gaps remain elusive. In the study, miR-371-5p was obviously down-regulated in primary CRC tissues compared with matched adjacent normal mucosa and correlated significantly with differentiation, tumor size, lymphatic and liver metastases. MiR-371-5p could attenuate proliferation, invasion in vitro and metastasis in vivo in CRC cells. It also suppressed EMT by regulating Wnt/β-catenin signaling and strongly decreased the CRC stemness phenotypes. Moreover, demethylation of SOX17 induced miR-371-5p expression and consequently suppressed its direct target SOX2 in CRC cells. MiR-371-5p was necessary for SOX17 mediated cancer-related traits and SOX2 was a functional target of miR-371-5p. A positive relationship between SOX17 and miR-371-5p expression and a negative one between miR-371-5p and SOX2 expression were observed in CRC cell lines and tissues. In conclusion, we identified miR-371-5p as an important “oncosuppressor” in CRC progression and elucidated a novel mechanism of the SOX17/miR-371-5p/SOX2 axis in the regulation of EMT, stemness and metastasis, which may be a potential therapeutic target.

The Serum microRNA Profile of Intrahepatic Cholestasis of Pregnancy: Identification of Novel Noninvasive Biomarkers

“…To date, miR-371-5p has been mentioned in works screening for or targeting prostate, colon, and gastric cancer, but few functional studies have appeared [21,22]. miR-1182 regulates the expression of human telomerase reverse transcriptase (hTERT) in gastric cancer cells, affecting cell migration [23].…”

Models of human core transcriptional regulatory circuitries

“…2D). SOX2 is identified as a highly probable target of miR-371a by multiple miRNA target predictor algorithms, including TargetScan (Lewis et al 2005), miRDB (Wong and Wang 2015), and PITA (Kertesz et al 2007) (Supplemental Table S6), and recent functional assays in human cancer cells (Li et al 2015) support a role for miR-371a in direct regulation of SOX2 expression. We therefore suggest that the ESC gene expression program is controlled by a CRC consisting of ten key TFs that (1) bind the SEs of their own genes and regulate their own expression, and (2) co-bind the SEs of many other genes important for ESC identity and regulate their expression.…”

Maintenance of Clonogenic KIT+ Human Colon Tumor Cells Requires Secretion of Stem Cell Factor by Differentiated Tumor Cells

“…Cells surviving imatinib or ISCK03 treatment showed a dramatic reduction in the expression of CRC stem cell markers (LGR5 15 , CD133 2 , OLFM4 16 , SOX2 [17][18][19] ), while CK20 expression was increased ( Figure 4A-B). A 3-day pretreatment with ISCK03 or imatinib reduced the percentage of Aldefluor high cells and clone-forming capacity by approximately half ( Figure 4D).…”