MiR-92a Promoters Stem Cell-like Properties By Activating Wnt/?-catenin Signaling In Colorectal Cancer

Objective: Colorectal cancer is one of most frequent malignancies worldwide.Furthermore,the morbidity of colorectal cancer is continuously increasing in economically developing countries by reason of population aging,smoking,excessive drinking,immoderate diet,etc.However,since the multiple complex and poorly understand molecular mechanisms is involved in the pathogenesis of colorectal cancer,there is currently no side-to-side effective control.MiRNAs are a cluster of endogenous,small non-coding RNA molecules,which play an important role in cancer formation,development,metastasis and recurrence via regulating some pathological and physiological process.Increasing research indicates that miR-92 a plays a significant role in the formation and development process of colorectal cancer.Therefore,this study further investigated the role of miR-92 a in regulation of CRC stem-like properties and examined the underlying molecular mechanisms.Methods: Firstly,miR-92 a expression was analyzed in chemoresistant CRC cells and tumor tissues by qRT-PCR.Then,the effect of miR-92 a on cell viability,tumorigenesis and drug resistance was examined in vitro and in vivo.Further,the role of miR-92 a in maintaining CRC stem-like properties was examined by tumor-sphere formation assay and expression of stem cell markers.Lastly,luciferase Immunoprecipitation assay,immunofluorescent analysis and luciferase assay were used for mechanism study.Results:1.MiR-92 a is upregulated in chemoresistant CRC cells and tumor tissues.2.Ectopic expression of miR-92 a confers resistance to 5-fluorouracil(5-FU)-induced apoptosis in vitro,while antagomiR-92 a significantly enhances chemosensitivity in vivo.3.Overexpression of miR-92 a promotes the tumor sphere formation and the expression of stem cell markers.4.Moreover,miR-92 a overexpression displays higher tumourigenesis in vivo.5.Furthermore,we demonstrate that miR-92 a upregulates the Wnt/?-catenin signaling activity via directly targeting KLF4,GSK3? and DKK3,which are multiple level negative regulators of the Wnt/?-catenin signaling cascade.6.In addition,our results indicate IL-6/STAT3 pathway increases miR-92 a expression by directly targeting its promoter,resulting in Wnt/?-catenin signaling activation and consequent promotion of stem-like phenotypes of CRC cells.Conclusions: Together,these data suggest the essential role of IL-6/STAT3/miR-92a/Wnt/?-catenin pathway in regulating the stem cell-like traits of CRC cells and provide a potential target for CRC therapy.