Cancer stem cells (CSCs) are believed to be the driving force behind the tumor growth. We performed this study to further explore the role of IGF2 epigenetic on CRC stem cells pluripotency which showed that IGF2 LOI CRC cells usually had a higher CD133 expression and sphere forming efficiency than MOI cells. IGF2 LOI CSCs were also found to have a higher level of autophagy than MOI CSCs. Moreover, IGF2/IR-A signal was determined to play a more important role in CSCs formation than IGF2/IGF1R. At last, by using miRNA-195 mimics, we fortunately found the increased IR-A expression might be due to the degradation of miRNA-195 in CRC. In conclusion, our results might reveal that IGF2 LOI could promote CRC stem cells pluripotency by promoting CSCs autophagy. For the degradation of miRNA-195, IGF2 showed a higher ability in interacting with overexpressed IR-A rather than IGF1R which would further activate CSCs autophagy. All these findings might provide a novel mechanistic insight into CRC diagnosis and therapy.