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Background Colorectal cancer (CRC) remains the most common gastrointestinal cancer and a leading cause of cancer deaths worldwide, with most showing pathologies indicating the malignant transformation of early stage intestinal stem cells. The long non-coding RNA  Meg3 , which functions as a tumor suppressor, has been reported to be abnormal in multiple tumorigenesis events; however, the underlying mechanism by which  Meg3  contributes to the malignant proliferation of colonic stem cells remains unclear. Methods We analyzed the expression levels of  Meg3 ,  miR-708 , and SOCS3 in samples from  Apc  loss-of-function ( Apc   min  ) mice and patients with CRC, particularly in colonic crypt cells.  Apc   min   mice and AMO/DSS-induced mice model (in vivo) and organoid culture system (in vitro) were used to explore the effect of the  Meg3 / miR-708 /SOCS3 axis on tumorigenesis in the colon. In vitro, we performed RNApull-down, RNA immunoprecipitation, and luciferase reporter assays using DLD1 and RKO cell lines. Findings The  Meg3 / miR-708 /SOCS3 signaling axis plays a critical role in the early stage of CRC development. Our data showed  Meg3  levels negatively correlate with  miR-708  levels both in clinical samples and in the  Apc   min   mouse model, which indicated that  Meg3  acts as a competitive endogenous RNA (ceRNA) of  miR-708 . Then,  miR-708  served as an oncogene, inducing neoplasia in both  Apc   min   mice and cultured colonic organoids. Put together,  miR-708  appears to promote malignant proliferation of colonic stem cells by targeting SOCS3/STAT3 signaling. Interpretation These data revealed that  Meg3  sponges  miR-708  to inhibit CRC development via SOCS3-mediated repression of the malignant proliferation of colonic stem cells. The  Meg3 / miR-708 /SOCS3 signaling axis provides potential targets for the diagnosis and treatment of CRC, particularly early stage CRC.

Long noncoding RNA Meg3 sponges miR-708 to inhibit intestinal tumorigenesis via SOCS3-repressed cancer stem cells growth